The Journal of Family Practice

THE CASE

A 94-year-old Hispanic man with hypertension, congestive heart failure (CHF), anemia of chronic disease, and end-stage renal disease (ESRD) presented to our facility with weakness and shortness of breath. We diagnosed a CHF exacerbation. Initially, he exhibited some respiratory distress that required observation in the coronary care unit and bi-level positive airway pressure therapy to maintain oxygen saturation. Our patient was then moved to a step-down unit where his primary caregiver, his granddaughter, told the medical team that he was limited at home in some of his instrumental activities of daily living. Specifically, he was unable to prepare meals or manage his finances on his own.

Nephrology was consulted for consideration of hemodialysis (HD) because our patient’s creatinine on admission was 7.2 mg/dL (normal for men is 0.7-1.3 mg/dL) and his estimated glomerular filtration rate (GFR) was 7 mL/min (normal is 90-120 mL/min). The patient’s family was conflicted over whether or not to start HD. Palliative Care was consulted to help establish goals of care.

A decision is made. In light of the patient’s limited functional status and his expressed desire to stay at home with his family and receive limited medical care there, the Nephrology and Palliative Care teams recommended delaying HD despite the patient’s worsening renal function. The patient was discharged home with home care services, and he and the family were instructed to follow up with Nephrology for supportive renal management.

DISCUSSION

The decision to delay HD in patients with ESRD is a difficult one that requires shared decision-making between patients and medical providers. Palliative Care consultation services are often involved in this process.

Recent literature supports an “intent-to-defer” based on an evaluation of the patient’s functionality. This represents a paradigm shift from the previous “intent-to-start-early” treatment strategy. In fact, rather than starting early, the Canadian Society of Nephrology recommends delaying initiation of HD in patients with a GFR <15 mL/min.¹ Close monitoring of these patients by both a primary care physician and nephrologist is essential.

When considering initiation of HD, it’s important to look at the overall benefit of this intervention in light of the patient’s mortality risk and quality of life. Many patients who receive HD—especially the elderly—report that it takes more than 6 hours to recover following a dialysis treatment.²

Not surprisingly, depression is common in elderly HD patients. Compared to their younger cohorts, older HD patients have a 62% increased risk of developing depression.³ Also, patients who are considered frail and are receiving HD have more than 3 times the mortality risk within one year than those who are not (hazard ratio=3.42; 95% confidence interval, 2.45-4.76).⁴ (The researchers’ definition of frailty included poor self-reported physical function, exhaustion/fatigue, low physical activity, and undernutrition.⁴)

Functional status. Although a patient’s age should not be a limiting factor for HD referral, functional status should be considered. Patients with limited functionality and significant dependence have an increased risk of death during the first year of HD.⁵

Palliative approach gains acceptance. It is becoming more accepted within the nephrology community to consider a palliative approach to patients with ESRD. Organizations such as the Renal Physicians Association recommend effective prognostication, early advanced care planning, forgoing HD in patients with a poor prognosis, and involving Palliative Care early in the decision-making process.⁶ Aligning the patient’s goals of care with the appropriate treatment method—particularly in patients with comorbid conditions—is an important practice when caring for those with limited life expectancy and functionality.⁷

THE TAKEAWAY

Intent-to-defer HD may be a preferred strategy when caring for many patients with ESRD. Taking into consideration a patient’s comorbidities and functional status, while considering mortality risk and quality of life are essential. Involving palliative care and nephrology specialists can help patients and families understand HD and make an educated decision regarding when to start it.

THE CASE

A 94-year-old Hispanic man with hypertension, congestive heart failure (CHF), anemia of chronic disease, and end-stage renal disease (ESRD) presented to our facility with weakness and shortness of breath. We diagnosed a CHF exacerbation. Initially, he exhibited some respiratory distress that required observation in the coronary care unit and bi-level positive airway pressure therapy to maintain oxygen saturation. Our patient was then moved to a step-down unit where his primary caregiver, his granddaughter, told the medical team that he was limited at home in some of his instrumental activities of daily living. Specifically, he was unable to prepare meals or manage his finances on his own.

Nephrology was consulted for consideration of hemodialysis (HD) because our patient’s creatinine on admission was 7.2 mg/dL (normal for men is 0.7-1.3 mg/dL) and his estimated glomerular filtration rate (GFR) was 7 mL/min (normal is 90-120 mL/min). The patient’s family was conflicted over whether or not to start HD. Palliative Care was consulted to help establish goals of care.

A decision is made. In light of the patient’s limited functional status and his expressed desire to stay at home with his family and receive limited medical care there, the Nephrology and Palliative Care teams recommended delaying HD despite the patient’s worsening renal function. The patient was discharged home with home care services, and he and the family were instructed to follow up with Nephrology for supportive renal management.

DISCUSSION

The decision to delay HD in patients with ESRD is a difficult one that requires shared decision-making between patients and medical providers. Palliative Care consultation services are often involved in this process.

Recent literature supports an “intent-to-defer” based on an evaluation of the patient’s functionality. This represents a paradigm shift from the previous “intent-to-start-early” treatment strategy. In fact, rather than starting early, the Canadian Society of Nephrology recommends delaying initiation of HD in patients with a GFR <15 mL/min.¹ Close monitoring of these patients by both a primary care physician and nephrologist is essential.

When considering initiation of HD, it’s important to look at the overall benefit of this intervention in light of the patient’s mortality risk and quality of life. Many patients who receive HD—especially the elderly—report that it takes more than 6 hours to recover following a dialysis treatment.²

Not surprisingly, depression is common in elderly HD patients. Compared to their younger cohorts, older HD patients have a 62% increased risk of developing depression.³ Also, patients who are considered frail and are receiving HD have more than 3 times the mortality risk within one year than those who are not (hazard ratio=3.42; 95% confidence interval, 2.45-4.76).⁴ (The researchers’ definition of frailty included poor self-reported physical function, exhaustion/fatigue, low physical activity, and undernutrition.⁴)

Functional status. Although a patient’s age should not be a limiting factor for HD referral, functional status should be considered. Patients with limited functionality and significant dependence have an increased risk of death during the first year of HD.⁵

Palliative approach gains acceptance. It is becoming more accepted within the nephrology community to consider a palliative approach to patients with ESRD. Organizations such as the Renal Physicians Association recommend effective prognostication, early advanced care planning, forgoing HD in patients with a poor prognosis, and involving Palliative Care early in the decision-making process.⁶ Aligning the patient’s goals of care with the appropriate treatment method—particularly in patients with comorbid conditions—is an important practice when caring for those with limited life expectancy and functionality.⁷

THE TAKEAWAY

Intent-to-defer HD may be a preferred strategy when caring for many patients with ESRD. Taking into consideration a patient’s comorbidities and functional status, while considering mortality risk and quality of life are essential. Involving palliative care and nephrology specialists can help patients and families understand HD and make an educated decision regarding when to start it.

THE CASE

A 94-year-old Hispanic man with hypertension, congestive heart failure (CHF), anemia of chronic disease, and end-stage renal disease (ESRD) presented to our facility with weakness and shortness of breath. We diagnosed a CHF exacerbation. Initially, he exhibited some respiratory distress that required observation in the coronary care unit and bi-level positive airway pressure therapy to maintain oxygen saturation. Our patient was then moved to a step-down unit where his primary caregiver, his granddaughter, told the medical team that he was limited at home in some of his instrumental activities of daily living. Specifically, he was unable to prepare meals or manage his finances on his own.

Nephrology was consulted for consideration of hemodialysis (HD) because our patient’s creatinine on admission was 7.2 mg/dL (normal for men is 0.7-1.3 mg/dL) and his estimated glomerular filtration rate (GFR) was 7 mL/min (normal is 90-120 mL/min). The patient’s family was conflicted over whether or not to start HD. Palliative Care was consulted to help establish goals of care.

A decision is made. In light of the patient’s limited functional status and his expressed desire to stay at home with his family and receive limited medical care there, the Nephrology and Palliative Care teams recommended delaying HD despite the patient’s worsening renal function. The patient was discharged home with home care services, and he and the family were instructed to follow up with Nephrology for supportive renal management.

DISCUSSION

The decision to delay HD in patients with ESRD is a difficult one that requires shared decision-making between patients and medical providers. Palliative Care consultation services are often involved in this process.

Recent literature supports an “intent-to-defer” based on an evaluation of the patient’s functionality. This represents a paradigm shift from the previous “intent-to-start-early” treatment strategy. In fact, rather than starting early, the Canadian Society of Nephrology recommends delaying initiation of HD in patients with a GFR <15 mL/min.¹ Close monitoring of these patients by both a primary care physician and nephrologist is essential.

When considering initiation of HD, it’s important to look at the overall benefit of this intervention in light of the patient’s mortality risk and quality of life. Many patients who receive HD—especially the elderly—report that it takes more than 6 hours to recover following a dialysis treatment.²

Not surprisingly, depression is common in elderly HD patients. Compared to their younger cohorts, older HD patients have a 62% increased risk of developing depression.³ Also, patients who are considered frail and are receiving HD have more than 3 times the mortality risk within one year than those who are not (hazard ratio=3.42; 95% confidence interval, 2.45-4.76).⁴ (The researchers’ definition of frailty included poor self-reported physical function, exhaustion/fatigue, low physical activity, and undernutrition.⁴)

Functional status. Although a patient’s age should not be a limiting factor for HD referral, functional status should be considered. Patients with limited functionality and significant dependence have an increased risk of death during the first year of HD.⁵

Palliative approach gains acceptance. It is becoming more accepted within the nephrology community to consider a palliative approach to patients with ESRD. Organizations such as the Renal Physicians Association recommend effective prognostication, early advanced care planning, forgoing HD in patients with a poor prognosis, and involving Palliative Care early in the decision-making process.⁶ Aligning the patient’s goals of care with the appropriate treatment method—particularly in patients with comorbid conditions—is an important practice when caring for those with limited life expectancy and functionality.⁷

THE TAKEAWAY

Intent-to-defer HD may be a preferred strategy when caring for many patients with ESRD. Taking into consideration a patient’s comorbidities and functional status, while considering mortality risk and quality of life are essential. Involving palliative care and nephrology specialists can help patients and families understand HD and make an educated decision regarding when to start it.

THE CASE

A 49-year-old Mexican immigrant woman was admitted to the hospital with a 5-month history of fatigue and a 30-pound unintentional weight loss. She was also experiencing arthralgia, swelling, and stiffness in her hands and feet that was worse in the morning. The patient, who was obese and suffered from type 2 diabetes and hypertension, said that at the onset of her illness 5 months earlier, she’d experienced approximately 2 weeks of night sweats and a few days of fever.

A month before being admitted to the hospital, she’d been seen in our southern New Mexico family medicine office. Her recent history of fever, joint symptoms, and weight loss raised concerns of an insidious infection, a new-onset rheumatologic condition, or an occult malignancy.

Initial lab tests revealed leukopenia (white blood cell count, 3200/mcL), microcytic anemia (hemoglobin, 9.4 g/dL), and an elevated erythrocyte sedimentation rate of 30 mm/hr (normal range, 0-20 mm/hr). A rheumatoid factor test was negative, and her thyroid, kidney, and liver function tests were all normal.

More testing… The patient frequently traveled between New Mexico and her hometown of Chihuahua, Mexico, but there had been no recent changes in her diet or environmental exposures. She denied drinking any unpasteurized milk in Chihuahua. But based on her travel history, we ordered enzyme-linked immunosorbent assay (ELISA) antibody titers for Brucella, immunoglobulin G, and immunoglobulin M, which all came back negative. Additionally, we ordered an abdominal and pelvic ultrasound and a chest x-ray that were nondiagnostic. Given the patient’s weight loss and anemia, we referred her to a gastroenterologist for upper and lower gastrointestinal endoscopic evaluations. Unfortunately, the patient was uninsured and did not go to see the gastroenterologist.

A month after seeing us, our patient’s fatigue, lack of appetite, and joint pain became debilitating and she was admitted to the hospital for further evaluation, including a consultation with an oncologist.

THE DIAGNOSIS

During our patient’s 6-day hospital stay, a bone scintigraphy showed a focus of uptake in her left parietal bone and computed tomography scans of her chest, abdomen, and pelvis revealed a left thyroid nodule, as well as multiple noncalcified pulmonary nodules. Blood cultures were also obtained.

Despite the initial negative antibody tests, the blood cultures drawn in the hospital revealed the presence of Brucella melitensis, and we diagnosed brucellosis in this patient.

DISCUSSION

Brucella melitensis is one of the 4 recognized, land-based species of the Brucella genus that can cause disease in humans. Goats, sheep, and camels are natural hosts of B melitensis and consumption of their unpasteurized, infected milk and milk products (especially soft cheeses, ice cream, milk, and butter) leads to human disease. (Once hospitalized, our patient admitted to frequently eating unpasteurized goat cheese from Chihuahua. The only other person in her household that ate the cheese was her 26-year-old daughter, who was also experiencing similar symptoms.)

Brucellosis can also result from inhaling infected, aerosolized material; therefore, individuals whose occupations involve close work with host animals or work in laboratories with the bacteria have an increased risk of infection.¹ Due to the risk of acquiring the infection via inhalation, brucellosis is considered a bioterrorism threat.² Additionally, there have been reports of human-to-human transmission via sexual intercourse, transplacental infection, blood and bone marrow transfusion, and breastfeeding.³

B melitensis is the cause of the majority of Brucella-related illnesses in the world, though symptoms of infection are similar among the different Brucella species. The pathogen can affect almost all organ systems after the initial 2- to 4-week incubation period. Symptoms of brucellosis can be highly variable, although fever is consistently present.¹ Other red flags include arthritis (usually affecting the peripheral joints, the sacroiliac joints, and the lower spine), epididymo-orchitis, and hepatitis resulting in transaminase elevation. Abscess formation can be seen in the liver, spleen, and other organs.

Less common but more ominous complications include central nervous system infections and abscesses, endocarditis, and pulmonary infections. Endocarditis and the resulting aortic valve involvement is the major cause of mortality.¹Brucella­-related uveitis, thyroiditis, nephritis, vasculitis, and acalculous cholecystitis have also been reported.^4-9

Rare in the United States. Pasteurization of dairy products and mass vaccination of livestock make Brucella infection rare in the United States. While there have only been 80 to 139 cases of brucellosis reported per year in the United States since 1993, it remains a persistent threat. International travel is common from the United States to the Middle East and other parts of the world where brucellosis is endemic.

Additionally, infection of livestock with Brucella remains widespread in Mexico and the consumption of unpasteurized Mexican dairy products from goats and sheep remains a high-risk activity for acquiring the disease.¹⁰ Consequently, Texas and California account for more than half of the brucellosis diagnoses in the United States. However, in 2010, cases were reported in 25 other states and the District of Columbia.¹¹

Texas and California account for more than half of the brucellosis diagnoses in the United States.

Repeat serology tests are preferred for confirming the Dx

It is interesting that our patient’s initial Brucella serology by ELISA was negative, because it was ordered months after her initial symptoms. Antibodies should be seen within a month of symptom onset. The Centers for Disease Control and Prevention (CDC) recommends taking 2 serum samples to establish a serologic diagnosis of brucellosis. The first should be drawn within 7 days of symptom onset and the second should be taken 2 to 4 weeks later. A greater than 4-fold rise in the antibody titer confirms the diagnosis. While ELISA is an acceptable serologic test, the CDC recommends using a serum tube agglutination test called the Brucella microagglutination test (BMAT).¹² Repeat serology was not performed on our patient because the diagnosis had been confirmed by blood culture.

A combination of antibiotics is the recommended treatment

Treatment of brucellosis should include a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin 600 mg/d for an all-oral regimen.¹³ Doxycycline 100 mg twice a day is preferred due to fewer gastrointestinal adverse effects than tetracycline. Relapse is not uncommon (10%) and usually occurs within one year of completing the antibiotics.⁸ However, there is a case report of a patient having reactivated brucellosis manifested as acalculous cholecystitis 28 years after completing antibiotics.⁸

Our patient was started on oral doxycycline 100 mg twice a day and oral rifampin 600 mg/d for 6 weeks. Within days of starting the antibiotics, her joint symptoms and fatigue rapidly abated and her appetite returned. Follow-up radiological testing was not performed after her initial hospital studies due to her lack of financial resources.

The patient’s daughter had also been experiencing night sweats, chills, malaise, anorexia, joint pains, weight loss, and alopecia over the previous 2 months. Her blood cultures were positive for B melitensis as well, and she was started on the same antibiotic regimen as her mother. The daughter was also seen in our clinic by another physician and improved quickly within a week of starting treatment.

Both our patient and her daughter remained symptom-free 6 years after treatment.

THE TAKEAWAY

Brucellosis is rare in the United States, but international travel to endemic areas is commonplace and consumption of unpasteurized Mexican dairy products from goats and sheep is widespread. Brucellosis has a wide range of symptoms, but a prompt diagnosis by an ELISA or BMAT serologic test and appropriate treatment can avoid morbidity and mortality. Treatment includes a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin.

THE CASE

A 49-year-old Mexican immigrant woman was admitted to the hospital with a 5-month history of fatigue and a 30-pound unintentional weight loss. She was also experiencing arthralgia, swelling, and stiffness in her hands and feet that was worse in the morning. The patient, who was obese and suffered from type 2 diabetes and hypertension, said that at the onset of her illness 5 months earlier, she’d experienced approximately 2 weeks of night sweats and a few days of fever.

A month before being admitted to the hospital, she’d been seen in our southern New Mexico family medicine office. Her recent history of fever, joint symptoms, and weight loss raised concerns of an insidious infection, a new-onset rheumatologic condition, or an occult malignancy.

Initial lab tests revealed leukopenia (white blood cell count, 3200/mcL), microcytic anemia (hemoglobin, 9.4 g/dL), and an elevated erythrocyte sedimentation rate of 30 mm/hr (normal range, 0-20 mm/hr). A rheumatoid factor test was negative, and her thyroid, kidney, and liver function tests were all normal.

More testing… The patient frequently traveled between New Mexico and her hometown of Chihuahua, Mexico, but there had been no recent changes in her diet or environmental exposures. She denied drinking any unpasteurized milk in Chihuahua. But based on her travel history, we ordered enzyme-linked immunosorbent assay (ELISA) antibody titers for Brucella, immunoglobulin G, and immunoglobulin M, which all came back negative. Additionally, we ordered an abdominal and pelvic ultrasound and a chest x-ray that were nondiagnostic. Given the patient’s weight loss and anemia, we referred her to a gastroenterologist for upper and lower gastrointestinal endoscopic evaluations. Unfortunately, the patient was uninsured and did not go to see the gastroenterologist.

A month after seeing us, our patient’s fatigue, lack of appetite, and joint pain became debilitating and she was admitted to the hospital for further evaluation, including a consultation with an oncologist.

THE DIAGNOSIS

During our patient’s 6-day hospital stay, a bone scintigraphy showed a focus of uptake in her left parietal bone and computed tomography scans of her chest, abdomen, and pelvis revealed a left thyroid nodule, as well as multiple noncalcified pulmonary nodules. Blood cultures were also obtained.

Despite the initial negative antibody tests, the blood cultures drawn in the hospital revealed the presence of Brucella melitensis, and we diagnosed brucellosis in this patient.

DISCUSSION

Brucella melitensis is one of the 4 recognized, land-based species of the Brucella genus that can cause disease in humans. Goats, sheep, and camels are natural hosts of B melitensis and consumption of their unpasteurized, infected milk and milk products (especially soft cheeses, ice cream, milk, and butter) leads to human disease. (Once hospitalized, our patient admitted to frequently eating unpasteurized goat cheese from Chihuahua. The only other person in her household that ate the cheese was her 26-year-old daughter, who was also experiencing similar symptoms.)

Brucellosis can also result from inhaling infected, aerosolized material; therefore, individuals whose occupations involve close work with host animals or work in laboratories with the bacteria have an increased risk of infection.¹ Due to the risk of acquiring the infection via inhalation, brucellosis is considered a bioterrorism threat.² Additionally, there have been reports of human-to-human transmission via sexual intercourse, transplacental infection, blood and bone marrow transfusion, and breastfeeding.³

B melitensis is the cause of the majority of Brucella-related illnesses in the world, though symptoms of infection are similar among the different Brucella species. The pathogen can affect almost all organ systems after the initial 2- to 4-week incubation period. Symptoms of brucellosis can be highly variable, although fever is consistently present.¹ Other red flags include arthritis (usually affecting the peripheral joints, the sacroiliac joints, and the lower spine), epididymo-orchitis, and hepatitis resulting in transaminase elevation. Abscess formation can be seen in the liver, spleen, and other organs.

Less common but more ominous complications include central nervous system infections and abscesses, endocarditis, and pulmonary infections. Endocarditis and the resulting aortic valve involvement is the major cause of mortality.¹Brucella­-related uveitis, thyroiditis, nephritis, vasculitis, and acalculous cholecystitis have also been reported.^4-9

Rare in the United States. Pasteurization of dairy products and mass vaccination of livestock make Brucella infection rare in the United States. While there have only been 80 to 139 cases of brucellosis reported per year in the United States since 1993, it remains a persistent threat. International travel is common from the United States to the Middle East and other parts of the world where brucellosis is endemic.

Additionally, infection of livestock with Brucella remains widespread in Mexico and the consumption of unpasteurized Mexican dairy products from goats and sheep remains a high-risk activity for acquiring the disease.¹⁰ Consequently, Texas and California account for more than half of the brucellosis diagnoses in the United States. However, in 2010, cases were reported in 25 other states and the District of Columbia.¹¹

Texas and California account for more than half of the brucellosis diagnoses in the United States.

Repeat serology tests are preferred for confirming the Dx

It is interesting that our patient’s initial Brucella serology by ELISA was negative, because it was ordered months after her initial symptoms. Antibodies should be seen within a month of symptom onset. The Centers for Disease Control and Prevention (CDC) recommends taking 2 serum samples to establish a serologic diagnosis of brucellosis. The first should be drawn within 7 days of symptom onset and the second should be taken 2 to 4 weeks later. A greater than 4-fold rise in the antibody titer confirms the diagnosis. While ELISA is an acceptable serologic test, the CDC recommends using a serum tube agglutination test called the Brucella microagglutination test (BMAT).¹² Repeat serology was not performed on our patient because the diagnosis had been confirmed by blood culture.

A combination of antibiotics is the recommended treatment

Treatment of brucellosis should include a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin 600 mg/d for an all-oral regimen.¹³ Doxycycline 100 mg twice a day is preferred due to fewer gastrointestinal adverse effects than tetracycline. Relapse is not uncommon (10%) and usually occurs within one year of completing the antibiotics.⁸ However, there is a case report of a patient having reactivated brucellosis manifested as acalculous cholecystitis 28 years after completing antibiotics.⁸

Our patient was started on oral doxycycline 100 mg twice a day and oral rifampin 600 mg/d for 6 weeks. Within days of starting the antibiotics, her joint symptoms and fatigue rapidly abated and her appetite returned. Follow-up radiological testing was not performed after her initial hospital studies due to her lack of financial resources.

The patient’s daughter had also been experiencing night sweats, chills, malaise, anorexia, joint pains, weight loss, and alopecia over the previous 2 months. Her blood cultures were positive for B melitensis as well, and she was started on the same antibiotic regimen as her mother. The daughter was also seen in our clinic by another physician and improved quickly within a week of starting treatment.

Both our patient and her daughter remained symptom-free 6 years after treatment.

THE TAKEAWAY

Brucellosis is rare in the United States, but international travel to endemic areas is commonplace and consumption of unpasteurized Mexican dairy products from goats and sheep is widespread. Brucellosis has a wide range of symptoms, but a prompt diagnosis by an ELISA or BMAT serologic test and appropriate treatment can avoid morbidity and mortality. Treatment includes a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin.

THE CASE

A 49-year-old Mexican immigrant woman was admitted to the hospital with a 5-month history of fatigue and a 30-pound unintentional weight loss. She was also experiencing arthralgia, swelling, and stiffness in her hands and feet that was worse in the morning. The patient, who was obese and suffered from type 2 diabetes and hypertension, said that at the onset of her illness 5 months earlier, she’d experienced approximately 2 weeks of night sweats and a few days of fever.

A month before being admitted to the hospital, she’d been seen in our southern New Mexico family medicine office. Her recent history of fever, joint symptoms, and weight loss raised concerns of an insidious infection, a new-onset rheumatologic condition, or an occult malignancy.

Initial lab tests revealed leukopenia (white blood cell count, 3200/mcL), microcytic anemia (hemoglobin, 9.4 g/dL), and an elevated erythrocyte sedimentation rate of 30 mm/hr (normal range, 0-20 mm/hr). A rheumatoid factor test was negative, and her thyroid, kidney, and liver function tests were all normal.

More testing… The patient frequently traveled between New Mexico and her hometown of Chihuahua, Mexico, but there had been no recent changes in her diet or environmental exposures. She denied drinking any unpasteurized milk in Chihuahua. But based on her travel history, we ordered enzyme-linked immunosorbent assay (ELISA) antibody titers for Brucella, immunoglobulin G, and immunoglobulin M, which all came back negative. Additionally, we ordered an abdominal and pelvic ultrasound and a chest x-ray that were nondiagnostic. Given the patient’s weight loss and anemia, we referred her to a gastroenterologist for upper and lower gastrointestinal endoscopic evaluations. Unfortunately, the patient was uninsured and did not go to see the gastroenterologist.

A month after seeing us, our patient’s fatigue, lack of appetite, and joint pain became debilitating and she was admitted to the hospital for further evaluation, including a consultation with an oncologist.

THE DIAGNOSIS

During our patient’s 6-day hospital stay, a bone scintigraphy showed a focus of uptake in her left parietal bone and computed tomography scans of her chest, abdomen, and pelvis revealed a left thyroid nodule, as well as multiple noncalcified pulmonary nodules. Blood cultures were also obtained.

Despite the initial negative antibody tests, the blood cultures drawn in the hospital revealed the presence of Brucella melitensis, and we diagnosed brucellosis in this patient.

DISCUSSION

Brucella melitensis is one of the 4 recognized, land-based species of the Brucella genus that can cause disease in humans. Goats, sheep, and camels are natural hosts of B melitensis and consumption of their unpasteurized, infected milk and milk products (especially soft cheeses, ice cream, milk, and butter) leads to human disease. (Once hospitalized, our patient admitted to frequently eating unpasteurized goat cheese from Chihuahua. The only other person in her household that ate the cheese was her 26-year-old daughter, who was also experiencing similar symptoms.)

Brucellosis can also result from inhaling infected, aerosolized material; therefore, individuals whose occupations involve close work with host animals or work in laboratories with the bacteria have an increased risk of infection.¹ Due to the risk of acquiring the infection via inhalation, brucellosis is considered a bioterrorism threat.² Additionally, there have been reports of human-to-human transmission via sexual intercourse, transplacental infection, blood and bone marrow transfusion, and breastfeeding.³

B melitensis is the cause of the majority of Brucella-related illnesses in the world, though symptoms of infection are similar among the different Brucella species. The pathogen can affect almost all organ systems after the initial 2- to 4-week incubation period. Symptoms of brucellosis can be highly variable, although fever is consistently present.¹ Other red flags include arthritis (usually affecting the peripheral joints, the sacroiliac joints, and the lower spine), epididymo-orchitis, and hepatitis resulting in transaminase elevation. Abscess formation can be seen in the liver, spleen, and other organs.

Less common but more ominous complications include central nervous system infections and abscesses, endocarditis, and pulmonary infections. Endocarditis and the resulting aortic valve involvement is the major cause of mortality.¹Brucella­-related uveitis, thyroiditis, nephritis, vasculitis, and acalculous cholecystitis have also been reported.^4-9

Rare in the United States. Pasteurization of dairy products and mass vaccination of livestock make Brucella infection rare in the United States. While there have only been 80 to 139 cases of brucellosis reported per year in the United States since 1993, it remains a persistent threat. International travel is common from the United States to the Middle East and other parts of the world where brucellosis is endemic.

Additionally, infection of livestock with Brucella remains widespread in Mexico and the consumption of unpasteurized Mexican dairy products from goats and sheep remains a high-risk activity for acquiring the disease.¹⁰ Consequently, Texas and California account for more than half of the brucellosis diagnoses in the United States. However, in 2010, cases were reported in 25 other states and the District of Columbia.¹¹

Texas and California account for more than half of the brucellosis diagnoses in the United States.

Repeat serology tests are preferred for confirming the Dx

It is interesting that our patient’s initial Brucella serology by ELISA was negative, because it was ordered months after her initial symptoms. Antibodies should be seen within a month of symptom onset. The Centers for Disease Control and Prevention (CDC) recommends taking 2 serum samples to establish a serologic diagnosis of brucellosis. The first should be drawn within 7 days of symptom onset and the second should be taken 2 to 4 weeks later. A greater than 4-fold rise in the antibody titer confirms the diagnosis. While ELISA is an acceptable serologic test, the CDC recommends using a serum tube agglutination test called the Brucella microagglutination test (BMAT).¹² Repeat serology was not performed on our patient because the diagnosis had been confirmed by blood culture.

A combination of antibiotics is the recommended treatment

Treatment of brucellosis should include a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin 600 mg/d for an all-oral regimen.¹³ Doxycycline 100 mg twice a day is preferred due to fewer gastrointestinal adverse effects than tetracycline. Relapse is not uncommon (10%) and usually occurs within one year of completing the antibiotics.⁸ However, there is a case report of a patient having reactivated brucellosis manifested as acalculous cholecystitis 28 years after completing antibiotics.⁸

Our patient was started on oral doxycycline 100 mg twice a day and oral rifampin 600 mg/d for 6 weeks. Within days of starting the antibiotics, her joint symptoms and fatigue rapidly abated and her appetite returned. Follow-up radiological testing was not performed after her initial hospital studies due to her lack of financial resources.

The patient’s daughter had also been experiencing night sweats, chills, malaise, anorexia, joint pains, weight loss, and alopecia over the previous 2 months. Her blood cultures were positive for B melitensis as well, and she was started on the same antibiotic regimen as her mother. The daughter was also seen in our clinic by another physician and improved quickly within a week of starting treatment.

Both our patient and her daughter remained symptom-free 6 years after treatment.

THE TAKEAWAY

Brucellosis is rare in the United States, but international travel to endemic areas is commonplace and consumption of unpasteurized Mexican dairy products from goats and sheep is widespread. Brucellosis has a wide range of symptoms, but a prompt diagnosis by an ELISA or BMAT serologic test and appropriate treatment can avoid morbidity and mortality. Treatment includes a tetracycline for at least 6 weeks in combination with an aminoglycoside or rifampin.

While some physicians prefer a narrower clinic focus, the wide variety and complexity of the care provided by family physicians is precisely what drew many of us to the specialty. We enjoy caring for patients of all ages who see us for the diagnosis and treatment of acute illnesses, management of chronic diseases, preventive care, and behavioral and mental health concerns.

The quantity, variety, and complexity of the care we provide has been well-documented in the literature. In a study performed by the Wisconsin Research Network,¹ 29 family physicians reported addressing an average of 3.05 problems per patient during 572 office visits. A chart review confirmed physician self-report: 2.82 problems were recorded on average for each visit. For patients older than age 65, an average of 3.88 problems were addressed at each visit. For patients with diabetes, the average was 4.60.

Using data from the 2000 National Ambulatory Medical Care Survey, Katerndahl et al² estimated the complexity of patient encounters in family practice, cardiology, and psychiatry. They used a formula that took into account the per-patient number of reasons for each visit, diagnoses, and body systems examined, and the variability and diversity of each of these factors. After adjusting the results for length of visit, they found the complexity of care provided per hour by family physicians was 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

The topics in this issue are a terrific illustration of the breadth of family medicine. Peripheral neuropathy, which we see almost daily, is difficult to diagnose and treat. Prolotherapy is an up-and-coming dextrose injection therapy for tendinopathies and joint pain that shows promise, and patients are likely to start asking us about it. Home apnea monitors are used frequently for newborns—but how effective are they, and when can you tell parents to discontinue their use?

The complexity of care provided per hour by family physicians is 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

It seems that vaccine recommendations change every year, and this issue’s Practice Alert covers the latest on meningococcal immunization. This month’s PURL answers the question: Do we really need to “bridge” patients with atrial fibrillation from warfarin to low molecular weight heparin immediately before and after a surgical procedure?

The authors and editors of The Journal of Family Practice constantly strive to bring you the most up-to-date information to support your work as a master of the complexity of primary care practice.

While some physicians prefer a narrower clinic focus, the wide variety and complexity of the care provided by family physicians is precisely what drew many of us to the specialty. We enjoy caring for patients of all ages who see us for the diagnosis and treatment of acute illnesses, management of chronic diseases, preventive care, and behavioral and mental health concerns.

The quantity, variety, and complexity of the care we provide has been well-documented in the literature. In a study performed by the Wisconsin Research Network,¹ 29 family physicians reported addressing an average of 3.05 problems per patient during 572 office visits. A chart review confirmed physician self-report: 2.82 problems were recorded on average for each visit. For patients older than age 65, an average of 3.88 problems were addressed at each visit. For patients with diabetes, the average was 4.60.

Using data from the 2000 National Ambulatory Medical Care Survey, Katerndahl et al² estimated the complexity of patient encounters in family practice, cardiology, and psychiatry. They used a formula that took into account the per-patient number of reasons for each visit, diagnoses, and body systems examined, and the variability and diversity of each of these factors. After adjusting the results for length of visit, they found the complexity of care provided per hour by family physicians was 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

The topics in this issue are a terrific illustration of the breadth of family medicine. Peripheral neuropathy, which we see almost daily, is difficult to diagnose and treat. Prolotherapy is an up-and-coming dextrose injection therapy for tendinopathies and joint pain that shows promise, and patients are likely to start asking us about it. Home apnea monitors are used frequently for newborns—but how effective are they, and when can you tell parents to discontinue their use?

The complexity of care provided per hour by family physicians is 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

It seems that vaccine recommendations change every year, and this issue’s Practice Alert covers the latest on meningococcal immunization. This month’s PURL answers the question: Do we really need to “bridge” patients with atrial fibrillation from warfarin to low molecular weight heparin immediately before and after a surgical procedure?

The authors and editors of The Journal of Family Practice constantly strive to bring you the most up-to-date information to support your work as a master of the complexity of primary care practice.

While some physicians prefer a narrower clinic focus, the wide variety and complexity of the care provided by family physicians is precisely what drew many of us to the specialty. We enjoy caring for patients of all ages who see us for the diagnosis and treatment of acute illnesses, management of chronic diseases, preventive care, and behavioral and mental health concerns.

The quantity, variety, and complexity of the care we provide has been well-documented in the literature. In a study performed by the Wisconsin Research Network,¹ 29 family physicians reported addressing an average of 3.05 problems per patient during 572 office visits. A chart review confirmed physician self-report: 2.82 problems were recorded on average for each visit. For patients older than age 65, an average of 3.88 problems were addressed at each visit. For patients with diabetes, the average was 4.60.

Using data from the 2000 National Ambulatory Medical Care Survey, Katerndahl et al² estimated the complexity of patient encounters in family practice, cardiology, and psychiatry. They used a formula that took into account the per-patient number of reasons for each visit, diagnoses, and body systems examined, and the variability and diversity of each of these factors. After adjusting the results for length of visit, they found the complexity of care provided per hour by family physicians was 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

The topics in this issue are a terrific illustration of the breadth of family medicine. Peripheral neuropathy, which we see almost daily, is difficult to diagnose and treat. Prolotherapy is an up-and-coming dextrose injection therapy for tendinopathies and joint pain that shows promise, and patients are likely to start asking us about it. Home apnea monitors are used frequently for newborns—but how effective are they, and when can you tell parents to discontinue their use?

The complexity of care provided per hour by family physicians is 33% higher than that of cardiologists and 5 times higher than that of psychiatrists.

It seems that vaccine recommendations change every year, and this issue’s Practice Alert covers the latest on meningococcal immunization. This month’s PURL answers the question: Do we really need to “bridge” patients with atrial fibrillation from warfarin to low molecular weight heparin immediately before and after a surgical procedure?

The authors and editors of The Journal of Family Practice constantly strive to bring you the most up-to-date information to support your work as a master of the complexity of primary care practice.

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; lmayans@kumc.edu.

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; lmayans@kumc.edu.

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; lmayans@kumc.edu.

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; perkins@health.southalabama.edu.

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; perkins@health.southalabama.edu.

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; perkins@health.southalabama.edu.