Reviews

Sessile serrated polyps are a type of polyp recently recognized to be a precursor of colorectal cancer. They arise from a pathway of genetic alterations different from the pathway that causes the more common and well-understood conventional adenomas (also called tubular adenomas, tubulovillous adenomas, and villous adenomas).

We do not yet know enough about the lifetime colorectal cancer risk for individuals with sessile serrated polyps, nor do we know the optimal surveillance interval for patients who have these polyps on colonoscopy. It is believed that sessile serrated polyps may be the cause of a substantial number of “interval” colorectal cancers—ie, cancers that occur after colonoscopy but before the next scheduled examination.

Serrated polyps get their name from their jagged appearance on microscopy. In the past, all serrated colorectal lesions were called hyperplastic polyps. But with the advent of molecular and genetic diagnostics and with the ability to recognize the subtle morphologic differences of serrated lesions, they have been reclassified into those without malignant potential (hyperplastic polyps) and those that are neoplastic (sessile serrated polyps and traditional serrated adenomas) (Table 1).

In this article, we discuss the evolving understanding of the different types of serrated polyps, and we offer our thoughts on a reasonable postpolypectomy surveillance plan in patients with these lesions. We focus on sessile serrated polyps, the most common form of serrated polyp with cancerous potential, since it may be one of our greatest challenges in optimal colorectal cancer prevention.

CLINICAL SCENARIO

A 65-year-old woman with no family history of colorectal cancer undergoes screening colonoscopy, during which three polyps are found and removed—a 3-mm tubular adenoma in the sigmoid colon, an 8-mm sessile serrated polyp at the hepatic flexure, and a 2-mm hyperplastic polyp in the rectum. When should she undergo follow-up colonoscopy?

Based on the number, size, and pathologic makeup of the polyps in this patient, we would recommend follow-up surveillance colonoscopy in 5 years.

THE SERRATED POLYP PATHWAY: A DIFFERENT PATH TO COLORECTAL CANCER

Colorectal cancer is the third most common cancer in the United States.¹ From 70% to 80% of these cancers arise from adenomatous polyps via the adenoma-carcinoma pathway. This molecular pathway develops through chromosomal instability (CIN) and involves the loss of heterozygosity (the loss of function of one allele). This leads to the progressive accumulation of mutations in tumor-suppressor genes such as adenomatous polyposis coli (APC) and p53, and oncogenes such as KRAS. The result of these mutations is the development of adenomatous polyps that lead to microsatellite-stable colorectal cancers (Figure 1).²

More recently, studies have shown that the other 20% to 30% of colorectal cancers likely arise through a separate pathway, called the serrated polyp pathway or serrated neoplasia pathway. In contrast to CIN, this pathway is characterized by methylation of CpG islands (CIMP–CpG island methylation phenotype, CIMP) in the promoter regions of specific genes.³ Central to the serrated polyp pathway is progressive methylation in colonic mucosa; mutation in the BRAF oncogene, activating cell proliferation leading to a sessile serrated polyp; and epigenetic silencing of the DNA mismatch repair gene hMLH1, which is a key step in the progression to a sessile serrated polyp with dysplasia, which may rapidly become a microsatellite-unstable colorectal cancer.⁴

Histologically, serrated polyps have a serrated or sawtooth appearance from the folding in of the crypt epithelium, and they include hyperplastic polyps, traditional serrated adenomas, and sessile serrated polyps (sessile serrated adenomas).

Sessile serrated polyps and traditional serrated adenomas (which are rare) are thought to be precancerous, whereas hyperplastic polyps do not have malignant potential.

COMMON, BUT PREVALENCE IS NOT CLEARLY ESTABLISHED

The histologic criteria for sessile serrated polyps and traditional serrated adenomas have been elucidated,^4–7 but the epidemiology of these serrated polyps is not clear. Small studies have shown that sessile serrated polyps account for 2% to 9% of all polyps removed at colonoscopy^8–10; however, larger studies are needed to determine the prevalence because detection by an endoscopist and pathologic diagnosis of these polyps are both operator-dependent.

Traditional serrated adenomas are the least common type of serrated polyp, with a reported prevalence of 0.3%.⁷ Hyperplastic polyps are by far the most common, accounting for 20% to 30% of all polyps removed at colonoscopy.^9,11 Sessile serrated polyps have a predilection for the proximal colon and are associated with female sex and with smoking, ^12,13 but no consistent effect of other factors on their formation has been reported. In contrast, Wallace et al¹³ found that obesity, cigarette smoking, dietary fat intake, total caloric intake, and the consumption of red meat were associated with an increased risk of distal (but not proximal) serrated polyps, including hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas.

HYPERPLASTIC POLYPS

Hyperplastic polyps usually occur in the rectosigmoid colon. They appear as slightly elevated, whitish lesions with a diameter less than 5 mm (Figure 2). Microscopically, the serrated architecture is present in the upper half of their crypts (Figure 3). The proliferative zone is more or less normally located in the basal half of the crypt (the nonserrated portion), with nuclei that are small, uniform, and basally located.¹⁴ The bases of the crypts have a rounded contour and do not grow laterally along the muscularis mucosae.

SESSILE SERRATED POLYPS

Endoscopically, sessile serrated polyps are often subtle, appear flat or slightly elevated, and can be covered by yellow mucus (Figure 4). They are typically found in the proximal colon and are usually larger than typical adenomas, with 50% being larger than 10 mm.¹⁰

Histologically, the serrations are more prominent than those of hyperplastic polyps and involve the entire length of the crypt (Figure 5). The crypt bases are often dilated and display lateral growth along the lamina muscularis mucosae, resembling a letter t or l. The lamina muscularis mucosae is often thinner than normal. Crypts from sessile serrated polyps are occasionally found beneath the muscularis mucosae, a condition called pseudoinvasion.⁷

TRADITIONAL SERRATED ADENOMAS

Traditional serrated adenomas are usually left-sided. In contrast to the other types of serrated polyps, they are histologically often villiform and are lined by cells with elongated nuclei and abundant eosinophilic cytoplasm (Figure 6). Unlike those in sessile serrated polyps, the crypt bases do not display an abnormal architecture; rather, traditional serrated adenomas have abundant ectopic crypts (“budding crypts”) in the long, slender villi.⁷

Traditional serrated adenomas also appear to be genetically distinct from sessile serrated polyps. They are most often characterized by a KRAS (or less commonly, BRAF) mutation and commonly have methylation of the DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) rather than hMLH1.

CHALLENGES TO EFFECTIVE COLONOSCOPY

Colonoscopic polypectomy of adenomatous polyps reduces the incidence of colorectal cancer and the rate of death from it.^15,16 However, recent data show that colonoscopy may not be as effective as once thought. As many as 9% of patients with colorectal cancer have had a “normal” colonoscopic examination in the preceding 3 years.^17,18 In addition, the reduction in incidence and mortality rates was less for cancers in the proximal colon than for cancers in the distal colon.^19,20

Possible explanations for this discrepancy include the skill of the endoscopist, technical limitations of the examination, incomplete removal of polyps, and inadequate bowel preparation. Several studies have shown that interval colorectal cancers are more likely to be found in the proximal colon and to have the same molecular characteristics as sessile serrated polyps and the serrated colorectal cancer pathway (CIMP-high and MSI-H).^21,22 Therefore, it is now thought that sessile serrated polyps may account for a substantial portion of “postcolonoscopy cancers” (ie, interval cancers) that arise in the proximal colon.

Two large studies of screening colonoscopy confirmed that the ability to detect sessile serrated polyps depends greatly on the skill of the endoscopist. Hetzel et al⁹ studied the differences in the rates of polyp detection among endoscopists performing more than 7,000 colonoscopies. Detection rates varied significantly for adenomas, hyperplastic polyps, and sessile serrated polyps, with the greatest variability noted in the detection of sessile serrated polyps. Significant variability was also noted in the ability of the pathologist to diagnose sessile serrated polyps.⁹

In the other study, a strong correlation was found between physicians who are “high detectors” of adenomas and their detection rates for proximal serrated polyps.²³ There is widespread acceptance that screening colonoscopy in average-risk patients age 50 and older should detect adenomas in more than 25% of men and more than 15% of women. There is no current minimum recommended detection rate for sessile serrated polyps, but some have suggested 1.5%.⁸

POLYPS AS PREDICTORS OF CANCER RISK

Certain polyp characteristics predict the risk of metachronous, advanced neoplasia. Advanced neoplasms are defined as invasive carcinomas, adenomas 10 mm or larger, or adenomas with any villous histology or high-grade dysplasia. Patients with one or two small tubular adenomas have a much lower risk of metachronous advanced neoplasia than do patients with more than two adenomas or advanced neoplasms.²⁴ Current recommended surveillance intervals vary on that basis (Table 2).²⁵

People who harbor serrated neoplasms are at high risk of synchronous serrated polyps and advanced adenomatous neoplasia. Pai et al²⁶ found that patients with one sessile serrated polyp were four times more likely to have additional serrated polyps at the same time than an unselected population. The authors suggested that this indicates a strong colonic mucosal-field defect in patients with sessile serrated polyps, thereby predisposing them to the development of synchronous serrated polyps.

Li et al²⁷ found that large serrated polyps (ie, > 10 mm) are associated with a risk of synchronous advanced neoplasia that is three times higher than in patients without adenomas. Schreiner et al²⁸ determined that patients with either a proximal or a large serrated polyp were at higher risk of synchronous advanced neoplasia compared with patients who did not have those lesions. Vu et al²⁹ found that patients who have both sessile serrated polyps and conventional adenomas have significantly larger and more numerous lesions of both types.²⁹ In addition, these lesions are more likely to be pathologically advanced when compared with people with only one or the other type.

In the only study of the risk of advanced neoplasia on follow-up colonoscopy,²⁸ patients with advanced neoplasia and proximal serrated polyps at baseline examination were twice as likely to have advanced neoplasia during subsequent surveillance than those with only advanced neoplasia at baseline examination.²⁸

Therefore, it seems clear that the presence of large or proximal serrated polyps or serrated neoplasms predicts the presence of synchronous and likely metachronous advanced neoplasms.

Guidelines for postpolypectomy surveillance for individuals with serrated lesions of the colon have recently been published.²⁵ Patients with large serrated lesions (≥ 10 mm) or an advanced serrated lesion (a sessile serrated polyp with or without cytologic dysplasia or a traditional serrated adenoma) should be followed closely. Patients with small (< 10-mm) rectosigmoid hyperplastic polyps should be followed as average-risk patients. If a patient with a sessile serrated polyp also has adenomas, the surveillance interval should be the shortest interval recommended for either lesion.²⁹

SURVEILLANCE FOR OUR PATIENT

In our patient, given the number, size, and histologic features of the polyps found, surveillance colonoscopy should be considered in 5 years. Although the clinical significance of the serrated pathway to colorectal cancer cannot be argued, further study is required to understand the lifetime risk to patients with serrated neoplasms and the optimal surveillance interval.

Sessile serrated polyps are a type of polyp recently recognized to be a precursor of colorectal cancer. They arise from a pathway of genetic alterations different from the pathway that causes the more common and well-understood conventional adenomas (also called tubular adenomas, tubulovillous adenomas, and villous adenomas).

We do not yet know enough about the lifetime colorectal cancer risk for individuals with sessile serrated polyps, nor do we know the optimal surveillance interval for patients who have these polyps on colonoscopy. It is believed that sessile serrated polyps may be the cause of a substantial number of “interval” colorectal cancers—ie, cancers that occur after colonoscopy but before the next scheduled examination.

Serrated polyps get their name from their jagged appearance on microscopy. In the past, all serrated colorectal lesions were called hyperplastic polyps. But with the advent of molecular and genetic diagnostics and with the ability to recognize the subtle morphologic differences of serrated lesions, they have been reclassified into those without malignant potential (hyperplastic polyps) and those that are neoplastic (sessile serrated polyps and traditional serrated adenomas) (Table 1).

In this article, we discuss the evolving understanding of the different types of serrated polyps, and we offer our thoughts on a reasonable postpolypectomy surveillance plan in patients with these lesions. We focus on sessile serrated polyps, the most common form of serrated polyp with cancerous potential, since it may be one of our greatest challenges in optimal colorectal cancer prevention.

CLINICAL SCENARIO

A 65-year-old woman with no family history of colorectal cancer undergoes screening colonoscopy, during which three polyps are found and removed—a 3-mm tubular adenoma in the sigmoid colon, an 8-mm sessile serrated polyp at the hepatic flexure, and a 2-mm hyperplastic polyp in the rectum. When should she undergo follow-up colonoscopy?

Based on the number, size, and pathologic makeup of the polyps in this patient, we would recommend follow-up surveillance colonoscopy in 5 years.

THE SERRATED POLYP PATHWAY: A DIFFERENT PATH TO COLORECTAL CANCER

Colorectal cancer is the third most common cancer in the United States.¹ From 70% to 80% of these cancers arise from adenomatous polyps via the adenoma-carcinoma pathway. This molecular pathway develops through chromosomal instability (CIN) and involves the loss of heterozygosity (the loss of function of one allele). This leads to the progressive accumulation of mutations in tumor-suppressor genes such as adenomatous polyposis coli (APC) and p53, and oncogenes such as KRAS. The result of these mutations is the development of adenomatous polyps that lead to microsatellite-stable colorectal cancers (Figure 1).²

More recently, studies have shown that the other 20% to 30% of colorectal cancers likely arise through a separate pathway, called the serrated polyp pathway or serrated neoplasia pathway. In contrast to CIN, this pathway is characterized by methylation of CpG islands (CIMP–CpG island methylation phenotype, CIMP) in the promoter regions of specific genes.³ Central to the serrated polyp pathway is progressive methylation in colonic mucosa; mutation in the BRAF oncogene, activating cell proliferation leading to a sessile serrated polyp; and epigenetic silencing of the DNA mismatch repair gene hMLH1, which is a key step in the progression to a sessile serrated polyp with dysplasia, which may rapidly become a microsatellite-unstable colorectal cancer.⁴

Histologically, serrated polyps have a serrated or sawtooth appearance from the folding in of the crypt epithelium, and they include hyperplastic polyps, traditional serrated adenomas, and sessile serrated polyps (sessile serrated adenomas).

Sessile serrated polyps and traditional serrated adenomas (which are rare) are thought to be precancerous, whereas hyperplastic polyps do not have malignant potential.

COMMON, BUT PREVALENCE IS NOT CLEARLY ESTABLISHED

The histologic criteria for sessile serrated polyps and traditional serrated adenomas have been elucidated,^4–7 but the epidemiology of these serrated polyps is not clear. Small studies have shown that sessile serrated polyps account for 2% to 9% of all polyps removed at colonoscopy^8–10; however, larger studies are needed to determine the prevalence because detection by an endoscopist and pathologic diagnosis of these polyps are both operator-dependent.

Traditional serrated adenomas are the least common type of serrated polyp, with a reported prevalence of 0.3%.⁷ Hyperplastic polyps are by far the most common, accounting for 20% to 30% of all polyps removed at colonoscopy.^9,11 Sessile serrated polyps have a predilection for the proximal colon and are associated with female sex and with smoking, ^12,13 but no consistent effect of other factors on their formation has been reported. In contrast, Wallace et al¹³ found that obesity, cigarette smoking, dietary fat intake, total caloric intake, and the consumption of red meat were associated with an increased risk of distal (but not proximal) serrated polyps, including hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas.

HYPERPLASTIC POLYPS

Hyperplastic polyps usually occur in the rectosigmoid colon. They appear as slightly elevated, whitish lesions with a diameter less than 5 mm (Figure 2). Microscopically, the serrated architecture is present in the upper half of their crypts (Figure 3). The proliferative zone is more or less normally located in the basal half of the crypt (the nonserrated portion), with nuclei that are small, uniform, and basally located.¹⁴ The bases of the crypts have a rounded contour and do not grow laterally along the muscularis mucosae.

SESSILE SERRATED POLYPS

Endoscopically, sessile serrated polyps are often subtle, appear flat or slightly elevated, and can be covered by yellow mucus (Figure 4). They are typically found in the proximal colon and are usually larger than typical adenomas, with 50% being larger than 10 mm.¹⁰

Histologically, the serrations are more prominent than those of hyperplastic polyps and involve the entire length of the crypt (Figure 5). The crypt bases are often dilated and display lateral growth along the lamina muscularis mucosae, resembling a letter t or l. The lamina muscularis mucosae is often thinner than normal. Crypts from sessile serrated polyps are occasionally found beneath the muscularis mucosae, a condition called pseudoinvasion.⁷

TRADITIONAL SERRATED ADENOMAS

Traditional serrated adenomas are usually left-sided. In contrast to the other types of serrated polyps, they are histologically often villiform and are lined by cells with elongated nuclei and abundant eosinophilic cytoplasm (Figure 6). Unlike those in sessile serrated polyps, the crypt bases do not display an abnormal architecture; rather, traditional serrated adenomas have abundant ectopic crypts (“budding crypts”) in the long, slender villi.⁷

Traditional serrated adenomas also appear to be genetically distinct from sessile serrated polyps. They are most often characterized by a KRAS (or less commonly, BRAF) mutation and commonly have methylation of the DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) rather than hMLH1.

CHALLENGES TO EFFECTIVE COLONOSCOPY

Colonoscopic polypectomy of adenomatous polyps reduces the incidence of colorectal cancer and the rate of death from it.^15,16 However, recent data show that colonoscopy may not be as effective as once thought. As many as 9% of patients with colorectal cancer have had a “normal” colonoscopic examination in the preceding 3 years.^17,18 In addition, the reduction in incidence and mortality rates was less for cancers in the proximal colon than for cancers in the distal colon.^19,20

Possible explanations for this discrepancy include the skill of the endoscopist, technical limitations of the examination, incomplete removal of polyps, and inadequate bowel preparation. Several studies have shown that interval colorectal cancers are more likely to be found in the proximal colon and to have the same molecular characteristics as sessile serrated polyps and the serrated colorectal cancer pathway (CIMP-high and MSI-H).^21,22 Therefore, it is now thought that sessile serrated polyps may account for a substantial portion of “postcolonoscopy cancers” (ie, interval cancers) that arise in the proximal colon.

Two large studies of screening colonoscopy confirmed that the ability to detect sessile serrated polyps depends greatly on the skill of the endoscopist. Hetzel et al⁹ studied the differences in the rates of polyp detection among endoscopists performing more than 7,000 colonoscopies. Detection rates varied significantly for adenomas, hyperplastic polyps, and sessile serrated polyps, with the greatest variability noted in the detection of sessile serrated polyps. Significant variability was also noted in the ability of the pathologist to diagnose sessile serrated polyps.⁹

In the other study, a strong correlation was found between physicians who are “high detectors” of adenomas and their detection rates for proximal serrated polyps.²³ There is widespread acceptance that screening colonoscopy in average-risk patients age 50 and older should detect adenomas in more than 25% of men and more than 15% of women. There is no current minimum recommended detection rate for sessile serrated polyps, but some have suggested 1.5%.⁸

POLYPS AS PREDICTORS OF CANCER RISK

Certain polyp characteristics predict the risk of metachronous, advanced neoplasia. Advanced neoplasms are defined as invasive carcinomas, adenomas 10 mm or larger, or adenomas with any villous histology or high-grade dysplasia. Patients with one or two small tubular adenomas have a much lower risk of metachronous advanced neoplasia than do patients with more than two adenomas or advanced neoplasms.²⁴ Current recommended surveillance intervals vary on that basis (Table 2).²⁵

People who harbor serrated neoplasms are at high risk of synchronous serrated polyps and advanced adenomatous neoplasia. Pai et al²⁶ found that patients with one sessile serrated polyp were four times more likely to have additional serrated polyps at the same time than an unselected population. The authors suggested that this indicates a strong colonic mucosal-field defect in patients with sessile serrated polyps, thereby predisposing them to the development of synchronous serrated polyps.

Li et al²⁷ found that large serrated polyps (ie, > 10 mm) are associated with a risk of synchronous advanced neoplasia that is three times higher than in patients without adenomas. Schreiner et al²⁸ determined that patients with either a proximal or a large serrated polyp were at higher risk of synchronous advanced neoplasia compared with patients who did not have those lesions. Vu et al²⁹ found that patients who have both sessile serrated polyps and conventional adenomas have significantly larger and more numerous lesions of both types.²⁹ In addition, these lesions are more likely to be pathologically advanced when compared with people with only one or the other type.

In the only study of the risk of advanced neoplasia on follow-up colonoscopy,²⁸ patients with advanced neoplasia and proximal serrated polyps at baseline examination were twice as likely to have advanced neoplasia during subsequent surveillance than those with only advanced neoplasia at baseline examination.²⁸

Therefore, it seems clear that the presence of large or proximal serrated polyps or serrated neoplasms predicts the presence of synchronous and likely metachronous advanced neoplasms.

Guidelines for postpolypectomy surveillance for individuals with serrated lesions of the colon have recently been published.²⁵ Patients with large serrated lesions (≥ 10 mm) or an advanced serrated lesion (a sessile serrated polyp with or without cytologic dysplasia or a traditional serrated adenoma) should be followed closely. Patients with small (< 10-mm) rectosigmoid hyperplastic polyps should be followed as average-risk patients. If a patient with a sessile serrated polyp also has adenomas, the surveillance interval should be the shortest interval recommended for either lesion.²⁹

SURVEILLANCE FOR OUR PATIENT

In our patient, given the number, size, and histologic features of the polyps found, surveillance colonoscopy should be considered in 5 years. Although the clinical significance of the serrated pathway to colorectal cancer cannot be argued, further study is required to understand the lifetime risk to patients with serrated neoplasms and the optimal surveillance interval.

Sessile serrated polyps are a type of polyp recently recognized to be a precursor of colorectal cancer. They arise from a pathway of genetic alterations different from the pathway that causes the more common and well-understood conventional adenomas (also called tubular adenomas, tubulovillous adenomas, and villous adenomas).

We do not yet know enough about the lifetime colorectal cancer risk for individuals with sessile serrated polyps, nor do we know the optimal surveillance interval for patients who have these polyps on colonoscopy. It is believed that sessile serrated polyps may be the cause of a substantial number of “interval” colorectal cancers—ie, cancers that occur after colonoscopy but before the next scheduled examination.

Serrated polyps get their name from their jagged appearance on microscopy. In the past, all serrated colorectal lesions were called hyperplastic polyps. But with the advent of molecular and genetic diagnostics and with the ability to recognize the subtle morphologic differences of serrated lesions, they have been reclassified into those without malignant potential (hyperplastic polyps) and those that are neoplastic (sessile serrated polyps and traditional serrated adenomas) (Table 1).

In this article, we discuss the evolving understanding of the different types of serrated polyps, and we offer our thoughts on a reasonable postpolypectomy surveillance plan in patients with these lesions. We focus on sessile serrated polyps, the most common form of serrated polyp with cancerous potential, since it may be one of our greatest challenges in optimal colorectal cancer prevention.

CLINICAL SCENARIO

A 65-year-old woman with no family history of colorectal cancer undergoes screening colonoscopy, during which three polyps are found and removed—a 3-mm tubular adenoma in the sigmoid colon, an 8-mm sessile serrated polyp at the hepatic flexure, and a 2-mm hyperplastic polyp in the rectum. When should she undergo follow-up colonoscopy?

Based on the number, size, and pathologic makeup of the polyps in this patient, we would recommend follow-up surveillance colonoscopy in 5 years.

THE SERRATED POLYP PATHWAY: A DIFFERENT PATH TO COLORECTAL CANCER

Colorectal cancer is the third most common cancer in the United States.¹ From 70% to 80% of these cancers arise from adenomatous polyps via the adenoma-carcinoma pathway. This molecular pathway develops through chromosomal instability (CIN) and involves the loss of heterozygosity (the loss of function of one allele). This leads to the progressive accumulation of mutations in tumor-suppressor genes such as adenomatous polyposis coli (APC) and p53, and oncogenes such as KRAS. The result of these mutations is the development of adenomatous polyps that lead to microsatellite-stable colorectal cancers (Figure 1).²

More recently, studies have shown that the other 20% to 30% of colorectal cancers likely arise through a separate pathway, called the serrated polyp pathway or serrated neoplasia pathway. In contrast to CIN, this pathway is characterized by methylation of CpG islands (CIMP–CpG island methylation phenotype, CIMP) in the promoter regions of specific genes.³ Central to the serrated polyp pathway is progressive methylation in colonic mucosa; mutation in the BRAF oncogene, activating cell proliferation leading to a sessile serrated polyp; and epigenetic silencing of the DNA mismatch repair gene hMLH1, which is a key step in the progression to a sessile serrated polyp with dysplasia, which may rapidly become a microsatellite-unstable colorectal cancer.⁴

Histologically, serrated polyps have a serrated or sawtooth appearance from the folding in of the crypt epithelium, and they include hyperplastic polyps, traditional serrated adenomas, and sessile serrated polyps (sessile serrated adenomas).

Sessile serrated polyps and traditional serrated adenomas (which are rare) are thought to be precancerous, whereas hyperplastic polyps do not have malignant potential.

COMMON, BUT PREVALENCE IS NOT CLEARLY ESTABLISHED

The histologic criteria for sessile serrated polyps and traditional serrated adenomas have been elucidated,^4–7 but the epidemiology of these serrated polyps is not clear. Small studies have shown that sessile serrated polyps account for 2% to 9% of all polyps removed at colonoscopy^8–10; however, larger studies are needed to determine the prevalence because detection by an endoscopist and pathologic diagnosis of these polyps are both operator-dependent.

Traditional serrated adenomas are the least common type of serrated polyp, with a reported prevalence of 0.3%.⁷ Hyperplastic polyps are by far the most common, accounting for 20% to 30% of all polyps removed at colonoscopy.^9,11 Sessile serrated polyps have a predilection for the proximal colon and are associated with female sex and with smoking, ^12,13 but no consistent effect of other factors on their formation has been reported. In contrast, Wallace et al¹³ found that obesity, cigarette smoking, dietary fat intake, total caloric intake, and the consumption of red meat were associated with an increased risk of distal (but not proximal) serrated polyps, including hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas.

HYPERPLASTIC POLYPS

Hyperplastic polyps usually occur in the rectosigmoid colon. They appear as slightly elevated, whitish lesions with a diameter less than 5 mm (Figure 2). Microscopically, the serrated architecture is present in the upper half of their crypts (Figure 3). The proliferative zone is more or less normally located in the basal half of the crypt (the nonserrated portion), with nuclei that are small, uniform, and basally located.¹⁴ The bases of the crypts have a rounded contour and do not grow laterally along the muscularis mucosae.

SESSILE SERRATED POLYPS

Endoscopically, sessile serrated polyps are often subtle, appear flat or slightly elevated, and can be covered by yellow mucus (Figure 4). They are typically found in the proximal colon and are usually larger than typical adenomas, with 50% being larger than 10 mm.¹⁰

Histologically, the serrations are more prominent than those of hyperplastic polyps and involve the entire length of the crypt (Figure 5). The crypt bases are often dilated and display lateral growth along the lamina muscularis mucosae, resembling a letter t or l. The lamina muscularis mucosae is often thinner than normal. Crypts from sessile serrated polyps are occasionally found beneath the muscularis mucosae, a condition called pseudoinvasion.⁷

TRADITIONAL SERRATED ADENOMAS

Traditional serrated adenomas are usually left-sided. In contrast to the other types of serrated polyps, they are histologically often villiform and are lined by cells with elongated nuclei and abundant eosinophilic cytoplasm (Figure 6). Unlike those in sessile serrated polyps, the crypt bases do not display an abnormal architecture; rather, traditional serrated adenomas have abundant ectopic crypts (“budding crypts”) in the long, slender villi.⁷

Traditional serrated adenomas also appear to be genetically distinct from sessile serrated polyps. They are most often characterized by a KRAS (or less commonly, BRAF) mutation and commonly have methylation of the DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) rather than hMLH1.

CHALLENGES TO EFFECTIVE COLONOSCOPY

Colonoscopic polypectomy of adenomatous polyps reduces the incidence of colorectal cancer and the rate of death from it.^15,16 However, recent data show that colonoscopy may not be as effective as once thought. As many as 9% of patients with colorectal cancer have had a “normal” colonoscopic examination in the preceding 3 years.^17,18 In addition, the reduction in incidence and mortality rates was less for cancers in the proximal colon than for cancers in the distal colon.^19,20

Possible explanations for this discrepancy include the skill of the endoscopist, technical limitations of the examination, incomplete removal of polyps, and inadequate bowel preparation. Several studies have shown that interval colorectal cancers are more likely to be found in the proximal colon and to have the same molecular characteristics as sessile serrated polyps and the serrated colorectal cancer pathway (CIMP-high and MSI-H).^21,22 Therefore, it is now thought that sessile serrated polyps may account for a substantial portion of “postcolonoscopy cancers” (ie, interval cancers) that arise in the proximal colon.

Two large studies of screening colonoscopy confirmed that the ability to detect sessile serrated polyps depends greatly on the skill of the endoscopist. Hetzel et al⁹ studied the differences in the rates of polyp detection among endoscopists performing more than 7,000 colonoscopies. Detection rates varied significantly for adenomas, hyperplastic polyps, and sessile serrated polyps, with the greatest variability noted in the detection of sessile serrated polyps. Significant variability was also noted in the ability of the pathologist to diagnose sessile serrated polyps.⁹

In the other study, a strong correlation was found between physicians who are “high detectors” of adenomas and their detection rates for proximal serrated polyps.²³ There is widespread acceptance that screening colonoscopy in average-risk patients age 50 and older should detect adenomas in more than 25% of men and more than 15% of women. There is no current minimum recommended detection rate for sessile serrated polyps, but some have suggested 1.5%.⁸

POLYPS AS PREDICTORS OF CANCER RISK

Certain polyp characteristics predict the risk of metachronous, advanced neoplasia. Advanced neoplasms are defined as invasive carcinomas, adenomas 10 mm or larger, or adenomas with any villous histology or high-grade dysplasia. Patients with one or two small tubular adenomas have a much lower risk of metachronous advanced neoplasia than do patients with more than two adenomas or advanced neoplasms.²⁴ Current recommended surveillance intervals vary on that basis (Table 2).²⁵

People who harbor serrated neoplasms are at high risk of synchronous serrated polyps and advanced adenomatous neoplasia. Pai et al²⁶ found that patients with one sessile serrated polyp were four times more likely to have additional serrated polyps at the same time than an unselected population. The authors suggested that this indicates a strong colonic mucosal-field defect in patients with sessile serrated polyps, thereby predisposing them to the development of synchronous serrated polyps.

Li et al²⁷ found that large serrated polyps (ie, > 10 mm) are associated with a risk of synchronous advanced neoplasia that is three times higher than in patients without adenomas. Schreiner et al²⁸ determined that patients with either a proximal or a large serrated polyp were at higher risk of synchronous advanced neoplasia compared with patients who did not have those lesions. Vu et al²⁹ found that patients who have both sessile serrated polyps and conventional adenomas have significantly larger and more numerous lesions of both types.²⁹ In addition, these lesions are more likely to be pathologically advanced when compared with people with only one or the other type.

In the only study of the risk of advanced neoplasia on follow-up colonoscopy,²⁸ patients with advanced neoplasia and proximal serrated polyps at baseline examination were twice as likely to have advanced neoplasia during subsequent surveillance than those with only advanced neoplasia at baseline examination.²⁸

Therefore, it seems clear that the presence of large or proximal serrated polyps or serrated neoplasms predicts the presence of synchronous and likely metachronous advanced neoplasms.

Guidelines for postpolypectomy surveillance for individuals with serrated lesions of the colon have recently been published.²⁵ Patients with large serrated lesions (≥ 10 mm) or an advanced serrated lesion (a sessile serrated polyp with or without cytologic dysplasia or a traditional serrated adenoma) should be followed closely. Patients with small (< 10-mm) rectosigmoid hyperplastic polyps should be followed as average-risk patients. If a patient with a sessile serrated polyp also has adenomas, the surveillance interval should be the shortest interval recommended for either lesion.²⁹

SURVEILLANCE FOR OUR PATIENT

In our patient, given the number, size, and histologic features of the polyps found, surveillance colonoscopy should be considered in 5 years. Although the clinical significance of the serrated pathway to colorectal cancer cannot be argued, further study is required to understand the lifetime risk to patients with serrated neoplasms and the optimal surveillance interval.

As our population ages, people are thinking more about preserving their quality of life, especially with regard to maintaining their cognitive and functional abilities. Older patients and caregivers often raise concerns about cognitive issues to their primary care providers: many patients have memory complaints, are worried about whether these are merely part of normal aging or symptoms of early dementia, and want strategies to forestall the progression of cognitive impairment.

Mild cognitive impairment (MCI) is a heterogeneous syndrome that in some cases represents a transition between normal aging and dementia. However, this condition is not yet well understood. Although some patients progress to dementia, others remain stable, or even improve. This article will review the current definitions and the underlying physiology of MCI, as well as diagnostic and management strategies.

See related editorial

COGNITIVE CHANGES OCCUR WITH NORMAL AGING

Cognition is defined as a means of acquiring and processing information about ourselves and our world. It includes memory as well as other domains such as attention, visuospatial skills, mental processing speed, language, and executive function. Cognitive abilities typically peak between ages 30 and 40, plateau in our 50s and 60s, and decline in our late 70s.

With age come detectable changes in the brain: brain weight declines by 10% by age 80, blood flow diminishes, neurons are lost throughout life, and nerve conduction slows. Despite these changes, the brain has a great deal of functional reserve capacity.

Table 1 compares the signs of normal aging, MCI, and dementia. Normally, cognitive abilities decline gradually with age without affecting overall function or activities of daily living. Even in normal aging, the processing of new information (new learning) is reduced. Mental processing becomes less efficient and slower. Visuospatial skills gradually decline, recall slows, and ultimately, the speed of performance slows as well. Additionally, distractibility increases. On the other hand, normal aging does not affect recognition, intelligence, or long-term memory.¹

The line between the normal effects of aging on cognition and true pathologic cognitive decline is blurry. In a busy clinical practice, it is often difficult to determine whether problems with memory and cognition that elderly patients and their family members describe represent true pathologic decline. In general, the clinical presentation of MCI is more profound than that of age-associated cognitive impairment: whereas normal aging may involve forgetting names and words and misplacing things, MCI frequently involves forgetting conversations, information that one would ordinarily remember, appointments, and planned events.

BETWEEN NORMAL AGING AND DEMENTIA

MCI is a transitional state between normal cognition and dementia. But the course is not inevitably downward: on follow-up, patients with MCI may be better, stable, or worse (see PROGNOSIS VARIES, below).

On autopsy studies, the brains of people with MCI appear intermediate between normal brains and brains of people with Alzheimer-type dementia, which have neurofibrillary tangles, amyloid senile plaques, and neuronal degeneration.

Definitions of MCI vary

True cognitive decline that is more profound than normal aging was named and defined differently in different studies, making comparisons difficult. The concept of MCI arose from the term “benign senescent forgetfulness,” used by Kral in 1962.² Other early terms include “cognitive impairment no dementia,” “memory impairment,” “mild cognitive disorder,” and “mild neurocognitive disorder.”^3,4

MCI was first defined as a precursor to Alzheimer dementia. The term later described a sometimes reversible but abnormal state. It is a heterogeneous syndrome in terms of etiology, incidence, prevalence, presentation, and overall prognosis.

Most recently, MCI has been defined as^5,6:

• Subjective memory complaints, preferably qualified by another person
• Memory impairment, with consideration for age and education
• Preserved general cognitive function
• Intact activities of daily living
• Absence of overt dementia.

MCI may arise from vascular, neurodegenerative, traumatic, metabolic, psychiatric, and other underlying medical disorders.^7–9

The prevalence of MCI is difficult to determine because of the various definitions, populations studied (eg, clinic-based vs community-dwelling), and evaluation techniques. Published rates vary from 2% to 4% in all patients to 10% to 20% in the elderly. Incidence rates in the elderly vary from 14 to 75 per 1,000 patient-years.^10–14

EARLY RECOGNITION ALLOWS PROMPT EVALUATION AND PLANNING

Pathologic cognitive decline is best detected early, for many reasons. Early recognition and intervention may help delay further decline. Establishing a diagnosis can also lessen family and caregiver stress and misunderstanding. Education of caregivers is important so that they can prepare for likely behavioral changes and plan for future care. Advance care planning, including advance directives, power of attorney, and designation of proxy for decision-making, is extremely important and is best considered before cognitive impairment becomes severe.

The diagnosis of MCI also provides the opportunity to assess safety concerns related to driving, working, medication compliance, the home environment, and firearms. Because patients with MCI are still highly functional, these issues need not be fully evaluated and should be handled on a case-by-case basis, depending on concerns raised. For example, if depression is an active concern, firearms safety should be addressed.

MEMORY LOSS MAY NOT BE THE PRIMARY CONCERN

MCI is categorized into two types based on whether memory loss is the primary cognitive deficit.

The amnestic type predominantly involves memory problems and is more common. Generally, several years elapse between initial memory concerns and a clinical diagnosis of MCI. Patients with amnestic MCI that progresses to dementia are more likely to develop Alzheimer disease.^2,15

Nonamnestic types involve domains of cognition other than memory, such as executive function, attention, visuospatial ability, and language. Nonamnestic MCI can be subcategorized through extensive neuropsychological evaluation as involving single or multiple impaired domains.^16,17 Such categorization is particularly important in determining prognosis, as patients with involvement of multiple domains are at higher risk of progressing to dementia.

Patients with nonamnestic MCI who progress to dementia are more likely to have non-Alzheimer types of dementia, such as Lewy body dementia and frontotemporal dementias.¹⁰

HISTORY SHOULD FOCUS ON FUNCTION, MEDICATIONS, AND DEPRESSION

Cognitive impairment should be clinically evaluated within the context of cognition, function, and behavior. Clinicians should focus on the time course of cognitive concerns, the specifics of the concerns, and their impact on day-to-day living and functioning. In assessing functional capacity, it is important to determine the level of assistance the patient needs to perform specific activities of daily living and instrumental activities of daily living (ie, the more advanced skills needed to live independently) (Table 2).

A thorough history includes consideration of baseline education, intellect, and previous learning disabilities; sensory impairments with emphasis on sight and hearing impairments; uncontrolled pain; head trauma; sleep disorders; concurrent medical and psychosocial illnesses such as depression and anxiety; substance abuse; and polypharmacy.

Depression, delirium, and the use of anticholinergic drugs are particularly important to evaluate, as these can result in cognitive deficits associated with MCI. The cognitive deficits may resolve with treatment or with stopping the drug.

Behavioral concerns such as wandering, agitation, and anger and sleep concerns, eating habits, and social etiquette are also important to evaluate.

PHYSICAL EVALUATION: RULE OUT REVERSIBLE CONDITIONS

The differential diagnosis of MCI includes delirium, depression, dementia, possibly reversible conditions affecting cognition (vitamin B₁₂ deficiency, hypothyroidism, effects of anticholinergic drugs), and uncommonly, central nervous system conditions (normal pressure hydrocephalus, subdural hematoma, tumor, stroke), and others (Table 3).¹⁸

A thorough physical examination should include neurologic, cardiovascular, hearing, and vision examinations, as well as an evaluation of functional status.

Laboratory studies. Although evidence is lacking to support a laboratory diagnostic workup for MCI, a selective evaluation including a comprehensive metabolic profile, complete blood count, thyroid studies, and a vitamin B₁₂ level can be useful. Occasionally, a treatable cause of impaired cognition such as vitamin B₁₂ deficiency or thyroid disease can be identified and resolved. A further comprehensive laboratory evaluation should be obtained if a patient progresses to dementia.

Imaging can be used in conjunction with other supportive evidence but should not be used solely to establish a diagnosis of MCI. Magnetic resonance imaging (MRI) can detect metastatic disease, normal pressure hydrocephalus, and subdural hematoma, in addition to traumatic, inflammatory, infectious, and vascular causes of cognitive impairment. MRI can also determine focal areas of atrophy; temporal lobe atrophy is a risk factor for progression to dementia.

Other studies. Structural MRI using techniques to evaluate the hippocampus, functional imaging, genetic testing for ApoE4 alleles, and biomarkers in cerebrospinal fluid are currently under evaluation to identify those at risk of progression to dementia. Recently published guidelines by the Alzheimer’s Association and the National Institute on Aging indicate that pathophysiologic findings in MCI that may predict future Alzheimer disease are meant to guide research and are not part of clinical practice at this time.¹⁹

COGNITIVE AND NEUROLOGIC TESTING IDENTIFIES DEFICITS

A number of global measures of cognition can be used in the office in clinical practice to help in evaluating significant cognitive concerns and to determine areas and severity of deficits at presentation. These include the Mini-Mental State Examination, the Montreal Cognitive Assessment, the Saint Louis University Mental Status, and many others (Table 4).²⁰

Caveats about interpreting the results: each of these tests has different sensitivities and specificities for detecting MCI. Also, we need to take into account the patient’s level of education, as highly educated people tend to do better on these tests.^21–23 It is important to note that some patients with MCI have normal results or only minimally abnormal results on these tests.

Neuropsychological testing is reserved for patients needing further evaluation, eg, those with atypical or complex cases, and those in whom the specific domains of cognition involved need to be identified. It can also provide additional insight into the contribution of depression to cognitive deficits. Neuropsychological testing is usually very time-intensive and requires patients to be able to perform complicated cognitive tasks. Not all patients are good candidates for this testing; sensory and motor impairments must be considered to determine if patients can adequately participate in testing. The cost of neuropsychological testing for MCI may not be covered by insurance and should be discussed with patients before referral. Specific concerns about cognitive problems that need further evaluation should be stated in the referral.

No one test should be used to make a diagnosis of MCI or dementia; clinical judgment is also necessary. The need for referral to a neurologist, geriatrician, or psychiatrist depends on the nature of the cognitive and behavioral concerns, the complexity of making a diagnosis, the need for further assessment of functional ability, and the need for evaluation of risk of progression to dementia.

MEDICATIONS HAVE LITTLE ROLE IN MANAGEMENT

No drug has yet been approved by the US Food and Drug Administration for treating MCI.

The acetylcholinesterase inhibitors donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) have undergone clinical trials for treatment of MCI but have not been definitely shown to significantly reduce the risk of progression to dementia.²⁴

On the other hand, Diniz et al²⁵ performed a meta-analysis of the use of cholinesterase inhibitors in patients with MCI as a means of delaying the progression to Alzheimer disease.²⁵ They calculated that 15.4% of patients who received these drugs progressed to dementia, compared with 20.4% of those who received placebo, for a relative risk of 0.75 (95% confidence interval 0.66–0.87, P < .001). They concluded that the use of these drugs in patients with MCI “may attenuate the risk of progression” to Alzheimer disease and dementia.

In addition to not being approved for this indication and showing mixed evidence of efficacy, these drugs have well-known side effects such as diarrhea, nausea, vomiting, anorexia, and rhinitis, as well as significant but lesser-known side effects such as syncope, bradycardia, gastrointestinal bleeding, and vivid dreams.²⁶

Nevertheless, some patients with MCI, particularly those at high risk with amnestic MCI, may still want to try these medications. In these cases, the risks and possible benefits (or lack of them) should be reviewed thoroughly with the patient and family, and the discussion should be documented before starting therapy. The lowest starting dose of acetylcholinesterase inhibitor should be used to determine tolerability; generally, the dose is increased after 4 weeks to a maintenance dosage, with particular consideration of side effects.

Other agents have also been evaluated for MCI but have shown no evidence of benefit. Nonsteroidal anti-inflammatory drugs have not been found to either improve symptoms or delay progression to dementia. Ginkgo biloba has shown unclear benefit in achieving important treatment goals for MCI,²⁷ and it increases the risk of bleeding in the elderly. Vitamin E was evaluated in one study and did not slow progression to dementia.²⁸

STAYING HEALTHY AND ACTIVE MAY HELP

We recommend optimizing vascular risk factors such as diabetes, blood pressure, smoking, and lipid levels in managing MCI, given that uncontrolled vascular risk factors may lead to progression to dementia. However, we can point to no research to support this recommendation.

Cognitive rehabilitation involves training in deficient domains and developing strategies to compensate for deficits. Different interventions are used, including computerized simulation exercises, memory aids, organizational techniques, personal digital assistants, crossword puzzles, mind games, and other mentally engaging activities.²⁹

Increasing physical activity is another aspect of treatment. Some studies have shown that it improves cognitive performance in MCI, at least in the short term.^30,31

Optimizing mood and emotions is also important. If present, depression should be identified and optimally treated. Social activity can be useful and leads to less emotional stress and to better coping mechanisms.

A multidisciplinary approach may help patients and may also help relieve the burden on the caregiver. Periodic reassessment of cognitive and functional symptoms may be warranted.

Maintaining disease-specific registries of patients who have MCI may be useful to longitudinally follow patients and ensure that they get the care they need.

PROGNOSIS VARIES

MCI is a heterogeneous condition that often does not predictably progress to dementia. Patients and families should be told that having MCI does not mean that the patient will necessarily get dementia.

Several studies have shown that the annual risk of progression to dementia for patients with MCI is 5% to 10% in community-dwelling populations and up to 15% in specialty-clinic patients.^24,32 In comparison, the incidence of dementia in the general elderly population is 1% to 3% per year.

On the other hand, a number of studies show that MCI improves significantly in up to 15% to 40% of patients and sometimes reverts to a normal cognitive state.^33,34 But prospective studies of patients with clinically diagnosed MCI usually find a low rate of reversion to a normal state.^35,36 Many are short-term follow-up studies of different populations, making generalizations difficult.¹⁴

Patients with impairment in instrumental activities of daily living may be more likely to have nonreversible MCI and may be at higher risk of progressing to dementia.³⁷

PATIENT AND FAMILY EDUCATION AND FOLLOW-UP CONSIDERATIONS

Caregiver education and stress management are important components of managing patients with MCI. Formally assessing caregiver stress is useful. Steps to prevent caregiver burnout include making use of respite care, counseling, education, and community resources such as adult day care and those offered by the Alzheimer’s Association.

Clinicians should follow patients with MCI closely to evaluate progression, address specific concerns, minimize risks, emphasize healthy habits, manage concurrent illnesses, and evaluate management.

Functional status, as demonstrated by activities of daily living, is the most important determinant of progression of MCI to dementia and should be evaluated at each visit. Repeat cognitive testing should be done on patients who have significant loss of functional status. Changes in work habits also warrant further attention.

Patients diagnosed with MCI or those who have persistent cognitive concerns should be considered for neuropsychological evaluation after 1 year to assess specific deficits and progression of cognitive impairment.

Finally, consideration should be given to current clinical research, and referrals should be made to research centers that focus on MCI management and treatment.

As our population ages, people are thinking more about preserving their quality of life, especially with regard to maintaining their cognitive and functional abilities. Older patients and caregivers often raise concerns about cognitive issues to their primary care providers: many patients have memory complaints, are worried about whether these are merely part of normal aging or symptoms of early dementia, and want strategies to forestall the progression of cognitive impairment.

Mild cognitive impairment (MCI) is a heterogeneous syndrome that in some cases represents a transition between normal aging and dementia. However, this condition is not yet well understood. Although some patients progress to dementia, others remain stable, or even improve. This article will review the current definitions and the underlying physiology of MCI, as well as diagnostic and management strategies.

See related editorial

COGNITIVE CHANGES OCCUR WITH NORMAL AGING

Cognition is defined as a means of acquiring and processing information about ourselves and our world. It includes memory as well as other domains such as attention, visuospatial skills, mental processing speed, language, and executive function. Cognitive abilities typically peak between ages 30 and 40, plateau in our 50s and 60s, and decline in our late 70s.

With age come detectable changes in the brain: brain weight declines by 10% by age 80, blood flow diminishes, neurons are lost throughout life, and nerve conduction slows. Despite these changes, the brain has a great deal of functional reserve capacity.

Table 1 compares the signs of normal aging, MCI, and dementia. Normally, cognitive abilities decline gradually with age without affecting overall function or activities of daily living. Even in normal aging, the processing of new information (new learning) is reduced. Mental processing becomes less efficient and slower. Visuospatial skills gradually decline, recall slows, and ultimately, the speed of performance slows as well. Additionally, distractibility increases. On the other hand, normal aging does not affect recognition, intelligence, or long-term memory.¹

The line between the normal effects of aging on cognition and true pathologic cognitive decline is blurry. In a busy clinical practice, it is often difficult to determine whether problems with memory and cognition that elderly patients and their family members describe represent true pathologic decline. In general, the clinical presentation of MCI is more profound than that of age-associated cognitive impairment: whereas normal aging may involve forgetting names and words and misplacing things, MCI frequently involves forgetting conversations, information that one would ordinarily remember, appointments, and planned events.

BETWEEN NORMAL AGING AND DEMENTIA

MCI is a transitional state between normal cognition and dementia. But the course is not inevitably downward: on follow-up, patients with MCI may be better, stable, or worse (see PROGNOSIS VARIES, below).

On autopsy studies, the brains of people with MCI appear intermediate between normal brains and brains of people with Alzheimer-type dementia, which have neurofibrillary tangles, amyloid senile plaques, and neuronal degeneration.

Definitions of MCI vary

True cognitive decline that is more profound than normal aging was named and defined differently in different studies, making comparisons difficult. The concept of MCI arose from the term “benign senescent forgetfulness,” used by Kral in 1962.² Other early terms include “cognitive impairment no dementia,” “memory impairment,” “mild cognitive disorder,” and “mild neurocognitive disorder.”^3,4

MCI was first defined as a precursor to Alzheimer dementia. The term later described a sometimes reversible but abnormal state. It is a heterogeneous syndrome in terms of etiology, incidence, prevalence, presentation, and overall prognosis.

Most recently, MCI has been defined as^5,6:

• Subjective memory complaints, preferably qualified by another person
• Memory impairment, with consideration for age and education
• Preserved general cognitive function
• Intact activities of daily living
• Absence of overt dementia.

MCI may arise from vascular, neurodegenerative, traumatic, metabolic, psychiatric, and other underlying medical disorders.^7–9

The prevalence of MCI is difficult to determine because of the various definitions, populations studied (eg, clinic-based vs community-dwelling), and evaluation techniques. Published rates vary from 2% to 4% in all patients to 10% to 20% in the elderly. Incidence rates in the elderly vary from 14 to 75 per 1,000 patient-years.^10–14

EARLY RECOGNITION ALLOWS PROMPT EVALUATION AND PLANNING

Pathologic cognitive decline is best detected early, for many reasons. Early recognition and intervention may help delay further decline. Establishing a diagnosis can also lessen family and caregiver stress and misunderstanding. Education of caregivers is important so that they can prepare for likely behavioral changes and plan for future care. Advance care planning, including advance directives, power of attorney, and designation of proxy for decision-making, is extremely important and is best considered before cognitive impairment becomes severe.

The diagnosis of MCI also provides the opportunity to assess safety concerns related to driving, working, medication compliance, the home environment, and firearms. Because patients with MCI are still highly functional, these issues need not be fully evaluated and should be handled on a case-by-case basis, depending on concerns raised. For example, if depression is an active concern, firearms safety should be addressed.

MEMORY LOSS MAY NOT BE THE PRIMARY CONCERN

MCI is categorized into two types based on whether memory loss is the primary cognitive deficit.

The amnestic type predominantly involves memory problems and is more common. Generally, several years elapse between initial memory concerns and a clinical diagnosis of MCI. Patients with amnestic MCI that progresses to dementia are more likely to develop Alzheimer disease.^2,15

Nonamnestic types involve domains of cognition other than memory, such as executive function, attention, visuospatial ability, and language. Nonamnestic MCI can be subcategorized through extensive neuropsychological evaluation as involving single or multiple impaired domains.^16,17 Such categorization is particularly important in determining prognosis, as patients with involvement of multiple domains are at higher risk of progressing to dementia.

Patients with nonamnestic MCI who progress to dementia are more likely to have non-Alzheimer types of dementia, such as Lewy body dementia and frontotemporal dementias.¹⁰

HISTORY SHOULD FOCUS ON FUNCTION, MEDICATIONS, AND DEPRESSION

Cognitive impairment should be clinically evaluated within the context of cognition, function, and behavior. Clinicians should focus on the time course of cognitive concerns, the specifics of the concerns, and their impact on day-to-day living and functioning. In assessing functional capacity, it is important to determine the level of assistance the patient needs to perform specific activities of daily living and instrumental activities of daily living (ie, the more advanced skills needed to live independently) (Table 2).

A thorough history includes consideration of baseline education, intellect, and previous learning disabilities; sensory impairments with emphasis on sight and hearing impairments; uncontrolled pain; head trauma; sleep disorders; concurrent medical and psychosocial illnesses such as depression and anxiety; substance abuse; and polypharmacy.

Depression, delirium, and the use of anticholinergic drugs are particularly important to evaluate, as these can result in cognitive deficits associated with MCI. The cognitive deficits may resolve with treatment or with stopping the drug.

Behavioral concerns such as wandering, agitation, and anger and sleep concerns, eating habits, and social etiquette are also important to evaluate.

PHYSICAL EVALUATION: RULE OUT REVERSIBLE CONDITIONS

The differential diagnosis of MCI includes delirium, depression, dementia, possibly reversible conditions affecting cognition (vitamin B₁₂ deficiency, hypothyroidism, effects of anticholinergic drugs), and uncommonly, central nervous system conditions (normal pressure hydrocephalus, subdural hematoma, tumor, stroke), and others (Table 3).¹⁸

A thorough physical examination should include neurologic, cardiovascular, hearing, and vision examinations, as well as an evaluation of functional status.

Laboratory studies. Although evidence is lacking to support a laboratory diagnostic workup for MCI, a selective evaluation including a comprehensive metabolic profile, complete blood count, thyroid studies, and a vitamin B₁₂ level can be useful. Occasionally, a treatable cause of impaired cognition such as vitamin B₁₂ deficiency or thyroid disease can be identified and resolved. A further comprehensive laboratory evaluation should be obtained if a patient progresses to dementia.

Imaging can be used in conjunction with other supportive evidence but should not be used solely to establish a diagnosis of MCI. Magnetic resonance imaging (MRI) can detect metastatic disease, normal pressure hydrocephalus, and subdural hematoma, in addition to traumatic, inflammatory, infectious, and vascular causes of cognitive impairment. MRI can also determine focal areas of atrophy; temporal lobe atrophy is a risk factor for progression to dementia.

Other studies. Structural MRI using techniques to evaluate the hippocampus, functional imaging, genetic testing for ApoE4 alleles, and biomarkers in cerebrospinal fluid are currently under evaluation to identify those at risk of progression to dementia. Recently published guidelines by the Alzheimer’s Association and the National Institute on Aging indicate that pathophysiologic findings in MCI that may predict future Alzheimer disease are meant to guide research and are not part of clinical practice at this time.¹⁹

COGNITIVE AND NEUROLOGIC TESTING IDENTIFIES DEFICITS

A number of global measures of cognition can be used in the office in clinical practice to help in evaluating significant cognitive concerns and to determine areas and severity of deficits at presentation. These include the Mini-Mental State Examination, the Montreal Cognitive Assessment, the Saint Louis University Mental Status, and many others (Table 4).²⁰

Caveats about interpreting the results: each of these tests has different sensitivities and specificities for detecting MCI. Also, we need to take into account the patient’s level of education, as highly educated people tend to do better on these tests.^21–23 It is important to note that some patients with MCI have normal results or only minimally abnormal results on these tests.

Neuropsychological testing is reserved for patients needing further evaluation, eg, those with atypical or complex cases, and those in whom the specific domains of cognition involved need to be identified. It can also provide additional insight into the contribution of depression to cognitive deficits. Neuropsychological testing is usually very time-intensive and requires patients to be able to perform complicated cognitive tasks. Not all patients are good candidates for this testing; sensory and motor impairments must be considered to determine if patients can adequately participate in testing. The cost of neuropsychological testing for MCI may not be covered by insurance and should be discussed with patients before referral. Specific concerns about cognitive problems that need further evaluation should be stated in the referral.

No one test should be used to make a diagnosis of MCI or dementia; clinical judgment is also necessary. The need for referral to a neurologist, geriatrician, or psychiatrist depends on the nature of the cognitive and behavioral concerns, the complexity of making a diagnosis, the need for further assessment of functional ability, and the need for evaluation of risk of progression to dementia.

MEDICATIONS HAVE LITTLE ROLE IN MANAGEMENT

No drug has yet been approved by the US Food and Drug Administration for treating MCI.

The acetylcholinesterase inhibitors donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) have undergone clinical trials for treatment of MCI but have not been definitely shown to significantly reduce the risk of progression to dementia.²⁴

On the other hand, Diniz et al²⁵ performed a meta-analysis of the use of cholinesterase inhibitors in patients with MCI as a means of delaying the progression to Alzheimer disease.²⁵ They calculated that 15.4% of patients who received these drugs progressed to dementia, compared with 20.4% of those who received placebo, for a relative risk of 0.75 (95% confidence interval 0.66–0.87, P < .001). They concluded that the use of these drugs in patients with MCI “may attenuate the risk of progression” to Alzheimer disease and dementia.

In addition to not being approved for this indication and showing mixed evidence of efficacy, these drugs have well-known side effects such as diarrhea, nausea, vomiting, anorexia, and rhinitis, as well as significant but lesser-known side effects such as syncope, bradycardia, gastrointestinal bleeding, and vivid dreams.²⁶

Nevertheless, some patients with MCI, particularly those at high risk with amnestic MCI, may still want to try these medications. In these cases, the risks and possible benefits (or lack of them) should be reviewed thoroughly with the patient and family, and the discussion should be documented before starting therapy. The lowest starting dose of acetylcholinesterase inhibitor should be used to determine tolerability; generally, the dose is increased after 4 weeks to a maintenance dosage, with particular consideration of side effects.

Other agents have also been evaluated for MCI but have shown no evidence of benefit. Nonsteroidal anti-inflammatory drugs have not been found to either improve symptoms or delay progression to dementia. Ginkgo biloba has shown unclear benefit in achieving important treatment goals for MCI,²⁷ and it increases the risk of bleeding in the elderly. Vitamin E was evaluated in one study and did not slow progression to dementia.²⁸

STAYING HEALTHY AND ACTIVE MAY HELP

We recommend optimizing vascular risk factors such as diabetes, blood pressure, smoking, and lipid levels in managing MCI, given that uncontrolled vascular risk factors may lead to progression to dementia. However, we can point to no research to support this recommendation.

Cognitive rehabilitation involves training in deficient domains and developing strategies to compensate for deficits. Different interventions are used, including computerized simulation exercises, memory aids, organizational techniques, personal digital assistants, crossword puzzles, mind games, and other mentally engaging activities.²⁹

Increasing physical activity is another aspect of treatment. Some studies have shown that it improves cognitive performance in MCI, at least in the short term.^30,31

Optimizing mood and emotions is also important. If present, depression should be identified and optimally treated. Social activity can be useful and leads to less emotional stress and to better coping mechanisms.

A multidisciplinary approach may help patients and may also help relieve the burden on the caregiver. Periodic reassessment of cognitive and functional symptoms may be warranted.

Maintaining disease-specific registries of patients who have MCI may be useful to longitudinally follow patients and ensure that they get the care they need.

PROGNOSIS VARIES

MCI is a heterogeneous condition that often does not predictably progress to dementia. Patients and families should be told that having MCI does not mean that the patient will necessarily get dementia.

Several studies have shown that the annual risk of progression to dementia for patients with MCI is 5% to 10% in community-dwelling populations and up to 15% in specialty-clinic patients.^24,32 In comparison, the incidence of dementia in the general elderly population is 1% to 3% per year.

On the other hand, a number of studies show that MCI improves significantly in up to 15% to 40% of patients and sometimes reverts to a normal cognitive state.^33,34 But prospective studies of patients with clinically diagnosed MCI usually find a low rate of reversion to a normal state.^35,36 Many are short-term follow-up studies of different populations, making generalizations difficult.¹⁴

Patients with impairment in instrumental activities of daily living may be more likely to have nonreversible MCI and may be at higher risk of progressing to dementia.³⁷

PATIENT AND FAMILY EDUCATION AND FOLLOW-UP CONSIDERATIONS

Caregiver education and stress management are important components of managing patients with MCI. Formally assessing caregiver stress is useful. Steps to prevent caregiver burnout include making use of respite care, counseling, education, and community resources such as adult day care and those offered by the Alzheimer’s Association.

Clinicians should follow patients with MCI closely to evaluate progression, address specific concerns, minimize risks, emphasize healthy habits, manage concurrent illnesses, and evaluate management.

Functional status, as demonstrated by activities of daily living, is the most important determinant of progression of MCI to dementia and should be evaluated at each visit. Repeat cognitive testing should be done on patients who have significant loss of functional status. Changes in work habits also warrant further attention.

Patients diagnosed with MCI or those who have persistent cognitive concerns should be considered for neuropsychological evaluation after 1 year to assess specific deficits and progression of cognitive impairment.

Finally, consideration should be given to current clinical research, and referrals should be made to research centers that focus on MCI management and treatment.

As our population ages, people are thinking more about preserving their quality of life, especially with regard to maintaining their cognitive and functional abilities. Older patients and caregivers often raise concerns about cognitive issues to their primary care providers: many patients have memory complaints, are worried about whether these are merely part of normal aging or symptoms of early dementia, and want strategies to forestall the progression of cognitive impairment.

Mild cognitive impairment (MCI) is a heterogeneous syndrome that in some cases represents a transition between normal aging and dementia. However, this condition is not yet well understood. Although some patients progress to dementia, others remain stable, or even improve. This article will review the current definitions and the underlying physiology of MCI, as well as diagnostic and management strategies.

See related editorial

COGNITIVE CHANGES OCCUR WITH NORMAL AGING

Cognition is defined as a means of acquiring and processing information about ourselves and our world. It includes memory as well as other domains such as attention, visuospatial skills, mental processing speed, language, and executive function. Cognitive abilities typically peak between ages 30 and 40, plateau in our 50s and 60s, and decline in our late 70s.

With age come detectable changes in the brain: brain weight declines by 10% by age 80, blood flow diminishes, neurons are lost throughout life, and nerve conduction slows. Despite these changes, the brain has a great deal of functional reserve capacity.

Table 1 compares the signs of normal aging, MCI, and dementia. Normally, cognitive abilities decline gradually with age without affecting overall function or activities of daily living. Even in normal aging, the processing of new information (new learning) is reduced. Mental processing becomes less efficient and slower. Visuospatial skills gradually decline, recall slows, and ultimately, the speed of performance slows as well. Additionally, distractibility increases. On the other hand, normal aging does not affect recognition, intelligence, or long-term memory.¹

The line between the normal effects of aging on cognition and true pathologic cognitive decline is blurry. In a busy clinical practice, it is often difficult to determine whether problems with memory and cognition that elderly patients and their family members describe represent true pathologic decline. In general, the clinical presentation of MCI is more profound than that of age-associated cognitive impairment: whereas normal aging may involve forgetting names and words and misplacing things, MCI frequently involves forgetting conversations, information that one would ordinarily remember, appointments, and planned events.

BETWEEN NORMAL AGING AND DEMENTIA

MCI is a transitional state between normal cognition and dementia. But the course is not inevitably downward: on follow-up, patients with MCI may be better, stable, or worse (see PROGNOSIS VARIES, below).

On autopsy studies, the brains of people with MCI appear intermediate between normal brains and brains of people with Alzheimer-type dementia, which have neurofibrillary tangles, amyloid senile plaques, and neuronal degeneration.

Definitions of MCI vary

True cognitive decline that is more profound than normal aging was named and defined differently in different studies, making comparisons difficult. The concept of MCI arose from the term “benign senescent forgetfulness,” used by Kral in 1962.² Other early terms include “cognitive impairment no dementia,” “memory impairment,” “mild cognitive disorder,” and “mild neurocognitive disorder.”^3,4

MCI was first defined as a precursor to Alzheimer dementia. The term later described a sometimes reversible but abnormal state. It is a heterogeneous syndrome in terms of etiology, incidence, prevalence, presentation, and overall prognosis.

Most recently, MCI has been defined as^5,6:

• Subjective memory complaints, preferably qualified by another person
• Memory impairment, with consideration for age and education
• Preserved general cognitive function
• Intact activities of daily living
• Absence of overt dementia.

MCI may arise from vascular, neurodegenerative, traumatic, metabolic, psychiatric, and other underlying medical disorders.^7–9

The prevalence of MCI is difficult to determine because of the various definitions, populations studied (eg, clinic-based vs community-dwelling), and evaluation techniques. Published rates vary from 2% to 4% in all patients to 10% to 20% in the elderly. Incidence rates in the elderly vary from 14 to 75 per 1,000 patient-years.^10–14

EARLY RECOGNITION ALLOWS PROMPT EVALUATION AND PLANNING

Pathologic cognitive decline is best detected early, for many reasons. Early recognition and intervention may help delay further decline. Establishing a diagnosis can also lessen family and caregiver stress and misunderstanding. Education of caregivers is important so that they can prepare for likely behavioral changes and plan for future care. Advance care planning, including advance directives, power of attorney, and designation of proxy for decision-making, is extremely important and is best considered before cognitive impairment becomes severe.

The diagnosis of MCI also provides the opportunity to assess safety concerns related to driving, working, medication compliance, the home environment, and firearms. Because patients with MCI are still highly functional, these issues need not be fully evaluated and should be handled on a case-by-case basis, depending on concerns raised. For example, if depression is an active concern, firearms safety should be addressed.

MEMORY LOSS MAY NOT BE THE PRIMARY CONCERN

MCI is categorized into two types based on whether memory loss is the primary cognitive deficit.

The amnestic type predominantly involves memory problems and is more common. Generally, several years elapse between initial memory concerns and a clinical diagnosis of MCI. Patients with amnestic MCI that progresses to dementia are more likely to develop Alzheimer disease.^2,15

Nonamnestic types involve domains of cognition other than memory, such as executive function, attention, visuospatial ability, and language. Nonamnestic MCI can be subcategorized through extensive neuropsychological evaluation as involving single or multiple impaired domains.^16,17 Such categorization is particularly important in determining prognosis, as patients with involvement of multiple domains are at higher risk of progressing to dementia.

Patients with nonamnestic MCI who progress to dementia are more likely to have non-Alzheimer types of dementia, such as Lewy body dementia and frontotemporal dementias.¹⁰

HISTORY SHOULD FOCUS ON FUNCTION, MEDICATIONS, AND DEPRESSION

Cognitive impairment should be clinically evaluated within the context of cognition, function, and behavior. Clinicians should focus on the time course of cognitive concerns, the specifics of the concerns, and their impact on day-to-day living and functioning. In assessing functional capacity, it is important to determine the level of assistance the patient needs to perform specific activities of daily living and instrumental activities of daily living (ie, the more advanced skills needed to live independently) (Table 2).

A thorough history includes consideration of baseline education, intellect, and previous learning disabilities; sensory impairments with emphasis on sight and hearing impairments; uncontrolled pain; head trauma; sleep disorders; concurrent medical and psychosocial illnesses such as depression and anxiety; substance abuse; and polypharmacy.

Depression, delirium, and the use of anticholinergic drugs are particularly important to evaluate, as these can result in cognitive deficits associated with MCI. The cognitive deficits may resolve with treatment or with stopping the drug.

Behavioral concerns such as wandering, agitation, and anger and sleep concerns, eating habits, and social etiquette are also important to evaluate.

PHYSICAL EVALUATION: RULE OUT REVERSIBLE CONDITIONS

The differential diagnosis of MCI includes delirium, depression, dementia, possibly reversible conditions affecting cognition (vitamin B₁₂ deficiency, hypothyroidism, effects of anticholinergic drugs), and uncommonly, central nervous system conditions (normal pressure hydrocephalus, subdural hematoma, tumor, stroke), and others (Table 3).¹⁸

A thorough physical examination should include neurologic, cardiovascular, hearing, and vision examinations, as well as an evaluation of functional status.

Laboratory studies. Although evidence is lacking to support a laboratory diagnostic workup for MCI, a selective evaluation including a comprehensive metabolic profile, complete blood count, thyroid studies, and a vitamin B₁₂ level can be useful. Occasionally, a treatable cause of impaired cognition such as vitamin B₁₂ deficiency or thyroid disease can be identified and resolved. A further comprehensive laboratory evaluation should be obtained if a patient progresses to dementia.

Imaging can be used in conjunction with other supportive evidence but should not be used solely to establish a diagnosis of MCI. Magnetic resonance imaging (MRI) can detect metastatic disease, normal pressure hydrocephalus, and subdural hematoma, in addition to traumatic, inflammatory, infectious, and vascular causes of cognitive impairment. MRI can also determine focal areas of atrophy; temporal lobe atrophy is a risk factor for progression to dementia.

Other studies. Structural MRI using techniques to evaluate the hippocampus, functional imaging, genetic testing for ApoE4 alleles, and biomarkers in cerebrospinal fluid are currently under evaluation to identify those at risk of progression to dementia. Recently published guidelines by the Alzheimer’s Association and the National Institute on Aging indicate that pathophysiologic findings in MCI that may predict future Alzheimer disease are meant to guide research and are not part of clinical practice at this time.¹⁹

COGNITIVE AND NEUROLOGIC TESTING IDENTIFIES DEFICITS

A number of global measures of cognition can be used in the office in clinical practice to help in evaluating significant cognitive concerns and to determine areas and severity of deficits at presentation. These include the Mini-Mental State Examination, the Montreal Cognitive Assessment, the Saint Louis University Mental Status, and many others (Table 4).²⁰

Caveats about interpreting the results: each of these tests has different sensitivities and specificities for detecting MCI. Also, we need to take into account the patient’s level of education, as highly educated people tend to do better on these tests.^21–23 It is important to note that some patients with MCI have normal results or only minimally abnormal results on these tests.

Neuropsychological testing is reserved for patients needing further evaluation, eg, those with atypical or complex cases, and those in whom the specific domains of cognition involved need to be identified. It can also provide additional insight into the contribution of depression to cognitive deficits. Neuropsychological testing is usually very time-intensive and requires patients to be able to perform complicated cognitive tasks. Not all patients are good candidates for this testing; sensory and motor impairments must be considered to determine if patients can adequately participate in testing. The cost of neuropsychological testing for MCI may not be covered by insurance and should be discussed with patients before referral. Specific concerns about cognitive problems that need further evaluation should be stated in the referral.

No one test should be used to make a diagnosis of MCI or dementia; clinical judgment is also necessary. The need for referral to a neurologist, geriatrician, or psychiatrist depends on the nature of the cognitive and behavioral concerns, the complexity of making a diagnosis, the need for further assessment of functional ability, and the need for evaluation of risk of progression to dementia.

MEDICATIONS HAVE LITTLE ROLE IN MANAGEMENT

No drug has yet been approved by the US Food and Drug Administration for treating MCI.

The acetylcholinesterase inhibitors donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) have undergone clinical trials for treatment of MCI but have not been definitely shown to significantly reduce the risk of progression to dementia.²⁴

On the other hand, Diniz et al²⁵ performed a meta-analysis of the use of cholinesterase inhibitors in patients with MCI as a means of delaying the progression to Alzheimer disease.²⁵ They calculated that 15.4% of patients who received these drugs progressed to dementia, compared with 20.4% of those who received placebo, for a relative risk of 0.75 (95% confidence interval 0.66–0.87, P < .001). They concluded that the use of these drugs in patients with MCI “may attenuate the risk of progression” to Alzheimer disease and dementia.

In addition to not being approved for this indication and showing mixed evidence of efficacy, these drugs have well-known side effects such as diarrhea, nausea, vomiting, anorexia, and rhinitis, as well as significant but lesser-known side effects such as syncope, bradycardia, gastrointestinal bleeding, and vivid dreams.²⁶

Nevertheless, some patients with MCI, particularly those at high risk with amnestic MCI, may still want to try these medications. In these cases, the risks and possible benefits (or lack of them) should be reviewed thoroughly with the patient and family, and the discussion should be documented before starting therapy. The lowest starting dose of acetylcholinesterase inhibitor should be used to determine tolerability; generally, the dose is increased after 4 weeks to a maintenance dosage, with particular consideration of side effects.

Other agents have also been evaluated for MCI but have shown no evidence of benefit. Nonsteroidal anti-inflammatory drugs have not been found to either improve symptoms or delay progression to dementia. Ginkgo biloba has shown unclear benefit in achieving important treatment goals for MCI,²⁷ and it increases the risk of bleeding in the elderly. Vitamin E was evaluated in one study and did not slow progression to dementia.²⁸

STAYING HEALTHY AND ACTIVE MAY HELP

We recommend optimizing vascular risk factors such as diabetes, blood pressure, smoking, and lipid levels in managing MCI, given that uncontrolled vascular risk factors may lead to progression to dementia. However, we can point to no research to support this recommendation.

Cognitive rehabilitation involves training in deficient domains and developing strategies to compensate for deficits. Different interventions are used, including computerized simulation exercises, memory aids, organizational techniques, personal digital assistants, crossword puzzles, mind games, and other mentally engaging activities.²⁹

Increasing physical activity is another aspect of treatment. Some studies have shown that it improves cognitive performance in MCI, at least in the short term.^30,31

Optimizing mood and emotions is also important. If present, depression should be identified and optimally treated. Social activity can be useful and leads to less emotional stress and to better coping mechanisms.

A multidisciplinary approach may help patients and may also help relieve the burden on the caregiver. Periodic reassessment of cognitive and functional symptoms may be warranted.

Maintaining disease-specific registries of patients who have MCI may be useful to longitudinally follow patients and ensure that they get the care they need.

PROGNOSIS VARIES

MCI is a heterogeneous condition that often does not predictably progress to dementia. Patients and families should be told that having MCI does not mean that the patient will necessarily get dementia.

Several studies have shown that the annual risk of progression to dementia for patients with MCI is 5% to 10% in community-dwelling populations and up to 15% in specialty-clinic patients.^24,32 In comparison, the incidence of dementia in the general elderly population is 1% to 3% per year.

On the other hand, a number of studies show that MCI improves significantly in up to 15% to 40% of patients and sometimes reverts to a normal cognitive state.^33,34 But prospective studies of patients with clinically diagnosed MCI usually find a low rate of reversion to a normal state.^35,36 Many are short-term follow-up studies of different populations, making generalizations difficult.¹⁴

Patients with impairment in instrumental activities of daily living may be more likely to have nonreversible MCI and may be at higher risk of progressing to dementia.³⁷

PATIENT AND FAMILY EDUCATION AND FOLLOW-UP CONSIDERATIONS

Caregiver education and stress management are important components of managing patients with MCI. Formally assessing caregiver stress is useful. Steps to prevent caregiver burnout include making use of respite care, counseling, education, and community resources such as adult day care and those offered by the Alzheimer’s Association.

Clinicians should follow patients with MCI closely to evaluate progression, address specific concerns, minimize risks, emphasize healthy habits, manage concurrent illnesses, and evaluate management.

Functional status, as demonstrated by activities of daily living, is the most important determinant of progression of MCI to dementia and should be evaluated at each visit. Repeat cognitive testing should be done on patients who have significant loss of functional status. Changes in work habits also warrant further attention.

Patients diagnosed with MCI or those who have persistent cognitive concerns should be considered for neuropsychological evaluation after 1 year to assess specific deficits and progression of cognitive impairment.

Finally, consideration should be given to current clinical research, and referrals should be made to research centers that focus on MCI management and treatment.

In 1944, Hans Asperger described a subset of children who exhibited “a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest, and clumsy movements.”¹

In recent years, Asperger syndrome has become increasingly recognized in the medical community and by the general public. It has been popularized in the media in John Elder Robison’s bestselling book, Look Me in the Eye; with the television character Sheldon Cooper in The Big Bang Theory; and in the 2009 film, Adam, a romantic comedy with the title character accurately portraying a young man with Asperger syndrome.

See related editorial

In this article, we discuss the causes and characteristics of Asperger syndrome, with special focus on adults: how it presents, how to treat it, and how to enhance the delivery of care.

PREVALENCE SEEMS TO BE INCREASING

One in 88 children is diagnosed with an autism spectrum disorder, and the rates of Asperger syndrome and other autism spectrum disorders appear to be increasing.² Whether this increase is the result of more thorough assessment and identification or of environmental changes is hotly debated.³ The rise began before the proposed changes to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) to combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified to simplify diagnosis.⁴ Asperger syndrome affects males three to four times more often than females.⁵ For most patients, the effects persist throughout life.

BEHAVIORAL IMPAIRMENTS CHARACTERIZE THE SYNDROME

Poor social skills are a hallmark

People with Asperger syndrome struggle with social interaction and face challenges in forming and maintaining relationships. They tend to have less eye contact (often the first indicator), smiling, animated speech, and physical communication such as hand gestures. They tend not to solicit another’s attention to something they themselves find interesting. They often lack social and emotional reciprocity and have difficulty understanding another person’s thoughts or feelings,⁶ and they have marked difficulty reading social cues. Some adults may appear rigid, selfish, or narrow-minded.

Sometimes behavior is in the normal range but is out of context for a particular situation.⁷ For example, a preprofessional student with Asperger syndrome might walk into a psychiatric evaluation to assess fitness for duty and take a seat cross-legged on the floor and have a snack. Poor grooming inappropriate for the occasion may also be observed, such as showing up for a formal photo with unkempt hair and in a stained shirt that is half tucked in.

Many adults with autism spectrum disorders are oblivious to their social reputation.⁸ They are often unaware that their behavior is out of place and only learn that it is not normal when they are told. Others recognize that they have trouble empathizing with or understanding the perspectives of others, but they are at a loss as to how to improve. The syndrome has a tremendous impact on broader aspects of life, such as employment, functional independence, relationships, and social networks.

Other odd behaviors are common

Repetitive behaviors. Many patients with Asperger syndrome have repetitive behaviors, which can manifest as repeating phrases or expressions, attempting to imitate others, and rocking. They tend to follow routines, do not enjoy spontaneity, and are more inflexible and uncomfortable when their planned regimen is altered.

Gait or balance issues may be observed on physical examination.⁹ Uncoordinated motion and clumsiness are common,¹⁰ and some patients may have a bouncy, stilted gait or may walk on their toes, although the latter is more common in children than adults. Many patients have illegible handwriting.¹¹

Fixations. Many Asperger patients have unusual and intense obsessions with subjects like numbers, dates, or aerodynamics of planes. Children with such fascinations are described as “little professors” or as having “geek syndrome.”¹² Certain obsessions often continue into adulthood, although one area of interest may fade and another may take over. Such “expertise” in adults may gain them respect, even though they may seem very odd in other ways.

Lack of boundaries. Patients with Asperger syndrome tend to have poor spatial awareness and to be unaware of physical boundaries, standing too close for others’ comfort or unusually far away. Lack of boundaries may extend beyond the physical, as patients may inappropriately help themselves to food or use an item belonging to another without invitation, being unaware that the behavior may be intrusive or inappropriate.

BEHAVIORAL ASSESSMENTS HELP MAKE DIAGNOSIS

Asperger syndrome is most often diagnosed in early childhood, although it may remain undiagnosed into adulthood. Coexisting depression, attention deficit hyperactivity disorder, or anxiety disorders are also often present.

Establishing the diagnosis is aided by information from family members and others who interact with the patient, from the observations of trained professionals, and from self-reported data. However, self-reported assessments are not always reliable, because the syndrome can affect insight.

The most common assessment tool for autism spectrum disorders is the Autism Diagnostic Interview-Revised (ADI-R),¹³ a battery of tests given in a structured interview to identify and quantify symptoms, determine where a patient falls on the autism spectrum,¹⁴ and point toward interventions. The ADI-R also organizes critical developmental history to evaluate if something else is present, such as prodromal schizophrenia. Although the ADI-R can be very useful in the diagnostic process, it is based on parental reporting, which is neither always available nor fully reliable.

A specific diagnostic tool for adults is the Adult Asperger Assessment.¹⁵ Patients are asked to complete two screening questionnaires that gauge cognitive function and gather information about thinking, processing, and behavior.

Table 1 lists the criteria for Asperger syndrome from the DSM Fourth Edition, Text Revision (DSM-IV-TR).¹⁶ Asperger syndrome differs from general autism in that it is not associated with language delay. In addition, patients with Asperger syndrome usually have average or above-average IQ scores.¹⁷ Still, determining whether a patient has Asperger syndrome or high-functioning autism is sometimes challenging.⁶

In DSM-V, Asperger syndrome will be subsumed under autism spectrum disorder

In 2013, the DSM-V will replace the DSMIV-TR and will combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise classified into a single diagnosis: autism spectrum disorder. The new system uses two instead of the previous three clusters of core symptoms, centered on “social reciprocity and communication” in one arm and “restricted interests and repetitive behavior” in the other.¹⁸ There will be less emphasis on play and imagination than in the past. Some authors suggest adding sensory criteria, particularly reduced pain and increased hearing sensitivity.¹⁹

The proposed system is sensitive and specific for autism spectrum disorders, allows early diagnosis, and indicates degree of severity.²⁰ It is hoped that the new system, which accounts for the range and severity of symptoms, should help physicians refer patients to the correct level of treatment.

On the other hand, it may be difficult to think of the three disorders as a single diagnosis. Asperger syndrome manifests in distinct ways, and clear behavioral criteria for diagnosis can be invaluable in helping people with the syndrome. Also, the public may continue to refer to it as Asperger syndrome, and parents and patients may feel uncomfortable having it considered to be the same diagnosis as autism.

BEHAVIORAL THERAPY CAN HELP ACHIEVE INDEPENDENCE

Although there is no cure for Asperger syndrome, various interventions can dramatically improve quality of life and independence. The health care team may include a primary care physician, psychologist, psychiatrist, neurologist, and speech therapist.

Behavioral therapies can help patients with Asperger syndrome learn skills to reduce their symptoms. Occupational and physical therapy can improve dexterity, fluidity, and coordination. Desensitization training may help patients adapt to uncomfortable sights, sounds, or smells that may arise. This can be critical in a job situation. For example, while an average person exposed to a foul odor in public is likely to react tactfully, a person with Asperger syndrome may scream loudly, make inappropriate comments, or run from the room. Social training, especially targeted to the workplace, can provide strategies for promoting typical behaviors and be key to maximizing functional independence.

Speech therapists can teach patients how to sound more relaxed and help them master the natural give-and-take of conversational exchange. Psychotherapy can provide a safe place to work on anxiety, express emotions, and manage restricted interests or repeated behaviors. Group therapy or social training can be a venue for learning improved interactions.

Living independently can be very challenging, and patients with Asperger syndrome may need functional independence training to help with a variety of skills, from handling finances to organizing the home.

Improving quality of life includes determining the best learning environments from childhood into college years and beyond.^21–23 Socialization can be enhanced with additional social support at home or on campus, through family interactions and collaborative learning, and by teaching empathy.²⁴ Vocational training can be extremely useful.

DRUG THERAPY MAY HAVE A ROLE

Medications are not usually prescribed unless depression or anxiety is also present, but they may also help manage irritability, anger, stereotypical mannerisms, and disturbing movements. Fluoxetine (Prozac) helps reduce repetitive behaviors in adults with Asperger syndrome. Propranolol (Inderal), a well-known antihypertensive, is also used for performance anxiety and improves word fluency, understanding of verbal communication, and verbal problem-solving in patients with an autism spectrum disorder.²⁵

Giving oxytocin (Pitocin) intranasally in a spray formulation is currently being tested to enhance social skills. Patients with an autism spectrum disorder were more able to perceive emotions of others and to respond more appropriately.²⁶ Oxytocin has long been associated with bonding and is believed to enhance mothering skills. It is naturally present in both sexes, but levels are higher in women, which may in part explain the lower rate of autism spectrum disorders in females.²⁷

HEALTH CARE REQUIRES SPECIAL CONSIDERATIONS

Medical care for patients with Asperger syndrome is enhanced by understanding the patient’s experience. Adults, in particular, may have learned to suppress symptoms of Asperger syndrome to better function in society but still experience stress in situations in which others would not. Patients with Asperger syndrome may struggle with social interactions during medical examinations or procedures, and clinicians may find interaction with the patient challenging.

It is important for health care providers to be calm and patient and to understand that anxiety may prevent people with Asperger syndrome from making eye contact. The clinician should confirm that a patient is engaged but should avoid seeming pushy or invasive.

When anxious, patients may employ strange gestures that they find soothing, such as flapping the hands, rocking, or cracking the knuckles. It is usually easier to allow them to continue unless the activity hinders the examination or treatment.

Patients are likely to respond better to direct requests than to subtle questions: eg, “Open your mouth, please” instead of “Could you open your mouth?” Using clear, specific language and avoiding metaphors, irony, and nonverbal communication are best. It is important to explicitly ask for everything needed, as patients may not volunteer information and may have trouble articulating what they are thinking or feeling. While educating patients about their health needs, physicians may need to reiterate guidance several times or approach the same topic from different angles in order for the patient to accept a concern.

All actions, especially touching the patient, should be explained clearly beforehand. If possible, the doctor should demonstrate using visuals or on his or her own body if appropriate. For invasive procedures, anesthetizing the local area is recommended.

People with Asperger syndrome often rely heavily on a regular routine to maintain a sense of organization. By interrupting this routine, a doctor’s visit can induce anxiety. Waiting also increases anxiety, so scheduling patients with Asperger syndrome either first or last in the day may help.

Hypersensitivity poses challenges

Many people with Asperger syndrome have abnormal sensitivity to stimuli, with differences in pain sensation and hearing perhaps most prominent. Loud noises, such as beeping equipment, whirring fans, or buzzing lights may be distressful and should be reduced if possible. Patients may also be strongly affected by bright lights or scents such as perfumes.

Patients may also have an altered sense of taste, with consequences that go beyond simple “picky eating.” Patients should be asked about unusual eating patterns, diets, or food aversions. People with autism spectrum disorders often do not consume adequate vitamin C because of an aversion to fruits and vegetables. Vitamin deficiency may have originated in infancy but may not be identified or treated until adulthood.²⁸

The sense of touch may be intensified, causing patients to be extremely ticklish; they may actually prefer to be touched more firmly. When it is necessary to make physical contact with patients, it will make the process easier if the physician determines their comfort level and finds ways to help them endure the experience with the least amount of discomfort.

Some patients with impaired sensory expression may have a high tolerance for extreme temperatures and pain, leading to delay in seeking aid.²⁹ Patients may downgrade pain levels, masking the severity of an illness or injury.

Transition from pediatric to adult care

Pediatrics is often a warm environment in which children develop a trusting relationship with their care providers. The transition to adult care can be daunting for patients with Asperger syndrome and their families, and many postpone the change for as long as possible.

Although time-consuming, a collaborative effort between the pediatric and adult care teams can dramatically smooth the transition. It can help to have a familiar person from the pediatric team, such as a nurse, be present at the initial interaction with the new adult care team. Both teams should be familiar with the other’s clinical practices and be aware of the patient’s stressors and ways to ameliorate them.³⁰

THE SEARCH FOR A CAUSE CONTINUES

Numerous studies are attempting to understand the anatomic and physiologic causes of autism spectrum disorders, and to find effective treatments and improve the quality of life.

Prenatal factors implicated

Several recent studies have focused on environmental factors during pregnancy as risk factors for autism spectrum disorder. Selective serotonin reuptake inhibitors were found to increase the risk,³¹ but the severity of the mother’s depressive illness must be considered before counseling against using these drugs. Older maternal or paternal age was also found to increase the risk of an autism spectrum disorder.³² Recent research indicates that older fathers are in particular more likely to have children with disorders such as autism because of an increase in random mutations associated with advanced age.³³

Maternal illness during pregnancy is also associated. Preliminary studies found an increased risk of autism if the mother had had a prenatal viral infection.³⁴ A more recent study found that untreated fever during pregnancy rather than a specific viral infection is more strongly linked.³⁵

Maternal antibodies have been implicated as well. One review found that psoriasis is the only maternal autoimmune condition significantly associated with the development of an autism spectrum disorder.³⁶ Elevated levels of antibodies against the fetal brain have been found in mothers with autistic children.³⁷ One study found that autistic children and their siblings have elevated antibrain antibodies in distinct brain regions, including the caudate nucleus, putamen, prefrontal cortex, cerebellum, and cingulate gyrus (why the siblings are spared from having the disorder is unclear).³⁸ Some have questioned whether a child’s own immune system might even be involved.³⁹

Functional magnetic resonance imaging (fMRI) has been used to investigate impaired social interaction, specific deficits of facial perception and recognition, sensory processing, working memory, and “theory of mind.” Hypoactivation, hyperactivation, and decreased functional connectivity have been observed depending on the mental processes evaluated.⁴⁰

When undergoing facial perception tasks, subjects with autism spectrum disorders exhibit hypoactivation in the lateral aspect of the middle region of the fusiform gyrus, responsible for face identification. But they have significant activation of the limbic system, specifically the amygdala, during facial recognition. Hypoactivity in the fusiform gyrus is observed when trying to identify faces or read facial expressions.^41,42 This cluster of findings helps explain misinterpretations, misidentification, and heightened affect.

A hallmark characteristic of autism is the difficulty patients have in determining intentions and interpreting others’ behavior, thoughts, or emotions. Studies of people with autism spectrum disorders show that areas often responsible for “sensitivity to others” are hypoactive.⁴³ There is also diminished activation in the medial cingulate cortex, normally activated when these people are asked to think about themselves and who they are.⁴⁴

The resting state in the brains of people with autism spectrum disorders is abnormally activated.⁴⁵ They are often particularly good at attention to detail but challenged in integrating information needed for general executive functioning. Impaired sensory processing makes it difficult for them to simultaneously interpret multiple sources of sensory input.⁴⁶

Perhaps some of the most exciting fMRI news comes from infant studies. Radical and axial diffusivity and fractional anisotropy techniques demonstrate differences in the brains of infants 6 to 24 months old, before symptoms of autism spectrum disorders are observed. It is hoped that early intervention could come into play before the syndrome develops fully.⁴⁷

The synthesis of input of social and emotional cues is sometimes referred to in the literature as “theory of mind.” It is impaired in Asperger syndrome,⁴⁸ as manifested by a lack of empathy and by challenges in perceiving others’ thoughts and feelings. The basis of impairment may be related to abnormalities in the amygdala.⁴⁹ Normal awareness involves the integration of multiple neural networks in the anterior paracingulate cortex, the superior temporal sulci, and the temporal poles bilaterally, but different regions appear to be used in patients with Asperger syndrome.⁵⁰ A small series of five case studies using positron emission tomography indicated that the left prefrontal cortex was the primary location for theory of mind in Asperger syndrome.⁵¹

Epilepsy, gastrointestinal problems, and sleep disturbances are associated

About 25% of people with autism spectrum disorders have epilepsy vs 2% to 3% in the general population. Asperger syndrome is associated with a much lower but still elevated risk of 4% to 6%.^47,52

Gastrointestinal complaints, most often constipation or chronic diarrhea, are much more common in children with autism spectrum disorders than in the general population. Preliminary data showed that children with an autism spectrum disorder have a 42% rate of gastrointestinal problems vs 12% in unaffected siblings. There is also a correlation between the severity of gastrointestinal problems and severity of autistic symptoms.⁵³

Research is ongoing to determine the prevalence of insomnia or interrupted sleep in those with autism spectrum disorders.^54–56 Changes in sleep architecture can explain nighttime activity.

NONTRADITIONAL CONSIDERATIONS

Dietary treatment: Mixed findings

A popular hypothesis is that adherence to a gluten-free or casein-free diet can reduce symptoms of autism spectrum disorders. Preliminary reports identified several cases of children showing improvement.⁵⁷ However, this has not been replicated, and more studies refute benefits of these diets.⁵⁸

Essential nutritional needs should be met with any diet, whether it is designed to reduce symptoms or not. Patients with autism spectrum disorders may have strong food aversions, and dietary supplements of vitamins and minerals may be required.

Vaccines do not cause autism

Despite popular concern, recent research indicates that vaccines do not cause autism. Thimerosal, a mercury-based preservative used in childhood vaccines, was at one time implicated as a risk factor for autism spectrum disorders. The US Centers for Disease Control and Prevention (CDC) issued a precaution against using thimerosal-containing vaccines while testing was done to determine the effects on neuropsychological development.⁵⁹ The CDC study as well as newer studies did not demonstrate that exposure to mercury causes these neuropsychological concerns, but researchers have continued to study the subject.^60–62 The original study implicating thimerosal was disproven as scientifically unsound and fraught with conflict of interest and legal concerns. It has since been retracted, and its findings have been completely discredited.⁶³

Other areas of research

Current research is exploring the higher prevalence of autism spectrum disorders in particular families.^64–66 Autism and autism spectrum disorders may be caused by hundreds of simultaneous gene alterations or may develop as a result of reduced gene expression in two areas of the cerebral cortex where higher-order processing occurs, in the frontal and temporal lobes.⁶⁷

Although genetic theories of autism predominate, a 2011 project suggests that environment is also important. A study of twins found that genetics accounted for 40% or less of cases of autism spectrum disorder, with at least 55% of cases being attributable to environmental factors.⁶⁸

In 1944, Hans Asperger described a subset of children who exhibited “a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest, and clumsy movements.”¹

In recent years, Asperger syndrome has become increasingly recognized in the medical community and by the general public. It has been popularized in the media in John Elder Robison’s bestselling book, Look Me in the Eye; with the television character Sheldon Cooper in The Big Bang Theory; and in the 2009 film, Adam, a romantic comedy with the title character accurately portraying a young man with Asperger syndrome.

See related editorial

In this article, we discuss the causes and characteristics of Asperger syndrome, with special focus on adults: how it presents, how to treat it, and how to enhance the delivery of care.

PREVALENCE SEEMS TO BE INCREASING

One in 88 children is diagnosed with an autism spectrum disorder, and the rates of Asperger syndrome and other autism spectrum disorders appear to be increasing.² Whether this increase is the result of more thorough assessment and identification or of environmental changes is hotly debated.³ The rise began before the proposed changes to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) to combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified to simplify diagnosis.⁴ Asperger syndrome affects males three to four times more often than females.⁵ For most patients, the effects persist throughout life.

BEHAVIORAL IMPAIRMENTS CHARACTERIZE THE SYNDROME

Poor social skills are a hallmark

People with Asperger syndrome struggle with social interaction and face challenges in forming and maintaining relationships. They tend to have less eye contact (often the first indicator), smiling, animated speech, and physical communication such as hand gestures. They tend not to solicit another’s attention to something they themselves find interesting. They often lack social and emotional reciprocity and have difficulty understanding another person’s thoughts or feelings,⁶ and they have marked difficulty reading social cues. Some adults may appear rigid, selfish, or narrow-minded.

Sometimes behavior is in the normal range but is out of context for a particular situation.⁷ For example, a preprofessional student with Asperger syndrome might walk into a psychiatric evaluation to assess fitness for duty and take a seat cross-legged on the floor and have a snack. Poor grooming inappropriate for the occasion may also be observed, such as showing up for a formal photo with unkempt hair and in a stained shirt that is half tucked in.

Many adults with autism spectrum disorders are oblivious to their social reputation.⁸ They are often unaware that their behavior is out of place and only learn that it is not normal when they are told. Others recognize that they have trouble empathizing with or understanding the perspectives of others, but they are at a loss as to how to improve. The syndrome has a tremendous impact on broader aspects of life, such as employment, functional independence, relationships, and social networks.

Other odd behaviors are common

Repetitive behaviors. Many patients with Asperger syndrome have repetitive behaviors, which can manifest as repeating phrases or expressions, attempting to imitate others, and rocking. They tend to follow routines, do not enjoy spontaneity, and are more inflexible and uncomfortable when their planned regimen is altered.

Gait or balance issues may be observed on physical examination.⁹ Uncoordinated motion and clumsiness are common,¹⁰ and some patients may have a bouncy, stilted gait or may walk on their toes, although the latter is more common in children than adults. Many patients have illegible handwriting.¹¹

Fixations. Many Asperger patients have unusual and intense obsessions with subjects like numbers, dates, or aerodynamics of planes. Children with such fascinations are described as “little professors” or as having “geek syndrome.”¹² Certain obsessions often continue into adulthood, although one area of interest may fade and another may take over. Such “expertise” in adults may gain them respect, even though they may seem very odd in other ways.

Lack of boundaries. Patients with Asperger syndrome tend to have poor spatial awareness and to be unaware of physical boundaries, standing too close for others’ comfort or unusually far away. Lack of boundaries may extend beyond the physical, as patients may inappropriately help themselves to food or use an item belonging to another without invitation, being unaware that the behavior may be intrusive or inappropriate.

BEHAVIORAL ASSESSMENTS HELP MAKE DIAGNOSIS

Asperger syndrome is most often diagnosed in early childhood, although it may remain undiagnosed into adulthood. Coexisting depression, attention deficit hyperactivity disorder, or anxiety disorders are also often present.

Establishing the diagnosis is aided by information from family members and others who interact with the patient, from the observations of trained professionals, and from self-reported data. However, self-reported assessments are not always reliable, because the syndrome can affect insight.

The most common assessment tool for autism spectrum disorders is the Autism Diagnostic Interview-Revised (ADI-R),¹³ a battery of tests given in a structured interview to identify and quantify symptoms, determine where a patient falls on the autism spectrum,¹⁴ and point toward interventions. The ADI-R also organizes critical developmental history to evaluate if something else is present, such as prodromal schizophrenia. Although the ADI-R can be very useful in the diagnostic process, it is based on parental reporting, which is neither always available nor fully reliable.

A specific diagnostic tool for adults is the Adult Asperger Assessment.¹⁵ Patients are asked to complete two screening questionnaires that gauge cognitive function and gather information about thinking, processing, and behavior.

Table 1 lists the criteria for Asperger syndrome from the DSM Fourth Edition, Text Revision (DSM-IV-TR).¹⁶ Asperger syndrome differs from general autism in that it is not associated with language delay. In addition, patients with Asperger syndrome usually have average or above-average IQ scores.¹⁷ Still, determining whether a patient has Asperger syndrome or high-functioning autism is sometimes challenging.⁶

In DSM-V, Asperger syndrome will be subsumed under autism spectrum disorder

In 2013, the DSM-V will replace the DSMIV-TR and will combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise classified into a single diagnosis: autism spectrum disorder. The new system uses two instead of the previous three clusters of core symptoms, centered on “social reciprocity and communication” in one arm and “restricted interests and repetitive behavior” in the other.¹⁸ There will be less emphasis on play and imagination than in the past. Some authors suggest adding sensory criteria, particularly reduced pain and increased hearing sensitivity.¹⁹

The proposed system is sensitive and specific for autism spectrum disorders, allows early diagnosis, and indicates degree of severity.²⁰ It is hoped that the new system, which accounts for the range and severity of symptoms, should help physicians refer patients to the correct level of treatment.

On the other hand, it may be difficult to think of the three disorders as a single diagnosis. Asperger syndrome manifests in distinct ways, and clear behavioral criteria for diagnosis can be invaluable in helping people with the syndrome. Also, the public may continue to refer to it as Asperger syndrome, and parents and patients may feel uncomfortable having it considered to be the same diagnosis as autism.

BEHAVIORAL THERAPY CAN HELP ACHIEVE INDEPENDENCE

Although there is no cure for Asperger syndrome, various interventions can dramatically improve quality of life and independence. The health care team may include a primary care physician, psychologist, psychiatrist, neurologist, and speech therapist.

Behavioral therapies can help patients with Asperger syndrome learn skills to reduce their symptoms. Occupational and physical therapy can improve dexterity, fluidity, and coordination. Desensitization training may help patients adapt to uncomfortable sights, sounds, or smells that may arise. This can be critical in a job situation. For example, while an average person exposed to a foul odor in public is likely to react tactfully, a person with Asperger syndrome may scream loudly, make inappropriate comments, or run from the room. Social training, especially targeted to the workplace, can provide strategies for promoting typical behaviors and be key to maximizing functional independence.

Speech therapists can teach patients how to sound more relaxed and help them master the natural give-and-take of conversational exchange. Psychotherapy can provide a safe place to work on anxiety, express emotions, and manage restricted interests or repeated behaviors. Group therapy or social training can be a venue for learning improved interactions.

Living independently can be very challenging, and patients with Asperger syndrome may need functional independence training to help with a variety of skills, from handling finances to organizing the home.

Improving quality of life includes determining the best learning environments from childhood into college years and beyond.^21–23 Socialization can be enhanced with additional social support at home or on campus, through family interactions and collaborative learning, and by teaching empathy.²⁴ Vocational training can be extremely useful.

DRUG THERAPY MAY HAVE A ROLE

Medications are not usually prescribed unless depression or anxiety is also present, but they may also help manage irritability, anger, stereotypical mannerisms, and disturbing movements. Fluoxetine (Prozac) helps reduce repetitive behaviors in adults with Asperger syndrome. Propranolol (Inderal), a well-known antihypertensive, is also used for performance anxiety and improves word fluency, understanding of verbal communication, and verbal problem-solving in patients with an autism spectrum disorder.²⁵

Giving oxytocin (Pitocin) intranasally in a spray formulation is currently being tested to enhance social skills. Patients with an autism spectrum disorder were more able to perceive emotions of others and to respond more appropriately.²⁶ Oxytocin has long been associated with bonding and is believed to enhance mothering skills. It is naturally present in both sexes, but levels are higher in women, which may in part explain the lower rate of autism spectrum disorders in females.²⁷

HEALTH CARE REQUIRES SPECIAL CONSIDERATIONS

Medical care for patients with Asperger syndrome is enhanced by understanding the patient’s experience. Adults, in particular, may have learned to suppress symptoms of Asperger syndrome to better function in society but still experience stress in situations in which others would not. Patients with Asperger syndrome may struggle with social interactions during medical examinations or procedures, and clinicians may find interaction with the patient challenging.

It is important for health care providers to be calm and patient and to understand that anxiety may prevent people with Asperger syndrome from making eye contact. The clinician should confirm that a patient is engaged but should avoid seeming pushy or invasive.

When anxious, patients may employ strange gestures that they find soothing, such as flapping the hands, rocking, or cracking the knuckles. It is usually easier to allow them to continue unless the activity hinders the examination or treatment.

Patients are likely to respond better to direct requests than to subtle questions: eg, “Open your mouth, please” instead of “Could you open your mouth?” Using clear, specific language and avoiding metaphors, irony, and nonverbal communication are best. It is important to explicitly ask for everything needed, as patients may not volunteer information and may have trouble articulating what they are thinking or feeling. While educating patients about their health needs, physicians may need to reiterate guidance several times or approach the same topic from different angles in order for the patient to accept a concern.

All actions, especially touching the patient, should be explained clearly beforehand. If possible, the doctor should demonstrate using visuals or on his or her own body if appropriate. For invasive procedures, anesthetizing the local area is recommended.

People with Asperger syndrome often rely heavily on a regular routine to maintain a sense of organization. By interrupting this routine, a doctor’s visit can induce anxiety. Waiting also increases anxiety, so scheduling patients with Asperger syndrome either first or last in the day may help.

Hypersensitivity poses challenges

Many people with Asperger syndrome have abnormal sensitivity to stimuli, with differences in pain sensation and hearing perhaps most prominent. Loud noises, such as beeping equipment, whirring fans, or buzzing lights may be distressful and should be reduced if possible. Patients may also be strongly affected by bright lights or scents such as perfumes.

Patients may also have an altered sense of taste, with consequences that go beyond simple “picky eating.” Patients should be asked about unusual eating patterns, diets, or food aversions. People with autism spectrum disorders often do not consume adequate vitamin C because of an aversion to fruits and vegetables. Vitamin deficiency may have originated in infancy but may not be identified or treated until adulthood.²⁸

The sense of touch may be intensified, causing patients to be extremely ticklish; they may actually prefer to be touched more firmly. When it is necessary to make physical contact with patients, it will make the process easier if the physician determines their comfort level and finds ways to help them endure the experience with the least amount of discomfort.

Some patients with impaired sensory expression may have a high tolerance for extreme temperatures and pain, leading to delay in seeking aid.²⁹ Patients may downgrade pain levels, masking the severity of an illness or injury.

Transition from pediatric to adult care

Pediatrics is often a warm environment in which children develop a trusting relationship with their care providers. The transition to adult care can be daunting for patients with Asperger syndrome and their families, and many postpone the change for as long as possible.

Although time-consuming, a collaborative effort between the pediatric and adult care teams can dramatically smooth the transition. It can help to have a familiar person from the pediatric team, such as a nurse, be present at the initial interaction with the new adult care team. Both teams should be familiar with the other’s clinical practices and be aware of the patient’s stressors and ways to ameliorate them.³⁰

THE SEARCH FOR A CAUSE CONTINUES

Numerous studies are attempting to understand the anatomic and physiologic causes of autism spectrum disorders, and to find effective treatments and improve the quality of life.

Prenatal factors implicated

Several recent studies have focused on environmental factors during pregnancy as risk factors for autism spectrum disorder. Selective serotonin reuptake inhibitors were found to increase the risk,³¹ but the severity of the mother’s depressive illness must be considered before counseling against using these drugs. Older maternal or paternal age was also found to increase the risk of an autism spectrum disorder.³² Recent research indicates that older fathers are in particular more likely to have children with disorders such as autism because of an increase in random mutations associated with advanced age.³³

Maternal illness during pregnancy is also associated. Preliminary studies found an increased risk of autism if the mother had had a prenatal viral infection.³⁴ A more recent study found that untreated fever during pregnancy rather than a specific viral infection is more strongly linked.³⁵

Maternal antibodies have been implicated as well. One review found that psoriasis is the only maternal autoimmune condition significantly associated with the development of an autism spectrum disorder.³⁶ Elevated levels of antibodies against the fetal brain have been found in mothers with autistic children.³⁷ One study found that autistic children and their siblings have elevated antibrain antibodies in distinct brain regions, including the caudate nucleus, putamen, prefrontal cortex, cerebellum, and cingulate gyrus (why the siblings are spared from having the disorder is unclear).³⁸ Some have questioned whether a child’s own immune system might even be involved.³⁹

Functional magnetic resonance imaging (fMRI) has been used to investigate impaired social interaction, specific deficits of facial perception and recognition, sensory processing, working memory, and “theory of mind.” Hypoactivation, hyperactivation, and decreased functional connectivity have been observed depending on the mental processes evaluated.⁴⁰

When undergoing facial perception tasks, subjects with autism spectrum disorders exhibit hypoactivation in the lateral aspect of the middle region of the fusiform gyrus, responsible for face identification. But they have significant activation of the limbic system, specifically the amygdala, during facial recognition. Hypoactivity in the fusiform gyrus is observed when trying to identify faces or read facial expressions.^41,42 This cluster of findings helps explain misinterpretations, misidentification, and heightened affect.

A hallmark characteristic of autism is the difficulty patients have in determining intentions and interpreting others’ behavior, thoughts, or emotions. Studies of people with autism spectrum disorders show that areas often responsible for “sensitivity to others” are hypoactive.⁴³ There is also diminished activation in the medial cingulate cortex, normally activated when these people are asked to think about themselves and who they are.⁴⁴

The resting state in the brains of people with autism spectrum disorders is abnormally activated.⁴⁵ They are often particularly good at attention to detail but challenged in integrating information needed for general executive functioning. Impaired sensory processing makes it difficult for them to simultaneously interpret multiple sources of sensory input.⁴⁶

Perhaps some of the most exciting fMRI news comes from infant studies. Radical and axial diffusivity and fractional anisotropy techniques demonstrate differences in the brains of infants 6 to 24 months old, before symptoms of autism spectrum disorders are observed. It is hoped that early intervention could come into play before the syndrome develops fully.⁴⁷

The synthesis of input of social and emotional cues is sometimes referred to in the literature as “theory of mind.” It is impaired in Asperger syndrome,⁴⁸ as manifested by a lack of empathy and by challenges in perceiving others’ thoughts and feelings. The basis of impairment may be related to abnormalities in the amygdala.⁴⁹ Normal awareness involves the integration of multiple neural networks in the anterior paracingulate cortex, the superior temporal sulci, and the temporal poles bilaterally, but different regions appear to be used in patients with Asperger syndrome.⁵⁰ A small series of five case studies using positron emission tomography indicated that the left prefrontal cortex was the primary location for theory of mind in Asperger syndrome.⁵¹

Epilepsy, gastrointestinal problems, and sleep disturbances are associated

About 25% of people with autism spectrum disorders have epilepsy vs 2% to 3% in the general population. Asperger syndrome is associated with a much lower but still elevated risk of 4% to 6%.^47,52

Gastrointestinal complaints, most often constipation or chronic diarrhea, are much more common in children with autism spectrum disorders than in the general population. Preliminary data showed that children with an autism spectrum disorder have a 42% rate of gastrointestinal problems vs 12% in unaffected siblings. There is also a correlation between the severity of gastrointestinal problems and severity of autistic symptoms.⁵³

Research is ongoing to determine the prevalence of insomnia or interrupted sleep in those with autism spectrum disorders.^54–56 Changes in sleep architecture can explain nighttime activity.

NONTRADITIONAL CONSIDERATIONS

Dietary treatment: Mixed findings

A popular hypothesis is that adherence to a gluten-free or casein-free diet can reduce symptoms of autism spectrum disorders. Preliminary reports identified several cases of children showing improvement.⁵⁷ However, this has not been replicated, and more studies refute benefits of these diets.⁵⁸

Essential nutritional needs should be met with any diet, whether it is designed to reduce symptoms or not. Patients with autism spectrum disorders may have strong food aversions, and dietary supplements of vitamins and minerals may be required.

Vaccines do not cause autism

Despite popular concern, recent research indicates that vaccines do not cause autism. Thimerosal, a mercury-based preservative used in childhood vaccines, was at one time implicated as a risk factor for autism spectrum disorders. The US Centers for Disease Control and Prevention (CDC) issued a precaution against using thimerosal-containing vaccines while testing was done to determine the effects on neuropsychological development.⁵⁹ The CDC study as well as newer studies did not demonstrate that exposure to mercury causes these neuropsychological concerns, but researchers have continued to study the subject.^60–62 The original study implicating thimerosal was disproven as scientifically unsound and fraught with conflict of interest and legal concerns. It has since been retracted, and its findings have been completely discredited.⁶³

Other areas of research

Current research is exploring the higher prevalence of autism spectrum disorders in particular families.^64–66 Autism and autism spectrum disorders may be caused by hundreds of simultaneous gene alterations or may develop as a result of reduced gene expression in two areas of the cerebral cortex where higher-order processing occurs, in the frontal and temporal lobes.⁶⁷

Although genetic theories of autism predominate, a 2011 project suggests that environment is also important. A study of twins found that genetics accounted for 40% or less of cases of autism spectrum disorder, with at least 55% of cases being attributable to environmental factors.⁶⁸

In 1944, Hans Asperger described a subset of children who exhibited “a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest, and clumsy movements.”¹

In recent years, Asperger syndrome has become increasingly recognized in the medical community and by the general public. It has been popularized in the media in John Elder Robison’s bestselling book, Look Me in the Eye; with the television character Sheldon Cooper in The Big Bang Theory; and in the 2009 film, Adam, a romantic comedy with the title character accurately portraying a young man with Asperger syndrome.

See related editorial

In this article, we discuss the causes and characteristics of Asperger syndrome, with special focus on adults: how it presents, how to treat it, and how to enhance the delivery of care.

PREVALENCE SEEMS TO BE INCREASING

One in 88 children is diagnosed with an autism spectrum disorder, and the rates of Asperger syndrome and other autism spectrum disorders appear to be increasing.² Whether this increase is the result of more thorough assessment and identification or of environmental changes is hotly debated.³ The rise began before the proposed changes to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) to combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified to simplify diagnosis.⁴ Asperger syndrome affects males three to four times more often than females.⁵ For most patients, the effects persist throughout life.

BEHAVIORAL IMPAIRMENTS CHARACTERIZE THE SYNDROME

Poor social skills are a hallmark

People with Asperger syndrome struggle with social interaction and face challenges in forming and maintaining relationships. They tend to have less eye contact (often the first indicator), smiling, animated speech, and physical communication such as hand gestures. They tend not to solicit another’s attention to something they themselves find interesting. They often lack social and emotional reciprocity and have difficulty understanding another person’s thoughts or feelings,⁶ and they have marked difficulty reading social cues. Some adults may appear rigid, selfish, or narrow-minded.

Sometimes behavior is in the normal range but is out of context for a particular situation.⁷ For example, a preprofessional student with Asperger syndrome might walk into a psychiatric evaluation to assess fitness for duty and take a seat cross-legged on the floor and have a snack. Poor grooming inappropriate for the occasion may also be observed, such as showing up for a formal photo with unkempt hair and in a stained shirt that is half tucked in.

Many adults with autism spectrum disorders are oblivious to their social reputation.⁸ They are often unaware that their behavior is out of place and only learn that it is not normal when they are told. Others recognize that they have trouble empathizing with or understanding the perspectives of others, but they are at a loss as to how to improve. The syndrome has a tremendous impact on broader aspects of life, such as employment, functional independence, relationships, and social networks.

Other odd behaviors are common

Repetitive behaviors. Many patients with Asperger syndrome have repetitive behaviors, which can manifest as repeating phrases or expressions, attempting to imitate others, and rocking. They tend to follow routines, do not enjoy spontaneity, and are more inflexible and uncomfortable when their planned regimen is altered.

Gait or balance issues may be observed on physical examination.⁹ Uncoordinated motion and clumsiness are common,¹⁰ and some patients may have a bouncy, stilted gait or may walk on their toes, although the latter is more common in children than adults. Many patients have illegible handwriting.¹¹

Fixations. Many Asperger patients have unusual and intense obsessions with subjects like numbers, dates, or aerodynamics of planes. Children with such fascinations are described as “little professors” or as having “geek syndrome.”¹² Certain obsessions often continue into adulthood, although one area of interest may fade and another may take over. Such “expertise” in adults may gain them respect, even though they may seem very odd in other ways.

Lack of boundaries. Patients with Asperger syndrome tend to have poor spatial awareness and to be unaware of physical boundaries, standing too close for others’ comfort or unusually far away. Lack of boundaries may extend beyond the physical, as patients may inappropriately help themselves to food or use an item belonging to another without invitation, being unaware that the behavior may be intrusive or inappropriate.

BEHAVIORAL ASSESSMENTS HELP MAKE DIAGNOSIS

Asperger syndrome is most often diagnosed in early childhood, although it may remain undiagnosed into adulthood. Coexisting depression, attention deficit hyperactivity disorder, or anxiety disorders are also often present.

Establishing the diagnosis is aided by information from family members and others who interact with the patient, from the observations of trained professionals, and from self-reported data. However, self-reported assessments are not always reliable, because the syndrome can affect insight.

The most common assessment tool for autism spectrum disorders is the Autism Diagnostic Interview-Revised (ADI-R),¹³ a battery of tests given in a structured interview to identify and quantify symptoms, determine where a patient falls on the autism spectrum,¹⁴ and point toward interventions. The ADI-R also organizes critical developmental history to evaluate if something else is present, such as prodromal schizophrenia. Although the ADI-R can be very useful in the diagnostic process, it is based on parental reporting, which is neither always available nor fully reliable.

A specific diagnostic tool for adults is the Adult Asperger Assessment.¹⁵ Patients are asked to complete two screening questionnaires that gauge cognitive function and gather information about thinking, processing, and behavior.

Table 1 lists the criteria for Asperger syndrome from the DSM Fourth Edition, Text Revision (DSM-IV-TR).¹⁶ Asperger syndrome differs from general autism in that it is not associated with language delay. In addition, patients with Asperger syndrome usually have average or above-average IQ scores.¹⁷ Still, determining whether a patient has Asperger syndrome or high-functioning autism is sometimes challenging.⁶

In DSM-V, Asperger syndrome will be subsumed under autism spectrum disorder

In 2013, the DSM-V will replace the DSMIV-TR and will combine autism, Asperger syndrome, and pervasive developmental disorder not otherwise classified into a single diagnosis: autism spectrum disorder. The new system uses two instead of the previous three clusters of core symptoms, centered on “social reciprocity and communication” in one arm and “restricted interests and repetitive behavior” in the other.¹⁸ There will be less emphasis on play and imagination than in the past. Some authors suggest adding sensory criteria, particularly reduced pain and increased hearing sensitivity.¹⁹

The proposed system is sensitive and specific for autism spectrum disorders, allows early diagnosis, and indicates degree of severity.²⁰ It is hoped that the new system, which accounts for the range and severity of symptoms, should help physicians refer patients to the correct level of treatment.

On the other hand, it may be difficult to think of the three disorders as a single diagnosis. Asperger syndrome manifests in distinct ways, and clear behavioral criteria for diagnosis can be invaluable in helping people with the syndrome. Also, the public may continue to refer to it as Asperger syndrome, and parents and patients may feel uncomfortable having it considered to be the same diagnosis as autism.

BEHAVIORAL THERAPY CAN HELP ACHIEVE INDEPENDENCE

Although there is no cure for Asperger syndrome, various interventions can dramatically improve quality of life and independence. The health care team may include a primary care physician, psychologist, psychiatrist, neurologist, and speech therapist.

Behavioral therapies can help patients with Asperger syndrome learn skills to reduce their symptoms. Occupational and physical therapy can improve dexterity, fluidity, and coordination. Desensitization training may help patients adapt to uncomfortable sights, sounds, or smells that may arise. This can be critical in a job situation. For example, while an average person exposed to a foul odor in public is likely to react tactfully, a person with Asperger syndrome may scream loudly, make inappropriate comments, or run from the room. Social training, especially targeted to the workplace, can provide strategies for promoting typical behaviors and be key to maximizing functional independence.

Speech therapists can teach patients how to sound more relaxed and help them master the natural give-and-take of conversational exchange. Psychotherapy can provide a safe place to work on anxiety, express emotions, and manage restricted interests or repeated behaviors. Group therapy or social training can be a venue for learning improved interactions.

Living independently can be very challenging, and patients with Asperger syndrome may need functional independence training to help with a variety of skills, from handling finances to organizing the home.

Improving quality of life includes determining the best learning environments from childhood into college years and beyond.^21–23 Socialization can be enhanced with additional social support at home or on campus, through family interactions and collaborative learning, and by teaching empathy.²⁴ Vocational training can be extremely useful.

DRUG THERAPY MAY HAVE A ROLE

Medications are not usually prescribed unless depression or anxiety is also present, but they may also help manage irritability, anger, stereotypical mannerisms, and disturbing movements. Fluoxetine (Prozac) helps reduce repetitive behaviors in adults with Asperger syndrome. Propranolol (Inderal), a well-known antihypertensive, is also used for performance anxiety and improves word fluency, understanding of verbal communication, and verbal problem-solving in patients with an autism spectrum disorder.²⁵

Giving oxytocin (Pitocin) intranasally in a spray formulation is currently being tested to enhance social skills. Patients with an autism spectrum disorder were more able to perceive emotions of others and to respond more appropriately.²⁶ Oxytocin has long been associated with bonding and is believed to enhance mothering skills. It is naturally present in both sexes, but levels are higher in women, which may in part explain the lower rate of autism spectrum disorders in females.²⁷

HEALTH CARE REQUIRES SPECIAL CONSIDERATIONS

Medical care for patients with Asperger syndrome is enhanced by understanding the patient’s experience. Adults, in particular, may have learned to suppress symptoms of Asperger syndrome to better function in society but still experience stress in situations in which others would not. Patients with Asperger syndrome may struggle with social interactions during medical examinations or procedures, and clinicians may find interaction with the patient challenging.

It is important for health care providers to be calm and patient and to understand that anxiety may prevent people with Asperger syndrome from making eye contact. The clinician should confirm that a patient is engaged but should avoid seeming pushy or invasive.

When anxious, patients may employ strange gestures that they find soothing, such as flapping the hands, rocking, or cracking the knuckles. It is usually easier to allow them to continue unless the activity hinders the examination or treatment.

Patients are likely to respond better to direct requests than to subtle questions: eg, “Open your mouth, please” instead of “Could you open your mouth?” Using clear, specific language and avoiding metaphors, irony, and nonverbal communication are best. It is important to explicitly ask for everything needed, as patients may not volunteer information and may have trouble articulating what they are thinking or feeling. While educating patients about their health needs, physicians may need to reiterate guidance several times or approach the same topic from different angles in order for the patient to accept a concern.

All actions, especially touching the patient, should be explained clearly beforehand. If possible, the doctor should demonstrate using visuals or on his or her own body if appropriate. For invasive procedures, anesthetizing the local area is recommended.

People with Asperger syndrome often rely heavily on a regular routine to maintain a sense of organization. By interrupting this routine, a doctor’s visit can induce anxiety. Waiting also increases anxiety, so scheduling patients with Asperger syndrome either first or last in the day may help.

Hypersensitivity poses challenges

Many people with Asperger syndrome have abnormal sensitivity to stimuli, with differences in pain sensation and hearing perhaps most prominent. Loud noises, such as beeping equipment, whirring fans, or buzzing lights may be distressful and should be reduced if possible. Patients may also be strongly affected by bright lights or scents such as perfumes.

Patients may also have an altered sense of taste, with consequences that go beyond simple “picky eating.” Patients should be asked about unusual eating patterns, diets, or food aversions. People with autism spectrum disorders often do not consume adequate vitamin C because of an aversion to fruits and vegetables. Vitamin deficiency may have originated in infancy but may not be identified or treated until adulthood.²⁸

The sense of touch may be intensified, causing patients to be extremely ticklish; they may actually prefer to be touched more firmly. When it is necessary to make physical contact with patients, it will make the process easier if the physician determines their comfort level and finds ways to help them endure the experience with the least amount of discomfort.

Some patients with impaired sensory expression may have a high tolerance for extreme temperatures and pain, leading to delay in seeking aid.²⁹ Patients may downgrade pain levels, masking the severity of an illness or injury.

Transition from pediatric to adult care

Pediatrics is often a warm environment in which children develop a trusting relationship with their care providers. The transition to adult care can be daunting for patients with Asperger syndrome and their families, and many postpone the change for as long as possible.

Although time-consuming, a collaborative effort between the pediatric and adult care teams can dramatically smooth the transition. It can help to have a familiar person from the pediatric team, such as a nurse, be present at the initial interaction with the new adult care team. Both teams should be familiar with the other’s clinical practices and be aware of the patient’s stressors and ways to ameliorate them.³⁰

THE SEARCH FOR A CAUSE CONTINUES

Numerous studies are attempting to understand the anatomic and physiologic causes of autism spectrum disorders, and to find effective treatments and improve the quality of life.

Prenatal factors implicated

Several recent studies have focused on environmental factors during pregnancy as risk factors for autism spectrum disorder. Selective serotonin reuptake inhibitors were found to increase the risk,³¹ but the severity of the mother’s depressive illness must be considered before counseling against using these drugs. Older maternal or paternal age was also found to increase the risk of an autism spectrum disorder.³² Recent research indicates that older fathers are in particular more likely to have children with disorders such as autism because of an increase in random mutations associated with advanced age.³³

Maternal illness during pregnancy is also associated. Preliminary studies found an increased risk of autism if the mother had had a prenatal viral infection.³⁴ A more recent study found that untreated fever during pregnancy rather than a specific viral infection is more strongly linked.³⁵

Maternal antibodies have been implicated as well. One review found that psoriasis is the only maternal autoimmune condition significantly associated with the development of an autism spectrum disorder.³⁶ Elevated levels of antibodies against the fetal brain have been found in mothers with autistic children.³⁷ One study found that autistic children and their siblings have elevated antibrain antibodies in distinct brain regions, including the caudate nucleus, putamen, prefrontal cortex, cerebellum, and cingulate gyrus (why the siblings are spared from having the disorder is unclear).³⁸ Some have questioned whether a child’s own immune system might even be involved.³⁹

Functional magnetic resonance imaging (fMRI) has been used to investigate impaired social interaction, specific deficits of facial perception and recognition, sensory processing, working memory, and “theory of mind.” Hypoactivation, hyperactivation, and decreased functional connectivity have been observed depending on the mental processes evaluated.⁴⁰

When undergoing facial perception tasks, subjects with autism spectrum disorders exhibit hypoactivation in the lateral aspect of the middle region of the fusiform gyrus, responsible for face identification. But they have significant activation of the limbic system, specifically the amygdala, during facial recognition. Hypoactivity in the fusiform gyrus is observed when trying to identify faces or read facial expressions.^41,42 This cluster of findings helps explain misinterpretations, misidentification, and heightened affect.

A hallmark characteristic of autism is the difficulty patients have in determining intentions and interpreting others’ behavior, thoughts, or emotions. Studies of people with autism spectrum disorders show that areas often responsible for “sensitivity to others” are hypoactive.⁴³ There is also diminished activation in the medial cingulate cortex, normally activated when these people are asked to think about themselves and who they are.⁴⁴

The resting state in the brains of people with autism spectrum disorders is abnormally activated.⁴⁵ They are often particularly good at attention to detail but challenged in integrating information needed for general executive functioning. Impaired sensory processing makes it difficult for them to simultaneously interpret multiple sources of sensory input.⁴⁶

Perhaps some of the most exciting fMRI news comes from infant studies. Radical and axial diffusivity and fractional anisotropy techniques demonstrate differences in the brains of infants 6 to 24 months old, before symptoms of autism spectrum disorders are observed. It is hoped that early intervention could come into play before the syndrome develops fully.⁴⁷

The synthesis of input of social and emotional cues is sometimes referred to in the literature as “theory of mind.” It is impaired in Asperger syndrome,⁴⁸ as manifested by a lack of empathy and by challenges in perceiving others’ thoughts and feelings. The basis of impairment may be related to abnormalities in the amygdala.⁴⁹ Normal awareness involves the integration of multiple neural networks in the anterior paracingulate cortex, the superior temporal sulci, and the temporal poles bilaterally, but different regions appear to be used in patients with Asperger syndrome.⁵⁰ A small series of five case studies using positron emission tomography indicated that the left prefrontal cortex was the primary location for theory of mind in Asperger syndrome.⁵¹

Epilepsy, gastrointestinal problems, and sleep disturbances are associated

About 25% of people with autism spectrum disorders have epilepsy vs 2% to 3% in the general population. Asperger syndrome is associated with a much lower but still elevated risk of 4% to 6%.^47,52

Gastrointestinal complaints, most often constipation or chronic diarrhea, are much more common in children with autism spectrum disorders than in the general population. Preliminary data showed that children with an autism spectrum disorder have a 42% rate of gastrointestinal problems vs 12% in unaffected siblings. There is also a correlation between the severity of gastrointestinal problems and severity of autistic symptoms.⁵³

Research is ongoing to determine the prevalence of insomnia or interrupted sleep in those with autism spectrum disorders.^54–56 Changes in sleep architecture can explain nighttime activity.

NONTRADITIONAL CONSIDERATIONS

Dietary treatment: Mixed findings

A popular hypothesis is that adherence to a gluten-free or casein-free diet can reduce symptoms of autism spectrum disorders. Preliminary reports identified several cases of children showing improvement.⁵⁷ However, this has not been replicated, and more studies refute benefits of these diets.⁵⁸

Essential nutritional needs should be met with any diet, whether it is designed to reduce symptoms or not. Patients with autism spectrum disorders may have strong food aversions, and dietary supplements of vitamins and minerals may be required.

Vaccines do not cause autism

Despite popular concern, recent research indicates that vaccines do not cause autism. Thimerosal, a mercury-based preservative used in childhood vaccines, was at one time implicated as a risk factor for autism spectrum disorders. The US Centers for Disease Control and Prevention (CDC) issued a precaution against using thimerosal-containing vaccines while testing was done to determine the effects on neuropsychological development.⁵⁹ The CDC study as well as newer studies did not demonstrate that exposure to mercury causes these neuropsychological concerns, but researchers have continued to study the subject.^60–62 The original study implicating thimerosal was disproven as scientifically unsound and fraught with conflict of interest and legal concerns. It has since been retracted, and its findings have been completely discredited.⁶³

Other areas of research

Current research is exploring the higher prevalence of autism spectrum disorders in particular families.^64–66 Autism and autism spectrum disorders may be caused by hundreds of simultaneous gene alterations or may develop as a result of reduced gene expression in two areas of the cerebral cortex where higher-order processing occurs, in the frontal and temporal lobes.⁶⁷

Although genetic theories of autism predominate, a 2011 project suggests that environment is also important. A study of twins found that genetics accounted for 40% or less of cases of autism spectrum disorder, with at least 55% of cases being attributable to environmental factors.⁶⁸