Medical care at home is emerging as a “disruptive innovation” on the US health care scene. New models of home care offer the promise of better service, higher quality, and a better experience at a lower cost compared with nursing home and hospital care. A tall order, indeed! Pioneers like Dr. Bruce Leff, however, have already shown quite convincingly that “hospital at home” programs can be implemented and can deliver on these promises for patients who are eligible for hospital admission.^1,2

See related article

In their essay “Bringing home the ‘medical home’ for older adults” in this issue of the Cleveland Clinic Journal of Medicine, Landers and colleagues discuss the opportunity of extending the medical home model to home health care as an integral part of the medical neighborhood to improve care coordination, reduce expensive hospitalizations, and improve the patient experience by caring for patients in their own homes. As a part of health care reform, the Center for Medicare and Medicaid Services intends to fund demonstration projects to determine to what extent home care can achieve these lofty goals.

A modernized, efficient, and effective home health care system would be a welcome improvement on the patchwork system we have had in the United States for the past 30 years. From my perspective as a family physician, this new legislation may provide the opportunity to get home health care right.

It did not start off on the right foot in the United States. Many home health agencies were established as independent, for-profit businesses detached from the primary care doctors who were ultimately responsible for patients’ care. Signing orders once a month on long forms that conveyed little useful information about my patients never seemed like adequate care oversight on my part. Communicating well with a dozen nurses I did not know or see on a regular basis was a daunting if not impossible task.

IT TAKES TWO TO PASS THE BATON

If home health care got off on the wrong foot in the United States in the 1970s, what then is the right foot?

To me, the key is a tight linkage of home health care to hospitals, physician offices, and nursing homes. Most elderly and frail people do not live out their lives in one venue. They move from home to hospital to nursing home and back again, often several times during their lives. These care transitions are fraught with the dangers of medication errors and forgotten test results. Home health care agencies can become experts in managing these dangerous care transitions.

Home health nurses and physicians can be experts at passing the baton without dropping it. Parenthetically, all physicians must become experts at passing the baton. It takes two to pass the baton successfully, whether it is from hospitalist to primary care physician, from home care nurse to primary care physician, or from primary care physician to hospitalist.

CHALLENGES: REIMBURSEMENT, COSTLY TECHNOLOGY, COMMUNICATION

What are the challenges Dr. Landers and his forward-thinking colleagues face in implementing modern medical care in the home?

Reimbursement is the obvious first issue. Current restrictions make it difficult to care for homebound and semi-homebound patients on more than an episodic basis. The proposed demonstration projects in home health must overcome this barrier.

Appropriate use of home health technology will be a second challenge, just as it is an opportunity. How much minute-by-minute information is really necessary for home monitoring? How expensive will the technology be? Will home health technology simply be another opportunity to make money, or will it really deliver economic value by preventing hospitalizations? Is fancy monitoring equipment more effective than low-tech daily phone calls and a scale in managing patients with congestive heart failure? How much monitoring and intervention is enough to achieve excellent outcomes? For congestive heart failure, there is good evidence from randomized clinical trials that telemonitoring reduces rates of all-cause mortality (relative risk 0.66, 95% confidence interval 0.54–0.81) and heart-failure-related hospitalizations (relative risk 0.79, 95% confidence interval 0.67–0.94).³

On the cost side of the value equation, what is the right “dose” of home health care for a given patient? At what point on the cost-quality curve does cost outweigh value? Integrating home health care into accountable health care organizations may be the only way to maximize quality and efficiency.

Communication challenges will be the toughest. If home health care becomes a well-developed island of care, I suspect we will not be much better off than we are now. Key to improving quality and lowering cost is effective communication across the spectrum of care. Can teams of doctors and other health care professionals who each claim a different venue as their territory—home, hospital, office, nursing home—provide the coordinated, evidence-based, and personalized medical care to which Dr. Landers and his colleagues aspire? I believe it is possible, but the jury is still out.

A seamless, shared electronic medical record is essential for communication, but current platforms are not designed to integrate home care, hospital, and office records. Several innovative home care companies are attempting to do so, however. Recently, Cleveland Clinic made home visit notes from its home care arm available to other providers on its electronic medical record platform.

Locating visiting nurses and home care physicians in proximity to primary care physician offices would greatly improve the chances of good communication. In a randomized trial of outpatient care of frail elderly patients living at home, having nurse care coordinators located in primary care physician offices resulted in fewer hospitalizations and nursing home placements and greater patient, family, and physician satisfaction compared with traditional outpatient care.^4.5

NO MORE ‘BUSINESS AS USUAL’

In this time of economic uncertainty, at least one thing is certain: “business as usual” does not apply to US health care delivery. I am hopeful that innovative models of home care will find their proper niche as we seek to provide the right care for the right patient at the right time in the right venue and at the right price.

Medical care at home is emerging as a “disruptive innovation” on the US health care scene. New models of home care offer the promise of better service, higher quality, and a better experience at a lower cost compared with nursing home and hospital care. A tall order, indeed! Pioneers like Dr. Bruce Leff, however, have already shown quite convincingly that “hospital at home” programs can be implemented and can deliver on these promises for patients who are eligible for hospital admission.^1,2

See related article

In their essay “Bringing home the ‘medical home’ for older adults” in this issue of the Cleveland Clinic Journal of Medicine, Landers and colleagues discuss the opportunity of extending the medical home model to home health care as an integral part of the medical neighborhood to improve care coordination, reduce expensive hospitalizations, and improve the patient experience by caring for patients in their own homes. As a part of health care reform, the Center for Medicare and Medicaid Services intends to fund demonstration projects to determine to what extent home care can achieve these lofty goals.

A modernized, efficient, and effective home health care system would be a welcome improvement on the patchwork system we have had in the United States for the past 30 years. From my perspective as a family physician, this new legislation may provide the opportunity to get home health care right.

It did not start off on the right foot in the United States. Many home health agencies were established as independent, for-profit businesses detached from the primary care doctors who were ultimately responsible for patients’ care. Signing orders once a month on long forms that conveyed little useful information about my patients never seemed like adequate care oversight on my part. Communicating well with a dozen nurses I did not know or see on a regular basis was a daunting if not impossible task.

IT TAKES TWO TO PASS THE BATON

If home health care got off on the wrong foot in the United States in the 1970s, what then is the right foot?

To me, the key is a tight linkage of home health care to hospitals, physician offices, and nursing homes. Most elderly and frail people do not live out their lives in one venue. They move from home to hospital to nursing home and back again, often several times during their lives. These care transitions are fraught with the dangers of medication errors and forgotten test results. Home health care agencies can become experts in managing these dangerous care transitions.

Home health nurses and physicians can be experts at passing the baton without dropping it. Parenthetically, all physicians must become experts at passing the baton. It takes two to pass the baton successfully, whether it is from hospitalist to primary care physician, from home care nurse to primary care physician, or from primary care physician to hospitalist.

CHALLENGES: REIMBURSEMENT, COSTLY TECHNOLOGY, COMMUNICATION

What are the challenges Dr. Landers and his forward-thinking colleagues face in implementing modern medical care in the home?

Reimbursement is the obvious first issue. Current restrictions make it difficult to care for homebound and semi-homebound patients on more than an episodic basis. The proposed demonstration projects in home health must overcome this barrier.

Appropriate use of home health technology will be a second challenge, just as it is an opportunity. How much minute-by-minute information is really necessary for home monitoring? How expensive will the technology be? Will home health technology simply be another opportunity to make money, or will it really deliver economic value by preventing hospitalizations? Is fancy monitoring equipment more effective than low-tech daily phone calls and a scale in managing patients with congestive heart failure? How much monitoring and intervention is enough to achieve excellent outcomes? For congestive heart failure, there is good evidence from randomized clinical trials that telemonitoring reduces rates of all-cause mortality (relative risk 0.66, 95% confidence interval 0.54–0.81) and heart-failure-related hospitalizations (relative risk 0.79, 95% confidence interval 0.67–0.94).³

On the cost side of the value equation, what is the right “dose” of home health care for a given patient? At what point on the cost-quality curve does cost outweigh value? Integrating home health care into accountable health care organizations may be the only way to maximize quality and efficiency.

Communication challenges will be the toughest. If home health care becomes a well-developed island of care, I suspect we will not be much better off than we are now. Key to improving quality and lowering cost is effective communication across the spectrum of care. Can teams of doctors and other health care professionals who each claim a different venue as their territory—home, hospital, office, nursing home—provide the coordinated, evidence-based, and personalized medical care to which Dr. Landers and his colleagues aspire? I believe it is possible, but the jury is still out.

A seamless, shared electronic medical record is essential for communication, but current platforms are not designed to integrate home care, hospital, and office records. Several innovative home care companies are attempting to do so, however. Recently, Cleveland Clinic made home visit notes from its home care arm available to other providers on its electronic medical record platform.

Locating visiting nurses and home care physicians in proximity to primary care physician offices would greatly improve the chances of good communication. In a randomized trial of outpatient care of frail elderly patients living at home, having nurse care coordinators located in primary care physician offices resulted in fewer hospitalizations and nursing home placements and greater patient, family, and physician satisfaction compared with traditional outpatient care.^4.5

NO MORE ‘BUSINESS AS USUAL’

In this time of economic uncertainty, at least one thing is certain: “business as usual” does not apply to US health care delivery. I am hopeful that innovative models of home care will find their proper niche as we seek to provide the right care for the right patient at the right time in the right venue and at the right price.

Medical care at home is emerging as a “disruptive innovation” on the US health care scene. New models of home care offer the promise of better service, higher quality, and a better experience at a lower cost compared with nursing home and hospital care. A tall order, indeed! Pioneers like Dr. Bruce Leff, however, have already shown quite convincingly that “hospital at home” programs can be implemented and can deliver on these promises for patients who are eligible for hospital admission.^1,2

See related article

In their essay “Bringing home the ‘medical home’ for older adults” in this issue of the Cleveland Clinic Journal of Medicine, Landers and colleagues discuss the opportunity of extending the medical home model to home health care as an integral part of the medical neighborhood to improve care coordination, reduce expensive hospitalizations, and improve the patient experience by caring for patients in their own homes. As a part of health care reform, the Center for Medicare and Medicaid Services intends to fund demonstration projects to determine to what extent home care can achieve these lofty goals.

A modernized, efficient, and effective home health care system would be a welcome improvement on the patchwork system we have had in the United States for the past 30 years. From my perspective as a family physician, this new legislation may provide the opportunity to get home health care right.

It did not start off on the right foot in the United States. Many home health agencies were established as independent, for-profit businesses detached from the primary care doctors who were ultimately responsible for patients’ care. Signing orders once a month on long forms that conveyed little useful information about my patients never seemed like adequate care oversight on my part. Communicating well with a dozen nurses I did not know or see on a regular basis was a daunting if not impossible task.

IT TAKES TWO TO PASS THE BATON

If home health care got off on the wrong foot in the United States in the 1970s, what then is the right foot?

To me, the key is a tight linkage of home health care to hospitals, physician offices, and nursing homes. Most elderly and frail people do not live out their lives in one venue. They move from home to hospital to nursing home and back again, often several times during their lives. These care transitions are fraught with the dangers of medication errors and forgotten test results. Home health care agencies can become experts in managing these dangerous care transitions.

Home health nurses and physicians can be experts at passing the baton without dropping it. Parenthetically, all physicians must become experts at passing the baton. It takes two to pass the baton successfully, whether it is from hospitalist to primary care physician, from home care nurse to primary care physician, or from primary care physician to hospitalist.

CHALLENGES: REIMBURSEMENT, COSTLY TECHNOLOGY, COMMUNICATION

What are the challenges Dr. Landers and his forward-thinking colleagues face in implementing modern medical care in the home?

Reimbursement is the obvious first issue. Current restrictions make it difficult to care for homebound and semi-homebound patients on more than an episodic basis. The proposed demonstration projects in home health must overcome this barrier.

Appropriate use of home health technology will be a second challenge, just as it is an opportunity. How much minute-by-minute information is really necessary for home monitoring? How expensive will the technology be? Will home health technology simply be another opportunity to make money, or will it really deliver economic value by preventing hospitalizations? Is fancy monitoring equipment more effective than low-tech daily phone calls and a scale in managing patients with congestive heart failure? How much monitoring and intervention is enough to achieve excellent outcomes? For congestive heart failure, there is good evidence from randomized clinical trials that telemonitoring reduces rates of all-cause mortality (relative risk 0.66, 95% confidence interval 0.54–0.81) and heart-failure-related hospitalizations (relative risk 0.79, 95% confidence interval 0.67–0.94).³

On the cost side of the value equation, what is the right “dose” of home health care for a given patient? At what point on the cost-quality curve does cost outweigh value? Integrating home health care into accountable health care organizations may be the only way to maximize quality and efficiency.

Communication challenges will be the toughest. If home health care becomes a well-developed island of care, I suspect we will not be much better off than we are now. Key to improving quality and lowering cost is effective communication across the spectrum of care. Can teams of doctors and other health care professionals who each claim a different venue as their territory—home, hospital, office, nursing home—provide the coordinated, evidence-based, and personalized medical care to which Dr. Landers and his colleagues aspire? I believe it is possible, but the jury is still out.

A seamless, shared electronic medical record is essential for communication, but current platforms are not designed to integrate home care, hospital, and office records. Several innovative home care companies are attempting to do so, however. Recently, Cleveland Clinic made home visit notes from its home care arm available to other providers on its electronic medical record platform.

Locating visiting nurses and home care physicians in proximity to primary care physician offices would greatly improve the chances of good communication. In a randomized trial of outpatient care of frail elderly patients living at home, having nurse care coordinators located in primary care physician offices resulted in fewer hospitalizations and nursing home placements and greater patient, family, and physician satisfaction compared with traditional outpatient care.^4.5

NO MORE ‘BUSINESS AS USUAL’

In this time of economic uncertainty, at least one thing is certain: “business as usual” does not apply to US health care delivery. I am hopeful that innovative models of home care will find their proper niche as we seek to provide the right care for the right patient at the right time in the right venue and at the right price.

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.

Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.

Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.

This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.

THE CANONICAL VIEW: AMYLOID IS THE CAUSE

The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.

Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.

The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.

This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.

GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?

Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.

In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease.^1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?”³ criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.

COULD AMYLOID BE NEUROPROTECTIVE?

A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, but in other concentrations, it actually facilitates neuronal repair, healing, and connection.

REDUCING METABOLIC STRESS: THE KEY TO PREVENTION?

If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A^1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia.⁴

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.

LINKS BETWEEN ALZHEIMER DISEASE AND DIABETES

Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes.⁵ The Framingham Heart Study⁶ found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review⁷ supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without.⁸ Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.

AN ALTERNATIVE TO THE AMYLOID HYPOTHESIS: THE ‘MITOCHONDRIAL CASCADE HYPOTHESIS’

Swerdlow and Khan⁹ have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic connections and, hence, losses in neuronal communication. This results in impaired cognition.

Replace. Some cells that are faced with metabolic stress re-enter the cell cycle by undergoing cell division. Neurons, however, are terminally postmitotic and die if they try to divide: by synthesizing cell division proteins, duplicating chromosomes, and reorganizing the complex internal structure, the cell cannot work properly and cell division fails. In the mitochondrial cascade hypothesis, neurofibrillary tangles result from this attempted remodeling of the cytoskeletal filaments, furthering neuronal dysfunction.

ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?

Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.

Alzheimer disease has been hypothesized as being a vascular disorder.¹⁰ It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.

Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.¹¹ At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.

Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.¹² In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.

Along the same lines as Kalaria’s model,¹¹ Snowden et al¹³ found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.

DOES INFLAMMATION PLAY A ROLE?

The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.^14,15

However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.

Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.¹⁶

It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.¹⁷

Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.

In a controversial pilot study, Tobinick et al¹⁸ studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.

Thiazolidinediones block microglial cell activation

The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.

Using a Veterans Administration database of more than 142,000 patients, Miller et al¹⁹ retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).

However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,²⁰ but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.

Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.

ESTROGEN: PROTECTIVE OR NOT?

Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. ^21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.^23,24

Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.²⁵

Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.

WHICH RISK FACTORS CAN WE CONTROL?

In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.

Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.²⁶ However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.

Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.²⁶ Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.

Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.

Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.²⁷ Those who adopt new physical activity late in life may also gain some protective or restorative benefit.²⁸

Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.

Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

Q: I frequently counsel patients on family planning, pregnancy expectations, and postpartum concerns. Would you please discuss the specifics of postpartum thyroiditis?

Postpartum thyroiditis (PPT) affects about 5% to 10% of postpartum patients, as evidenced by biochemical thyroid dysfunction. It usually presents during the first three to nine months postpartum.

The condition may present as transient hyperthyroidism, transient hypothyroidism, or hyperthyroidism resolving to transient or permanent hypothyroidism. Only one-quarter to one-third of women experience both the hyperthyroid and hypothyroid phases; one-third of patients will have only a thyrotoxic or hypothyroid phase.

Those who are at risk for or develop PPT have underlying autoimmune thyroid disease (eg, Hashimoto’s thyroiditis). During pregnancy, the maternal immune system is partially suppressed; it rebounds dramatically after delivery, leading to increased risk for autoimmune thyroid disease in patients with thyroid peroxidase antibodies (TPOAb).

Q: How do I know if my patients are at risk for thyroid disease during or following pregnancy?

We need to ascertain who is at risk for PPT so we can appropriately evaluate and screen for the condition. It is important to educate your patients prior to or during pregnancy about the risk, timeline of occurrence, and signs/symptoms of PPT.

If possible, I recommend discussing this with patients in the family-planning stages. It would be helpful to ask the prospective mother about a family history of hyperthyroid or hypothyroid disease (eg, Grave’s disease or Hashimoto’s thyroiditis). It’s also important to inquire about other autoimmune diseases in the patient or in her family.

Other autoimmune conditions that increase the risk for thyroid disease are: systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, vitiligo, type 1 diabetes, and Addison’s disease. Of note, patients with type 1 diabetes are three times more likely than those without that condition to develop PPT.

Q: Which tests will provide the best information about risk for or presence of PPT? When should I order such tests? 

The thyroid-stimulating hormone (TSH) assay is the most sensitive laboratory test for thyroid function in a patient with a normal pituitary-thyroid axis. Testing for TPOAb is the best available screening tool for postpartum thyroiditis, being widely available, economical, and reproducible. Studies evaluating the utility of TPOAb have demonstrated a sensitivity of 46% to 89%, with a specificity of 91% to 98%. Depending on the timeline of the postpartum presentation, an elevated or low TSH level in conjunction with positive TPOAb is pathognomonic for PPT.

If the prospective or expectant mother has a personal or family history of an autoimmune disease, it would be a good idea to obtain a baseline TSH level and TPOAb. If unobtainable beforehand, a baseline TSH during pregnancy is prudent, since many of the signs and symptoms of hyper/hypothyroidism can be similar to those seen in “normal” pregnancy. A normal TSH in the face of elevated TPOAb increases the patient’s likelihood of developing Hashimoto’s thyroiditis or PPT. The best time to check TPOAb is before pregnancy or after delivery, since these antibodies can decrease or even normalize during pregnancy.

Q: Since PPT can be elusive, how might one clinically evaluate the postpartum patient?

The reasons for missed diagnosis of PPT are twofold. First, it results from women reporting few to no symptoms or simply “writing off” the signs and symptoms, thinking they’re related to the significant emotional/physical demands of caring for the new baby. Second, there is a lack of clinician recognition regarding the risk factors, clinical presentation, and frequency of PPT. Since one-third of the hyperthyroidism of PPT is asymptomatic or unreported by patients, it’s easy to see how clinicians can be uncertain whether postpartum anxiety, insomnia, palpitations, increased heart rate, and fatigue reflect thyrotoxicosis or “new mother demands.” Similarly, fatigue, constipation, impaired concentration/memory, weight gain, and depression can be interpreted as hypothyroidism or the emotional and physical challenges of infant care. Since either hyperthyroid or hypothyroid symptoms can be subtle, PPT goes undiagnosed—and therefore, untreated.

Here is an example to provide a clearer understanding:

PPT can go from hyperthyroid to hypothyroid over a four- to six-month period. I like to refer to this evolving process in its three phases to foster understanding of what is going on not only symptomatically but biochemically as well. The first phase starts with a bout of hyperthyroidism from an increased release of thyroid hormone (T4 and/or T3) as a result of nonpainful/nontender thyroid inflammation.

During this first phase, it’s unfortunate that many new mothers’ symptoms are “written off” as the anxieties associated with being a new mother. If a TSH is not ordered, the woman may feel that the clinician is correct in the assessment and that this is all a natural part of the postpartum period. If her hyperthyroid symptoms worsen, she is unlikely to seek follow-up care for fear of being deemed an “anxious mother,” and as a result, the correct diagnosis is missed. 

After approximately two months, the new mother feels better, as the excess thyroid hormones normalize. This is the second (euthryoid) phase. She may now be convinced that her symptoms of anxiety, agitation, palpitations, and insomnia were from the new experience of motherhood or from the new addition to her existing family. 

After two to three months of feeling well, she begins to experience symptoms of hypothyroidism, which is the third phase of PPT. Her symptoms may include depression, constipation, fatigue, and difficulty concentrating. This is another critical time in which the patient or her clinician may attribute her symptoms to all of the emotional changes and demands of caring for her infant. The clinician may question how the mother has felt over the previous couple of months, and since she has felt well, no thyroid studies are ordered. Again, not questioning the assessment, the mother moves on, only to experience worsening symptoms.

The problem here is that if her hypothyroidism is of a permanent nature, as in the case of autoimmune thyroid disease from Hashimoto’s, she will eventually become more symptomatic but may not return for screening or treatment, thinking this is part of the “normal” postpartum period.

Nearly 20% of PPT patients will remain hypothyroid and require lifelong thyroid hormone replacement. The remaining 80% may develop temporary hypothyroidism, requiring thyroid hormone replacement for up to one year, or the thyroiditis will be mild and resolve without the need for such treatment.

Things to Keep in Mind

Understanding who is at increased risk for PPT should prompt the clinician to check the TSH level and TPOAb before pregnancy, if possible. If the patient is pregnant and has the above stated risk factors for autoimmune thyroiditis, obtaining a baseline TSH level is prudent. In order to obtain a more accurate laboratory evaluation, it would be advisable to wait until after pregnancy to check TPOAb, since the maternal immune system is partially suppressed.

If TPOAb can’t be checked until after delivery, it would make clinical sense to test TSH at the same time (around month 3). In women with positive TPOAb before pregnancy and normal thyroid function throughout pregnancy, TSH should be checked at three and six months postpartum. Clinicians should remain astute and order a TSH any time in the interim if they suspect thyroid dysfunction based on patients’ symptoms. Literature supports annual TSH assays in patients in whom PPT resolved, as they have a markedly increased risk for permanent hypothyroidism.

Suggested Reading

Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92(8 suppl):S1-S47.

American Thyroid Association Web site. www.thyroid.org.

Stagno-Green A. Postpartum thyroiditis. J Clin Endocrinol Metab. 2002;87(9):4042-4047.

Q: I frequently counsel patients on family planning, pregnancy expectations, and postpartum concerns. Would you please discuss the specifics of postpartum thyroiditis?

Postpartum thyroiditis (PPT) affects about 5% to 10% of postpartum patients, as evidenced by biochemical thyroid dysfunction. It usually presents during the first three to nine months postpartum.

The condition may present as transient hyperthyroidism, transient hypothyroidism, or hyperthyroidism resolving to transient or permanent hypothyroidism. Only one-quarter to one-third of women experience both the hyperthyroid and hypothyroid phases; one-third of patients will have only a thyrotoxic or hypothyroid phase.

Those who are at risk for or develop PPT have underlying autoimmune thyroid disease (eg, Hashimoto’s thyroiditis). During pregnancy, the maternal immune system is partially suppressed; it rebounds dramatically after delivery, leading to increased risk for autoimmune thyroid disease in patients with thyroid peroxidase antibodies (TPOAb).

Q: How do I know if my patients are at risk for thyroid disease during or following pregnancy?

We need to ascertain who is at risk for PPT so we can appropriately evaluate and screen for the condition. It is important to educate your patients prior to or during pregnancy about the risk, timeline of occurrence, and signs/symptoms of PPT.

If possible, I recommend discussing this with patients in the family-planning stages. It would be helpful to ask the prospective mother about a family history of hyperthyroid or hypothyroid disease (eg, Grave’s disease or Hashimoto’s thyroiditis). It’s also important to inquire about other autoimmune diseases in the patient or in her family.

Other autoimmune conditions that increase the risk for thyroid disease are: systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, vitiligo, type 1 diabetes, and Addison’s disease. Of note, patients with type 1 diabetes are three times more likely than those without that condition to develop PPT.

Q: Which tests will provide the best information about risk for or presence of PPT? When should I order such tests? 

The thyroid-stimulating hormone (TSH) assay is the most sensitive laboratory test for thyroid function in a patient with a normal pituitary-thyroid axis. Testing for TPOAb is the best available screening tool for postpartum thyroiditis, being widely available, economical, and reproducible. Studies evaluating the utility of TPOAb have demonstrated a sensitivity of 46% to 89%, with a specificity of 91% to 98%. Depending on the timeline of the postpartum presentation, an elevated or low TSH level in conjunction with positive TPOAb is pathognomonic for PPT.

If the prospective or expectant mother has a personal or family history of an autoimmune disease, it would be a good idea to obtain a baseline TSH level and TPOAb. If unobtainable beforehand, a baseline TSH during pregnancy is prudent, since many of the signs and symptoms of hyper/hypothyroidism can be similar to those seen in “normal” pregnancy. A normal TSH in the face of elevated TPOAb increases the patient’s likelihood of developing Hashimoto’s thyroiditis or PPT. The best time to check TPOAb is before pregnancy or after delivery, since these antibodies can decrease or even normalize during pregnancy.

Q: Since PPT can be elusive, how might one clinically evaluate the postpartum patient?

The reasons for missed diagnosis of PPT are twofold. First, it results from women reporting few to no symptoms or simply “writing off” the signs and symptoms, thinking they’re related to the significant emotional/physical demands of caring for the new baby. Second, there is a lack of clinician recognition regarding the risk factors, clinical presentation, and frequency of PPT. Since one-third of the hyperthyroidism of PPT is asymptomatic or unreported by patients, it’s easy to see how clinicians can be uncertain whether postpartum anxiety, insomnia, palpitations, increased heart rate, and fatigue reflect thyrotoxicosis or “new mother demands.” Similarly, fatigue, constipation, impaired concentration/memory, weight gain, and depression can be interpreted as hypothyroidism or the emotional and physical challenges of infant care. Since either hyperthyroid or hypothyroid symptoms can be subtle, PPT goes undiagnosed—and therefore, untreated.

Here is an example to provide a clearer understanding:

PPT can go from hyperthyroid to hypothyroid over a four- to six-month period. I like to refer to this evolving process in its three phases to foster understanding of what is going on not only symptomatically but biochemically as well. The first phase starts with a bout of hyperthyroidism from an increased release of thyroid hormone (T4 and/or T3) as a result of nonpainful/nontender thyroid inflammation.

During this first phase, it’s unfortunate that many new mothers’ symptoms are “written off” as the anxieties associated with being a new mother. If a TSH is not ordered, the woman may feel that the clinician is correct in the assessment and that this is all a natural part of the postpartum period. If her hyperthyroid symptoms worsen, she is unlikely to seek follow-up care for fear of being deemed an “anxious mother,” and as a result, the correct diagnosis is missed. 

After approximately two months, the new mother feels better, as the excess thyroid hormones normalize. This is the second (euthryoid) phase. She may now be convinced that her symptoms of anxiety, agitation, palpitations, and insomnia were from the new experience of motherhood or from the new addition to her existing family. 

After two to three months of feeling well, she begins to experience symptoms of hypothyroidism, which is the third phase of PPT. Her symptoms may include depression, constipation, fatigue, and difficulty concentrating. This is another critical time in which the patient or her clinician may attribute her symptoms to all of the emotional changes and demands of caring for her infant. The clinician may question how the mother has felt over the previous couple of months, and since she has felt well, no thyroid studies are ordered. Again, not questioning the assessment, the mother moves on, only to experience worsening symptoms.

The problem here is that if her hypothyroidism is of a permanent nature, as in the case of autoimmune thyroid disease from Hashimoto’s, she will eventually become more symptomatic but may not return for screening or treatment, thinking this is part of the “normal” postpartum period.

Nearly 20% of PPT patients will remain hypothyroid and require lifelong thyroid hormone replacement. The remaining 80% may develop temporary hypothyroidism, requiring thyroid hormone replacement for up to one year, or the thyroiditis will be mild and resolve without the need for such treatment.

Things to Keep in Mind

Understanding who is at increased risk for PPT should prompt the clinician to check the TSH level and TPOAb before pregnancy, if possible. If the patient is pregnant and has the above stated risk factors for autoimmune thyroiditis, obtaining a baseline TSH level is prudent. In order to obtain a more accurate laboratory evaluation, it would be advisable to wait until after pregnancy to check TPOAb, since the maternal immune system is partially suppressed.

If TPOAb can’t be checked until after delivery, it would make clinical sense to test TSH at the same time (around month 3). In women with positive TPOAb before pregnancy and normal thyroid function throughout pregnancy, TSH should be checked at three and six months postpartum. Clinicians should remain astute and order a TSH any time in the interim if they suspect thyroid dysfunction based on patients’ symptoms. Literature supports annual TSH assays in patients in whom PPT resolved, as they have a markedly increased risk for permanent hypothyroidism.

Suggested Reading

Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92(8 suppl):S1-S47.

American Thyroid Association Web site. www.thyroid.org.

Stagno-Green A. Postpartum thyroiditis. J Clin Endocrinol Metab. 2002;87(9):4042-4047.

Q: I frequently counsel patients on family planning, pregnancy expectations, and postpartum concerns. Would you please discuss the specifics of postpartum thyroiditis?

Postpartum thyroiditis (PPT) affects about 5% to 10% of postpartum patients, as evidenced by biochemical thyroid dysfunction. It usually presents during the first three to nine months postpartum.

The condition may present as transient hyperthyroidism, transient hypothyroidism, or hyperthyroidism resolving to transient or permanent hypothyroidism. Only one-quarter to one-third of women experience both the hyperthyroid and hypothyroid phases; one-third of patients will have only a thyrotoxic or hypothyroid phase.

Those who are at risk for or develop PPT have underlying autoimmune thyroid disease (eg, Hashimoto’s thyroiditis). During pregnancy, the maternal immune system is partially suppressed; it rebounds dramatically after delivery, leading to increased risk for autoimmune thyroid disease in patients with thyroid peroxidase antibodies (TPOAb).

Q: How do I know if my patients are at risk for thyroid disease during or following pregnancy?

We need to ascertain who is at risk for PPT so we can appropriately evaluate and screen for the condition. It is important to educate your patients prior to or during pregnancy about the risk, timeline of occurrence, and signs/symptoms of PPT.

If possible, I recommend discussing this with patients in the family-planning stages. It would be helpful to ask the prospective mother about a family history of hyperthyroid or hypothyroid disease (eg, Grave’s disease or Hashimoto’s thyroiditis). It’s also important to inquire about other autoimmune diseases in the patient or in her family.

Other autoimmune conditions that increase the risk for thyroid disease are: systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, vitiligo, type 1 diabetes, and Addison’s disease. Of note, patients with type 1 diabetes are three times more likely than those without that condition to develop PPT.

Q: Which tests will provide the best information about risk for or presence of PPT? When should I order such tests? 

The thyroid-stimulating hormone (TSH) assay is the most sensitive laboratory test for thyroid function in a patient with a normal pituitary-thyroid axis. Testing for TPOAb is the best available screening tool for postpartum thyroiditis, being widely available, economical, and reproducible. Studies evaluating the utility of TPOAb have demonstrated a sensitivity of 46% to 89%, with a specificity of 91% to 98%. Depending on the timeline of the postpartum presentation, an elevated or low TSH level in conjunction with positive TPOAb is pathognomonic for PPT.

If the prospective or expectant mother has a personal or family history of an autoimmune disease, it would be a good idea to obtain a baseline TSH level and TPOAb. If unobtainable beforehand, a baseline TSH during pregnancy is prudent, since many of the signs and symptoms of hyper/hypothyroidism can be similar to those seen in “normal” pregnancy. A normal TSH in the face of elevated TPOAb increases the patient’s likelihood of developing Hashimoto’s thyroiditis or PPT. The best time to check TPOAb is before pregnancy or after delivery, since these antibodies can decrease or even normalize during pregnancy.

Q: Since PPT can be elusive, how might one clinically evaluate the postpartum patient?

The reasons for missed diagnosis of PPT are twofold. First, it results from women reporting few to no symptoms or simply “writing off” the signs and symptoms, thinking they’re related to the significant emotional/physical demands of caring for the new baby. Second, there is a lack of clinician recognition regarding the risk factors, clinical presentation, and frequency of PPT. Since one-third of the hyperthyroidism of PPT is asymptomatic or unreported by patients, it’s easy to see how clinicians can be uncertain whether postpartum anxiety, insomnia, palpitations, increased heart rate, and fatigue reflect thyrotoxicosis or “new mother demands.” Similarly, fatigue, constipation, impaired concentration/memory, weight gain, and depression can be interpreted as hypothyroidism or the emotional and physical challenges of infant care. Since either hyperthyroid or hypothyroid symptoms can be subtle, PPT goes undiagnosed—and therefore, untreated.

Here is an example to provide a clearer understanding:

PPT can go from hyperthyroid to hypothyroid over a four- to six-month period. I like to refer to this evolving process in its three phases to foster understanding of what is going on not only symptomatically but biochemically as well. The first phase starts with a bout of hyperthyroidism from an increased release of thyroid hormone (T4 and/or T3) as a result of nonpainful/nontender thyroid inflammation.

During this first phase, it’s unfortunate that many new mothers’ symptoms are “written off” as the anxieties associated with being a new mother. If a TSH is not ordered, the woman may feel that the clinician is correct in the assessment and that this is all a natural part of the postpartum period. If her hyperthyroid symptoms worsen, she is unlikely to seek follow-up care for fear of being deemed an “anxious mother,” and as a result, the correct diagnosis is missed. 

After approximately two months, the new mother feels better, as the excess thyroid hormones normalize. This is the second (euthryoid) phase. She may now be convinced that her symptoms of anxiety, agitation, palpitations, and insomnia were from the new experience of motherhood or from the new addition to her existing family. 

After two to three months of feeling well, she begins to experience symptoms of hypothyroidism, which is the third phase of PPT. Her symptoms may include depression, constipation, fatigue, and difficulty concentrating. This is another critical time in which the patient or her clinician may attribute her symptoms to all of the emotional changes and demands of caring for her infant. The clinician may question how the mother has felt over the previous couple of months, and since she has felt well, no thyroid studies are ordered. Again, not questioning the assessment, the mother moves on, only to experience worsening symptoms.

The problem here is that if her hypothyroidism is of a permanent nature, as in the case of autoimmune thyroid disease from Hashimoto’s, she will eventually become more symptomatic but may not return for screening or treatment, thinking this is part of the “normal” postpartum period.

Nearly 20% of PPT patients will remain hypothyroid and require lifelong thyroid hormone replacement. The remaining 80% may develop temporary hypothyroidism, requiring thyroid hormone replacement for up to one year, or the thyroiditis will be mild and resolve without the need for such treatment.

Things to Keep in Mind

Understanding who is at increased risk for PPT should prompt the clinician to check the TSH level and TPOAb before pregnancy, if possible. If the patient is pregnant and has the above stated risk factors for autoimmune thyroiditis, obtaining a baseline TSH level is prudent. In order to obtain a more accurate laboratory evaluation, it would be advisable to wait until after pregnancy to check TPOAb, since the maternal immune system is partially suppressed.

If TPOAb can’t be checked until after delivery, it would make clinical sense to test TSH at the same time (around month 3). In women with positive TPOAb before pregnancy and normal thyroid function throughout pregnancy, TSH should be checked at three and six months postpartum. Clinicians should remain astute and order a TSH any time in the interim if they suspect thyroid dysfunction based on patients’ symptoms. Literature supports annual TSH assays in patients in whom PPT resolved, as they have a markedly increased risk for permanent hypothyroidism.

Suggested Reading

Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92(8 suppl):S1-S47.

American Thyroid Association Web site. www.thyroid.org.

Stagno-Green A. Postpartum thyroiditis. J Clin Endocrinol Metab. 2002;87(9):4042-4047.

When a woman has advanced prolapse of the anterior vaginal wall, it is highly likely that she has apical prolapse as well. Consider a study by Rooney and associates that determined that clinically significant vault prolapse is present in most women who have anterior vaginal prolapse of stage II or higher.¹ For that reason, suspension of the vaginal apex should be considered whenever surgical treatment of anterior wall defects is planned.

Sacrocolpopexy involves suspension of the vaginal vault from the anterior longitudinal ligament of the sacrum, using Y-shaped mesh to augment native tissue (FIGURE).² It is an effective, durable treatment for vaginal apical prolapse. With a success rate approaching 93%, this procedure has become the gold standard for repair of vault prolapse. Among its advantages are maximization of vaginal depth and preservation of a normal vaginal axis.

Sacrocolpopexy preserves the vaginal axis

With the vaginal vault suspended from the anterior longitudinal
ligament of the sacrum, the normal vaginal axis is preserved
and vaginal depth is maximized.

Sacrocolpopexy can be performed via the abdominal, laparoscopic, or robotic-assisted approach (TABLE 1). Minimally invasive techniques are attractive because they involve faster recovery than abdominal sacrocolpopexy does. Minimally invasive techniques have also advanced to the point that they are both effective and durable. However, these advantages must be weighed against the effort required to learn the techniques, as well as their higher cost.

TABLE 1

How the 3 approaches to sacrocolpopexy compare

In this article, we highlight:

• a comparison of the laparoscopic and abdominal approaches to sacrocolpopexy
• an investigation of the learning curve associated with robotic-assisted sacrocolpopexy
• a study exploring the durability of robotic-assisted repair
• an estimate of the costs associated with each route of operation.

Laparoscopic vs abdominal sacrocolpopexy—how do they compare?

Paraiso MF, Walters MD, Rackley RR, Melek S, Hugney C. Laparoscopic and abdominal sacral colpopexies: a comparative cohort study. Am J Obstet Gynecol. 2005;192(5):1752–1758.

When surgeons at the Cleveland Clinic performed a retrospective cohort study to compare laparoscopic and abdominal sacrocolpopexy, they found significantly longer operative time with the laparoscopic route, with an average difference of 51 minutes (P < .0001). However, the laparoscopic approach was associated with lower blood loss (although there was no difference between groups in hematocrit on postoperative day 1); shorter hospital stay (average of 1.8 days versus 4 days [P < .001]); and comparable rates of intraoperative and postoperative complications.

Details of the trial

Paraiso and colleagues reviewed the medical charts of 56 consecutive patients who had undergone laparoscopic sacrocolpopexy, comparing them with the charts of 61 consecutive patients who had undergone the procedure using the abdominal approach. The operations had been performed between 1998 and 2003 for treatment of posthysterectomy vaginal prolapse.

The groups underwent similar rates of concurrent procedures. The laparotomy group had a significantly higher number of Burch procedures (P = .007), and the laparoscopic group had a significantly higher rate of adhesiolysis (P = .002).

Among the complications noted— which occurred at comparable rates between groups—were cystotomy, enterotomy, need for transfusion, deep-vein thrombosis, ileus, small bowel obstruction, wound infection, ventral hernia, mesh erosion, and recurrent prolapse. One laparoscopic case was converted to laparotomy because of excessive bleeding during the rectopexy portion of the operation.

Laparoscopy may have taken longer than this trial suggests

This study is one of very few well-designed trials comparing laparoscopic sacrocolpopexy to the historical gold standard of abdominal sacrocolpopexy for vault prolapse.

Twenty-eight percent of laparoscopic procedures in this study used tacking devices in lieu of suturing. Had suturing been performed universally, an even greater difference in surgical time may have been observed.

There may also be differences between groups in the durability of the two types of repair, an outcome not included in this particular study.

How steep is the learning curve for robotic-assisted sacrocolpopexy?

Akl MN, Long JB, Giles DL, et al. Robotic-assisted sacrocolpopexy: technique and learning curve. Surg Endosc. 2009;23(10):2390–2394.

Akl and coworkers reviewed the medical records of all patients who had undergone robotic-assisted sacrocolpopexy at the Mayo Clinics in Arizona and Florida between 2004 and 2007. All operations were performed by the same four urogynecologists, with an average operative time of 197.9 minutes (standard deviation, ± 66.8 minutes). However, after the first 10 cases, the operative time decreased by 64.3 minutes—a decline of 25.4% (P < .01; 95% confidence interval [CI], 16.1–112.4 minutes).

Details of the trial

Researchers collected baseline information on participants’ age, stage of prolapse, and concomitant procedures. They also gathered data on average operative time, estimated blood loss, intraoperative and postoperative complications, conversion to laparotomy, and length of hospitalization.

Of 80 women who had advanced pelvic organ prolapse (stage III/IV) who underwent robotic-assisted sacrocolpopexy, 88% underwent concomitant robotic and vaginal procedures, including robotic supracervical hysterectomy, Burch procedure, paravaginal repair, lysis of adhesions, bilateral salpingooophorectomy, vaginal cystocele or rectocele repair, and placement of a midurethral sling.

Estimated blood loss for the robotic-assisted approach ranged from 25 mL to 300 mL, with a mean loss of 96.8 mL. Average length of hospitalization was 2.6 days. Four cases (5%) were converted to laparotomy because of limited exposure and one intraoperative bladder injury. Other intraoperative complications included small-bowel injury during trocar placement and one ureteral injury. Postoperative complications included one case of ileus and five (6%) vaginal mesh erosions. Three patients developed recurrent prolapse and underwent subsequent correction.

Learning curve could have been measured more precisely

The authors did not specifically measure the learning curve for robotic-assisted sacrocolpopexy, as they took into account the concomitant procedures. For this reason, the decrease in operative time observed after 10 cases may not accurately reflect an improvement in the performance of sacrocolpopexy.

Akl and colleagues consider this detail to be a strength of the study because most women who undergo prolapse surgery have concomitant procedures. However, recording the length of time it took to perform the sacrocolpopexy portion of the procedure would have been more accurate.

The average length of stay approached that of the abdominal route. Length of stay may decline as a surgeon gains experience with the robotic-assisted approach.

Does robotic-assisted sacrocolpopexy provide durable support?

Elliott DS, Krambeck AE, Chow GK. Long-term results of robotic assisted laparoscopic sacrocolpopexy for the treatment of high grade vaginal vault prolapse. J Urol. 2006;176(2):655–659.

Among the few recent series reporting long-term outcomes after robotic-assisted sacrocolpopexy is this observational study from the Mayo Clinic. It involved 30 women who underwent the operation for the treatment of Baden Walker grade 4/4 posthysterectomy vaginal vault prolapse. The authors concluded that advanced prolapse can be treated with robotic-assisted sacrocolpopexy with long-term success and minimal complications.

Details of the trial

Of 30 women in this trial, 52% underwent an anti-incontinence procedure at the time of sacrocolpopexy. Women who had multiple vaginal defects or a history of abdominal surgery were excluded from the study.

Average operative time was 3.1 hours (range, 2.15–4.75 hours) in the early phase of development of operative technique (described in the manuscript) but diminished over time to an average of 2.5 hours.

Twenty-nine patients were discharged from the hospital after an overnight stay. Very few immediate postoperative complications were observed. Two patients experienced mild port-site infections that required outpatient treatment, and one patient had persistent vaginal bleeding from the incision made during the anti-incontinence procedure.

Most patients were followed for at least 1 year

The mean follow-up in this study was 24 months (range, 16–39 months). During this period, 21 women were followed for a full year. Long-term observation revealed that the repair of vault prolapse remained successful in 19 of these women.

One patient experienced recurrent prolapse 7 months after surgery. Another developed a rectocele 9 months after sacrocolpopexy. Vaginal mesh erosions occurred in two patients within 6 months after the procedure; both patients were treated with outpatient resection of the exposed mesh, with no recurrence of the prolapse.

Although a larger sample size and longer follow-up would be ideal, this study demonstrates a low rate of recurrent prolapse 1 year after the procedure.

How much do laparoscopic, abdominal, and robotic-assisted sacrocolpopexy cost?

Judd JP, Siddiqui NY, Barnett JC, et al. Cost-minimization analysis of robotic-assisted, laparoscopic, and abdominal sacrocolpopexy. J Minim Invasive Gynecol. 2010;17: 493–499.

This cost-minimization analysis concluded that robotic-assisted sacrocolpopexy incurs the highest hospital charges but is reimbursed by Medicare at a rate similar to reimbursement for the abdominal and laparoscopic routes (TABLE 2).

TABLE 2

Cost of sacrocolpopexy is significant—especially using the robotic approach

The analysis accounted for realistic practices, such as the inclusion of concurrent hysterectomy and other procedures.

Details of the trial

Surgeons from Duke University developed a decision-analysis model in which a hypothetical group of women with advanced vaginal prolapse could choose between one of the three routes of sacrocolpopexy: abdominal, laparoscopic, or robotic-assisted. Researchers postulated two different scenarios:

• the hospital had ownership of a robotic system
• the hospital invested in the initial purchase and maintenance of such a system.

Researchers reviewed the literature to formulate their estimates of operative time, rate of conversion to laparotomy, rate of transfusion, and length of hospital stay. In addition, the costs of initial anesthesia setup, professional fees, per-minute intraoperative fees, and postanesthesia care were applied to each approach. Operating room costs per minute and the cost of disposable items such as drapes, gowns, gloves, and single-use instruments were added. For the robotic approach, the costs of reusable instruments were distributed across 10 operations. Reusable instruments for laparoscopic and abdominal surgery were assumed to incur no additional investment. Last, postoperative care—including laboratory tests, pharmacy usage, and the need for a hospital room—were individualized for each route of surgery and applied to the cost.

Costs were estimated in 2008 US dollars, based on procedure costs incurred at Duke University Medical Center.

Physician reimbursement data were obtained from Medicare reimbursement rates for anesthesia and from surgeon Current Procedural Terminology (CPT) codes specific to each procedure.

Quality-of-life assessments were not measured. Nor was the cost to society of the postoperative loss of productivity and wages for each surgical route. Had these losses been recognized, the authors observed, the cost of robotic surgery may have been lower.

The cost of robotic surgery was equivalent to the cost of laparoscopy in only two instances:

• when the operative time of robotic surgery was reduced to 149 minutes
• when the cost of robotic disposable items was less than $2,132 (reduced from a baseline cost of $3,293).

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

When a woman has advanced prolapse of the anterior vaginal wall, it is highly likely that she has apical prolapse as well. Consider a study by Rooney and associates that determined that clinically significant vault prolapse is present in most women who have anterior vaginal prolapse of stage II or higher.¹ For that reason, suspension of the vaginal apex should be considered whenever surgical treatment of anterior wall defects is planned.

Sacrocolpopexy involves suspension of the vaginal vault from the anterior longitudinal ligament of the sacrum, using Y-shaped mesh to augment native tissue (FIGURE).² It is an effective, durable treatment for vaginal apical prolapse. With a success rate approaching 93%, this procedure has become the gold standard for repair of vault prolapse. Among its advantages are maximization of vaginal depth and preservation of a normal vaginal axis.

Sacrocolpopexy preserves the vaginal axis

With the vaginal vault suspended from the anterior longitudinal
ligament of the sacrum, the normal vaginal axis is preserved
and vaginal depth is maximized.

Sacrocolpopexy can be performed via the abdominal, laparoscopic, or robotic-assisted approach (TABLE 1). Minimally invasive techniques are attractive because they involve faster recovery than abdominal sacrocolpopexy does. Minimally invasive techniques have also advanced to the point that they are both effective and durable. However, these advantages must be weighed against the effort required to learn the techniques, as well as their higher cost.

TABLE 1

How the 3 approaches to sacrocolpopexy compare

In this article, we highlight:

• a comparison of the laparoscopic and abdominal approaches to sacrocolpopexy
• an investigation of the learning curve associated with robotic-assisted sacrocolpopexy
• a study exploring the durability of robotic-assisted repair
• an estimate of the costs associated with each route of operation.

Laparoscopic vs abdominal sacrocolpopexy—how do they compare?

Paraiso MF, Walters MD, Rackley RR, Melek S, Hugney C. Laparoscopic and abdominal sacral colpopexies: a comparative cohort study. Am J Obstet Gynecol. 2005;192(5):1752–1758.

When surgeons at the Cleveland Clinic performed a retrospective cohort study to compare laparoscopic and abdominal sacrocolpopexy, they found significantly longer operative time with the laparoscopic route, with an average difference of 51 minutes (P < .0001). However, the laparoscopic approach was associated with lower blood loss (although there was no difference between groups in hematocrit on postoperative day 1); shorter hospital stay (average of 1.8 days versus 4 days [P < .001]); and comparable rates of intraoperative and postoperative complications.

Details of the trial

Paraiso and colleagues reviewed the medical charts of 56 consecutive patients who had undergone laparoscopic sacrocolpopexy, comparing them with the charts of 61 consecutive patients who had undergone the procedure using the abdominal approach. The operations had been performed between 1998 and 2003 for treatment of posthysterectomy vaginal prolapse.

The groups underwent similar rates of concurrent procedures. The laparotomy group had a significantly higher number of Burch procedures (P = .007), and the laparoscopic group had a significantly higher rate of adhesiolysis (P = .002).

Among the complications noted— which occurred at comparable rates between groups—were cystotomy, enterotomy, need for transfusion, deep-vein thrombosis, ileus, small bowel obstruction, wound infection, ventral hernia, mesh erosion, and recurrent prolapse. One laparoscopic case was converted to laparotomy because of excessive bleeding during the rectopexy portion of the operation.

Laparoscopy may have taken longer than this trial suggests

This study is one of very few well-designed trials comparing laparoscopic sacrocolpopexy to the historical gold standard of abdominal sacrocolpopexy for vault prolapse.

Twenty-eight percent of laparoscopic procedures in this study used tacking devices in lieu of suturing. Had suturing been performed universally, an even greater difference in surgical time may have been observed.

There may also be differences between groups in the durability of the two types of repair, an outcome not included in this particular study.

How steep is the learning curve for robotic-assisted sacrocolpopexy?

Akl MN, Long JB, Giles DL, et al. Robotic-assisted sacrocolpopexy: technique and learning curve. Surg Endosc. 2009;23(10):2390–2394.

Akl and coworkers reviewed the medical records of all patients who had undergone robotic-assisted sacrocolpopexy at the Mayo Clinics in Arizona and Florida between 2004 and 2007. All operations were performed by the same four urogynecologists, with an average operative time of 197.9 minutes (standard deviation, ± 66.8 minutes). However, after the first 10 cases, the operative time decreased by 64.3 minutes—a decline of 25.4% (P < .01; 95% confidence interval [CI], 16.1–112.4 minutes).

Details of the trial

Researchers collected baseline information on participants’ age, stage of prolapse, and concomitant procedures. They also gathered data on average operative time, estimated blood loss, intraoperative and postoperative complications, conversion to laparotomy, and length of hospitalization.

Of 80 women who had advanced pelvic organ prolapse (stage III/IV) who underwent robotic-assisted sacrocolpopexy, 88% underwent concomitant robotic and vaginal procedures, including robotic supracervical hysterectomy, Burch procedure, paravaginal repair, lysis of adhesions, bilateral salpingooophorectomy, vaginal cystocele or rectocele repair, and placement of a midurethral sling.

Estimated blood loss for the robotic-assisted approach ranged from 25 mL to 300 mL, with a mean loss of 96.8 mL. Average length of hospitalization was 2.6 days. Four cases (5%) were converted to laparotomy because of limited exposure and one intraoperative bladder injury. Other intraoperative complications included small-bowel injury during trocar placement and one ureteral injury. Postoperative complications included one case of ileus and five (6%) vaginal mesh erosions. Three patients developed recurrent prolapse and underwent subsequent correction.

Learning curve could have been measured more precisely

The authors did not specifically measure the learning curve for robotic-assisted sacrocolpopexy, as they took into account the concomitant procedures. For this reason, the decrease in operative time observed after 10 cases may not accurately reflect an improvement in the performance of sacrocolpopexy.

Akl and colleagues consider this detail to be a strength of the study because most women who undergo prolapse surgery have concomitant procedures. However, recording the length of time it took to perform the sacrocolpopexy portion of the procedure would have been more accurate.

The average length of stay approached that of the abdominal route. Length of stay may decline as a surgeon gains experience with the robotic-assisted approach.

Does robotic-assisted sacrocolpopexy provide durable support?

Elliott DS, Krambeck AE, Chow GK. Long-term results of robotic assisted laparoscopic sacrocolpopexy for the treatment of high grade vaginal vault prolapse. J Urol. 2006;176(2):655–659.

Among the few recent series reporting long-term outcomes after robotic-assisted sacrocolpopexy is this observational study from the Mayo Clinic. It involved 30 women who underwent the operation for the treatment of Baden Walker grade 4/4 posthysterectomy vaginal vault prolapse. The authors concluded that advanced prolapse can be treated with robotic-assisted sacrocolpopexy with long-term success and minimal complications.

Details of the trial

Of 30 women in this trial, 52% underwent an anti-incontinence procedure at the time of sacrocolpopexy. Women who had multiple vaginal defects or a history of abdominal surgery were excluded from the study.

Average operative time was 3.1 hours (range, 2.15–4.75 hours) in the early phase of development of operative technique (described in the manuscript) but diminished over time to an average of 2.5 hours.

Twenty-nine patients were discharged from the hospital after an overnight stay. Very few immediate postoperative complications were observed. Two patients experienced mild port-site infections that required outpatient treatment, and one patient had persistent vaginal bleeding from the incision made during the anti-incontinence procedure.

Most patients were followed for at least 1 year

The mean follow-up in this study was 24 months (range, 16–39 months). During this period, 21 women were followed for a full year. Long-term observation revealed that the repair of vault prolapse remained successful in 19 of these women.

One patient experienced recurrent prolapse 7 months after surgery. Another developed a rectocele 9 months after sacrocolpopexy. Vaginal mesh erosions occurred in two patients within 6 months after the procedure; both patients were treated with outpatient resection of the exposed mesh, with no recurrence of the prolapse.

Although a larger sample size and longer follow-up would be ideal, this study demonstrates a low rate of recurrent prolapse 1 year after the procedure.

How much do laparoscopic, abdominal, and robotic-assisted sacrocolpopexy cost?

Judd JP, Siddiqui NY, Barnett JC, et al. Cost-minimization analysis of robotic-assisted, laparoscopic, and abdominal sacrocolpopexy. J Minim Invasive Gynecol. 2010;17: 493–499.

This cost-minimization analysis concluded that robotic-assisted sacrocolpopexy incurs the highest hospital charges but is reimbursed by Medicare at a rate similar to reimbursement for the abdominal and laparoscopic routes (TABLE 2).

TABLE 2

Cost of sacrocolpopexy is significant—especially using the robotic approach

The analysis accounted for realistic practices, such as the inclusion of concurrent hysterectomy and other procedures.

Details of the trial

Surgeons from Duke University developed a decision-analysis model in which a hypothetical group of women with advanced vaginal prolapse could choose between one of the three routes of sacrocolpopexy: abdominal, laparoscopic, or robotic-assisted. Researchers postulated two different scenarios:

• the hospital had ownership of a robotic system
• the hospital invested in the initial purchase and maintenance of such a system.

Researchers reviewed the literature to formulate their estimates of operative time, rate of conversion to laparotomy, rate of transfusion, and length of hospital stay. In addition, the costs of initial anesthesia setup, professional fees, per-minute intraoperative fees, and postanesthesia care were applied to each approach. Operating room costs per minute and the cost of disposable items such as drapes, gowns, gloves, and single-use instruments were added. For the robotic approach, the costs of reusable instruments were distributed across 10 operations. Reusable instruments for laparoscopic and abdominal surgery were assumed to incur no additional investment. Last, postoperative care—including laboratory tests, pharmacy usage, and the need for a hospital room—were individualized for each route of surgery and applied to the cost.

Costs were estimated in 2008 US dollars, based on procedure costs incurred at Duke University Medical Center.

Physician reimbursement data were obtained from Medicare reimbursement rates for anesthesia and from surgeon Current Procedural Terminology (CPT) codes specific to each procedure.

Quality-of-life assessments were not measured. Nor was the cost to society of the postoperative loss of productivity and wages for each surgical route. Had these losses been recognized, the authors observed, the cost of robotic surgery may have been lower.

The cost of robotic surgery was equivalent to the cost of laparoscopy in only two instances:

• when the operative time of robotic surgery was reduced to 149 minutes
• when the cost of robotic disposable items was less than $2,132 (reduced from a baseline cost of $3,293).

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

When a woman has advanced prolapse of the anterior vaginal wall, it is highly likely that she has apical prolapse as well. Consider a study by Rooney and associates that determined that clinically significant vault prolapse is present in most women who have anterior vaginal prolapse of stage II or higher.¹ For that reason, suspension of the vaginal apex should be considered whenever surgical treatment of anterior wall defects is planned.

Sacrocolpopexy involves suspension of the vaginal vault from the anterior longitudinal ligament of the sacrum, using Y-shaped mesh to augment native tissue (FIGURE).² It is an effective, durable treatment for vaginal apical prolapse. With a success rate approaching 93%, this procedure has become the gold standard for repair of vault prolapse. Among its advantages are maximization of vaginal depth and preservation of a normal vaginal axis.

Sacrocolpopexy preserves the vaginal axis

With the vaginal vault suspended from the anterior longitudinal
ligament of the sacrum, the normal vaginal axis is preserved
and vaginal depth is maximized.

Sacrocolpopexy can be performed via the abdominal, laparoscopic, or robotic-assisted approach (TABLE 1). Minimally invasive techniques are attractive because they involve faster recovery than abdominal sacrocolpopexy does. Minimally invasive techniques have also advanced to the point that they are both effective and durable. However, these advantages must be weighed against the effort required to learn the techniques, as well as their higher cost.

TABLE 1

How the 3 approaches to sacrocolpopexy compare

In this article, we highlight:

• a comparison of the laparoscopic and abdominal approaches to sacrocolpopexy
• an investigation of the learning curve associated with robotic-assisted sacrocolpopexy
• a study exploring the durability of robotic-assisted repair
• an estimate of the costs associated with each route of operation.

Laparoscopic vs abdominal sacrocolpopexy—how do they compare?

Paraiso MF, Walters MD, Rackley RR, Melek S, Hugney C. Laparoscopic and abdominal sacral colpopexies: a comparative cohort study. Am J Obstet Gynecol. 2005;192(5):1752–1758.

When surgeons at the Cleveland Clinic performed a retrospective cohort study to compare laparoscopic and abdominal sacrocolpopexy, they found significantly longer operative time with the laparoscopic route, with an average difference of 51 minutes (P < .0001). However, the laparoscopic approach was associated with lower blood loss (although there was no difference between groups in hematocrit on postoperative day 1); shorter hospital stay (average of 1.8 days versus 4 days [P < .001]); and comparable rates of intraoperative and postoperative complications.

Details of the trial

Paraiso and colleagues reviewed the medical charts of 56 consecutive patients who had undergone laparoscopic sacrocolpopexy, comparing them with the charts of 61 consecutive patients who had undergone the procedure using the abdominal approach. The operations had been performed between 1998 and 2003 for treatment of posthysterectomy vaginal prolapse.

The groups underwent similar rates of concurrent procedures. The laparotomy group had a significantly higher number of Burch procedures (P = .007), and the laparoscopic group had a significantly higher rate of adhesiolysis (P = .002).

Among the complications noted— which occurred at comparable rates between groups—were cystotomy, enterotomy, need for transfusion, deep-vein thrombosis, ileus, small bowel obstruction, wound infection, ventral hernia, mesh erosion, and recurrent prolapse. One laparoscopic case was converted to laparotomy because of excessive bleeding during the rectopexy portion of the operation.

Laparoscopy may have taken longer than this trial suggests

This study is one of very few well-designed trials comparing laparoscopic sacrocolpopexy to the historical gold standard of abdominal sacrocolpopexy for vault prolapse.

Twenty-eight percent of laparoscopic procedures in this study used tacking devices in lieu of suturing. Had suturing been performed universally, an even greater difference in surgical time may have been observed.

There may also be differences between groups in the durability of the two types of repair, an outcome not included in this particular study.

How steep is the learning curve for robotic-assisted sacrocolpopexy?

Akl MN, Long JB, Giles DL, et al. Robotic-assisted sacrocolpopexy: technique and learning curve. Surg Endosc. 2009;23(10):2390–2394.

Akl and coworkers reviewed the medical records of all patients who had undergone robotic-assisted sacrocolpopexy at the Mayo Clinics in Arizona and Florida between 2004 and 2007. All operations were performed by the same four urogynecologists, with an average operative time of 197.9 minutes (standard deviation, ± 66.8 minutes). However, after the first 10 cases, the operative time decreased by 64.3 minutes—a decline of 25.4% (P < .01; 95% confidence interval [CI], 16.1–112.4 minutes).

Details of the trial

Researchers collected baseline information on participants’ age, stage of prolapse, and concomitant procedures. They also gathered data on average operative time, estimated blood loss, intraoperative and postoperative complications, conversion to laparotomy, and length of hospitalization.

Of 80 women who had advanced pelvic organ prolapse (stage III/IV) who underwent robotic-assisted sacrocolpopexy, 88% underwent concomitant robotic and vaginal procedures, including robotic supracervical hysterectomy, Burch procedure, paravaginal repair, lysis of adhesions, bilateral salpingooophorectomy, vaginal cystocele or rectocele repair, and placement of a midurethral sling.

Estimated blood loss for the robotic-assisted approach ranged from 25 mL to 300 mL, with a mean loss of 96.8 mL. Average length of hospitalization was 2.6 days. Four cases (5%) were converted to laparotomy because of limited exposure and one intraoperative bladder injury. Other intraoperative complications included small-bowel injury during trocar placement and one ureteral injury. Postoperative complications included one case of ileus and five (6%) vaginal mesh erosions. Three patients developed recurrent prolapse and underwent subsequent correction.

Learning curve could have been measured more precisely

The authors did not specifically measure the learning curve for robotic-assisted sacrocolpopexy, as they took into account the concomitant procedures. For this reason, the decrease in operative time observed after 10 cases may not accurately reflect an improvement in the performance of sacrocolpopexy.

Akl and colleagues consider this detail to be a strength of the study because most women who undergo prolapse surgery have concomitant procedures. However, recording the length of time it took to perform the sacrocolpopexy portion of the procedure would have been more accurate.

The average length of stay approached that of the abdominal route. Length of stay may decline as a surgeon gains experience with the robotic-assisted approach.

Does robotic-assisted sacrocolpopexy provide durable support?

Elliott DS, Krambeck AE, Chow GK. Long-term results of robotic assisted laparoscopic sacrocolpopexy for the treatment of high grade vaginal vault prolapse. J Urol. 2006;176(2):655–659.

Among the few recent series reporting long-term outcomes after robotic-assisted sacrocolpopexy is this observational study from the Mayo Clinic. It involved 30 women who underwent the operation for the treatment of Baden Walker grade 4/4 posthysterectomy vaginal vault prolapse. The authors concluded that advanced prolapse can be treated with robotic-assisted sacrocolpopexy with long-term success and minimal complications.

Details of the trial

Of 30 women in this trial, 52% underwent an anti-incontinence procedure at the time of sacrocolpopexy. Women who had multiple vaginal defects or a history of abdominal surgery were excluded from the study.

Average operative time was 3.1 hours (range, 2.15–4.75 hours) in the early phase of development of operative technique (described in the manuscript) but diminished over time to an average of 2.5 hours.

Twenty-nine patients were discharged from the hospital after an overnight stay. Very few immediate postoperative complications were observed. Two patients experienced mild port-site infections that required outpatient treatment, and one patient had persistent vaginal bleeding from the incision made during the anti-incontinence procedure.

Most patients were followed for at least 1 year

The mean follow-up in this study was 24 months (range, 16–39 months). During this period, 21 women were followed for a full year. Long-term observation revealed that the repair of vault prolapse remained successful in 19 of these women.

One patient experienced recurrent prolapse 7 months after surgery. Another developed a rectocele 9 months after sacrocolpopexy. Vaginal mesh erosions occurred in two patients within 6 months after the procedure; both patients were treated with outpatient resection of the exposed mesh, with no recurrence of the prolapse.

Although a larger sample size and longer follow-up would be ideal, this study demonstrates a low rate of recurrent prolapse 1 year after the procedure.

How much do laparoscopic, abdominal, and robotic-assisted sacrocolpopexy cost?

Judd JP, Siddiqui NY, Barnett JC, et al. Cost-minimization analysis of robotic-assisted, laparoscopic, and abdominal sacrocolpopexy. J Minim Invasive Gynecol. 2010;17: 493–499.

This cost-minimization analysis concluded that robotic-assisted sacrocolpopexy incurs the highest hospital charges but is reimbursed by Medicare at a rate similar to reimbursement for the abdominal and laparoscopic routes (TABLE 2).

TABLE 2

Cost of sacrocolpopexy is significant—especially using the robotic approach

The analysis accounted for realistic practices, such as the inclusion of concurrent hysterectomy and other procedures.

Details of the trial

Surgeons from Duke University developed a decision-analysis model in which a hypothetical group of women with advanced vaginal prolapse could choose between one of the three routes of sacrocolpopexy: abdominal, laparoscopic, or robotic-assisted. Researchers postulated two different scenarios:

• the hospital had ownership of a robotic system
• the hospital invested in the initial purchase and maintenance of such a system.

Researchers reviewed the literature to formulate their estimates of operative time, rate of conversion to laparotomy, rate of transfusion, and length of hospital stay. In addition, the costs of initial anesthesia setup, professional fees, per-minute intraoperative fees, and postanesthesia care were applied to each approach. Operating room costs per minute and the cost of disposable items such as drapes, gowns, gloves, and single-use instruments were added. For the robotic approach, the costs of reusable instruments were distributed across 10 operations. Reusable instruments for laparoscopic and abdominal surgery were assumed to incur no additional investment. Last, postoperative care—including laboratory tests, pharmacy usage, and the need for a hospital room—were individualized for each route of surgery and applied to the cost.

Costs were estimated in 2008 US dollars, based on procedure costs incurred at Duke University Medical Center.

Physician reimbursement data were obtained from Medicare reimbursement rates for anesthesia and from surgeon Current Procedural Terminology (CPT) codes specific to each procedure.

Quality-of-life assessments were not measured. Nor was the cost to society of the postoperative loss of productivity and wages for each surgical route. Had these losses been recognized, the authors observed, the cost of robotic surgery may have been lower.

The cost of robotic surgery was equivalent to the cost of laparoscopy in only two instances:

• when the operative time of robotic surgery was reduced to 149 minutes
• when the cost of robotic disposable items was less than $2,132 (reduced from a baseline cost of $3,293).

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Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).¹ FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.

Table 1

Doxepin: Fast facts

Clinical implications

Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.^1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)

How it works

Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.² Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).^2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.³ However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.^4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.

Pharmacokinetics

When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.^1-3

Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.^1-3

Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.

Efficacy

Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).^4,5 Clinical studies lasted up to 3 months.^1-3,6-8

In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.⁴ In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7^th and 8^th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.

Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.⁴

The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.⁵ Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.

In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.⁵

Table 2

Evidence of effectiveness of doxepin for insomnia

Tolerability

Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.¹ All reported adverse events were mild to moderate.

Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.^2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.¹ Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.

Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.^2-4

Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.¹ There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.¹

Contraindications

Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.¹

Dosing

In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.¹

Related Resources

• Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
• Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
• National Sleep Foundation. www.sleepfoundation.org.

Drug Brand Names

• Amitriptyline • Elavil
• Cimetidine • Tagamet
• Desipramine • Norpramin
• Doxepin (3 mg and 6 mg) • Silenor
• Doxepin (10 to 150 mg, oral) • Sinequan
• Doxepin cream • Prudoxin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Ramelteon • Rozerem

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).¹ FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.

Table 1

Doxepin: Fast facts

Clinical implications

Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.^1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)

How it works

Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.² Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).^2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.³ However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.^4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.

Pharmacokinetics

When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.^1-3

Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.^1-3

Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.

Efficacy

Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).^4,5 Clinical studies lasted up to 3 months.^1-3,6-8

In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.⁴ In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7^th and 8^th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.

Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.⁴

The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.⁵ Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.

In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.⁵

Table 2

Evidence of effectiveness of doxepin for insomnia

Tolerability

Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.¹ All reported adverse events were mild to moderate.

Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.^2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.¹ Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.

Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.^2-4

Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.¹ There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.¹

Contraindications

Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.¹

Dosing

In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.¹

Related Resources

• Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
• Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
• National Sleep Foundation. www.sleepfoundation.org.

Drug Brand Names

• Amitriptyline • Elavil
• Cimetidine • Tagamet
• Desipramine • Norpramin
• Doxepin (3 mg and 6 mg) • Silenor
• Doxepin (10 to 150 mg, oral) • Sinequan
• Doxepin cream • Prudoxin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Ramelteon • Rozerem

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).¹ FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.

Table 1

Doxepin: Fast facts

Clinical implications

Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.^1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)

How it works

Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.² Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).^2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.³ However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.^4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.

Pharmacokinetics

When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.^1-3

Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.^1-3

Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.

Efficacy

Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).^4,5 Clinical studies lasted up to 3 months.^1-3,6-8

In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.⁴ In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7^th and 8^th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.

Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.⁴

The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.⁵ Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.

In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.⁵

Table 2

Evidence of effectiveness of doxepin for insomnia

Tolerability

Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.¹ All reported adverse events were mild to moderate.

Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.^2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.¹ Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.

Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.^2-4

Symptoms of withdrawal and rebound insomnia—an increase in WASO compared with baseline after discontinuing the medication—were assessed in a 35-day double-blind study of adults with chronic insomnia.¹ There was no evidence of withdrawal syndrome as measured by Tyler’s Symptom Checklist after doxepin 3 mg and 6 mg was discontinued. Discontinuation period-emergent nausea and vomiting was noted in 5% of patients taking 6 mg of doxepin, but not in those taking placebo or 3 mg of doxepin. There was no evidence of rebound insomnia after doxepin 3 mg and 6 mg was discontinued.¹

Contraindications

Doxepin is contraindicated in patients with hypersensitivity to doxepin hydrochloride, with severe urinary retention, with narrow angle glaucoma, and who have used monoamine oxidase inhibitors (MAOIs) within the previous 2 weeks. Serious adverse effects, including hypertensive crisis and death, have been reported with coadministration of MAOIs and certain drugs, such as serotonergic antidepressants and some opioids derivatives. There are no reports of concomitant use of doxepin with MAOIs.¹

Dosing

In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes before bedtime. For patients age ≥65, the recommended starting hypnotic dose is 3 mg 30 minutes before bedtime, which can be increased to 6 mg if indicated.¹

Related Resources

• Doghramji K, Grewal R, Markov D. Evaluation and management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454.
• Psychiatric Clinics of North America. December 2006. All articles in this issue address sleep disorders encountered in psychiatric practice.
• National Sleep Foundation. www.sleepfoundation.org.

Drug Brand Names

• Amitriptyline • Elavil
• Cimetidine • Tagamet
• Desipramine • Norpramin
• Doxepin (3 mg and 6 mg) • Silenor
• Doxepin (10 to 150 mg, oral) • Sinequan
• Doxepin cream • Prudoxin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Ramelteon • Rozerem

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.