Kerri Wachter

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

BALTIMORE — Several classic parameters of melanoma histology are associated with survival and thus have a role in evaluating black patients, according to a poster presented at the annual meeting of the American Society of Dermatopathology.

"The incidence of melanoma in [blacks] is approximately 20 times lower than in [whites], presumptively because of the protective effects of melanin," wrote Dr. Doru T. Alexandrescu of the melanoma center at the Washington (D.C.) Hospital Center and his colleagues.

When blacks do present with melanoma, they are more likely to have stage III or IV disease, thicker primaries, and a poor prognosis. Histologic parameters of melanoma have not previously been described in black patients, the investigators noted.

For this study, the researchers analyzed the biopsy specimens of 68 black patients with malignant melanoma, of which 34 were evaluable histologically. The average patient age was 62 years.

Classic "histological parameters in melanoma such as Breslow depth, Clark level, ulceration, number of mitoses, and neutropism confirm their value in [black] patients by associating a statistically significant influence on survival," Dr. Alexandrescu and his associates wrote.

The mean Breslow depth of the biopsy specimens was 3.28 mm, and the mean Clark level was IV.

Pagetoid spread was found in 90% of specimens. Vertical growth phase was found in 70%, ulceration in 44%, neutropism in 36%, and necrosis in 30%.

The mean number of mitoses per high-power field was 1.36. Sentinel lymph-node positivity was 38%, and the local recurrence rate was 25%.

Tumor fibrosis was rated as none (0), mild (1), moderate (2), and severe (3). Mean tumor fibrosis was 1.5. In addition, the microvascular density inside the tumor was less (0.85) than it was under the tumor (1.85), compared with the surrounding skin.

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” said Dr. McCalmont. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. The confirmation was made by immuno- histochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens.

“If you see a juxtaposition of eosinophils and plasma cells, then it's probably not syphilis,” said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” said Dr. McCalmont. The organism load is usually high.

There are a variety of different patterns that can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

The main image shows the textbook 'lichenoid-psoriasiform' configuration that is commonly seen in biopsies of secondary syphilis. The inset image shows how the immunoperoxidase staining for T. pallidum readily demonstrates the causative spirochetes. Courtesy Dr. Timothy H. McCalmont

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” said Dr. McCalmont. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. The confirmation was made by immuno- histochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens.

“If you see a juxtaposition of eosinophils and plasma cells, then it's probably not syphilis,” said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” said Dr. McCalmont. The organism load is usually high.

There are a variety of different patterns that can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

The main image shows the textbook 'lichenoid-psoriasiform' configuration that is commonly seen in biopsies of secondary syphilis. The inset image shows how the immunoperoxidase staining for T. pallidum readily demonstrates the causative spirochetes. Courtesy Dr. Timothy H. McCalmont

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” said Dr. McCalmont. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. The confirmation was made by immuno- histochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens.

“If you see a juxtaposition of eosinophils and plasma cells, then it's probably not syphilis,” said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” said Dr. McCalmont. The organism load is usually high.

There are a variety of different patterns that can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

The main image shows the textbook 'lichenoid-psoriasiform' configuration that is commonly seen in biopsies of secondary syphilis. The inset image shows how the immunoperoxidase staining for T. pallidum readily demonstrates the causative spirochetes. Courtesy Dr. Timothy H. McCalmont

WASHINGTON — Lewy body pathology—the accumulation of α-synuclein protein—appears to be associated with cerebral atherosclerosis.

In a study of 403 preserved brains, those with moderate to severe cerebral atherosclerosis were more than twice as likely to also have Lewy bodies present as were those with no cerebral atherosclerosis.

This association between cerebral atherosclerosis and Lewy body burden was discovered by examining brains from the Columbia University Medical Center databank. The brains were obtained between 1990 and 2007. Neuropathologic evaluation of Lewy bodies involved immunostaining with ubiquitin or α-synuclein. Degree of cerebral atherosclerosis was determined by gross rating of the Circle of Willis, according to Dr. Nikolaos Scarmeas, of the Taub Institute at Columbia University, New York, and his colleagues.

Lewy bodies were present in roughly a quarter of the brains (26%). Patients with Lewy bodies died at an older age on average than did those without the pathology—78 years vs. 75 years. Those with Lewy bodies were also slightly more educated—16 years vs. 14 years. Lewy bodies were more likely to be found in men (66%). Changes associated with Alzheimer's disease (AD) were found in roughly half of those with and without Lewy bodies.

Cerebral atherosclerosis was classified as not present, mild, or moderate to severe. No atherosclerosis was found in 31%, mild atherosclerosis in 36%, and moderate to severe in 33%. Atherosclerosis appeared more frequently with increasing age—68 years for those without, 76 years for those with mild, and 82 years for those with moderate to severe.

The presence of AD-related changes increased with increasing cerebral atherosclerosis—44% of those with none, 56% of those with mild, and 64% of those with moderate to severe, they reported.

The researchers used logistic regression analysis to determine if the presence of mild or moderate to severe cerebral atherosclerosis was predictive of the presence of Lewy bodies in the brain. In the unadjusted model, those with both mild (OR 1.25) and moderate to severe (OR 2.38) atherosclerosis were more likely to have Lewy bodies, versus patients without atherosclerosis, as seen in this study presented as a poster at the annual meeting of the American Neurological Association.

After adjustment for gender, age at death, and AD pathologic changes, those with mild atherosclerosis were only slightly more likely to have Lewy bodies (OR 1.07). Those with moderate to severe atherosclerosis were still more than twice as likely to have them (OR 2.20).

In addition, “stratified analyses indicated that the association between Lewy bodies and atherosclerosis was stronger in women and in patients without AD pathological changes,” the researchers wrote.

The researchers also examined the effect of restricting their analyses to include only more recent cases—those cases that used α-synuclein immunostaining. However, this restriction did not affect the associations.

WASHINGTON — Lewy body pathology—the accumulation of α-synuclein protein—appears to be associated with cerebral atherosclerosis.

In a study of 403 preserved brains, those with moderate to severe cerebral atherosclerosis were more than twice as likely to also have Lewy bodies present as were those with no cerebral atherosclerosis.

This association between cerebral atherosclerosis and Lewy body burden was discovered by examining brains from the Columbia University Medical Center databank. The brains were obtained between 1990 and 2007. Neuropathologic evaluation of Lewy bodies involved immunostaining with ubiquitin or α-synuclein. Degree of cerebral atherosclerosis was determined by gross rating of the Circle of Willis, according to Dr. Nikolaos Scarmeas, of the Taub Institute at Columbia University, New York, and his colleagues.

Lewy bodies were present in roughly a quarter of the brains (26%). Patients with Lewy bodies died at an older age on average than did those without the pathology—78 years vs. 75 years. Those with Lewy bodies were also slightly more educated—16 years vs. 14 years. Lewy bodies were more likely to be found in men (66%). Changes associated with Alzheimer's disease (AD) were found in roughly half of those with and without Lewy bodies.

Cerebral atherosclerosis was classified as not present, mild, or moderate to severe. No atherosclerosis was found in 31%, mild atherosclerosis in 36%, and moderate to severe in 33%. Atherosclerosis appeared more frequently with increasing age—68 years for those without, 76 years for those with mild, and 82 years for those with moderate to severe.

The presence of AD-related changes increased with increasing cerebral atherosclerosis—44% of those with none, 56% of those with mild, and 64% of those with moderate to severe, they reported.

The researchers used logistic regression analysis to determine if the presence of mild or moderate to severe cerebral atherosclerosis was predictive of the presence of Lewy bodies in the brain. In the unadjusted model, those with both mild (OR 1.25) and moderate to severe (OR 2.38) atherosclerosis were more likely to have Lewy bodies, versus patients without atherosclerosis, as seen in this study presented as a poster at the annual meeting of the American Neurological Association.

After adjustment for gender, age at death, and AD pathologic changes, those with mild atherosclerosis were only slightly more likely to have Lewy bodies (OR 1.07). Those with moderate to severe atherosclerosis were still more than twice as likely to have them (OR 2.20).

In addition, “stratified analyses indicated that the association between Lewy bodies and atherosclerosis was stronger in women and in patients without AD pathological changes,” the researchers wrote.

The researchers also examined the effect of restricting their analyses to include only more recent cases—those cases that used α-synuclein immunostaining. However, this restriction did not affect the associations.

WASHINGTON — Lewy body pathology—the accumulation of α-synuclein protein—appears to be associated with cerebral atherosclerosis.

In a study of 403 preserved brains, those with moderate to severe cerebral atherosclerosis were more than twice as likely to also have Lewy bodies present as were those with no cerebral atherosclerosis.

This association between cerebral atherosclerosis and Lewy body burden was discovered by examining brains from the Columbia University Medical Center databank. The brains were obtained between 1990 and 2007. Neuropathologic evaluation of Lewy bodies involved immunostaining with ubiquitin or α-synuclein. Degree of cerebral atherosclerosis was determined by gross rating of the Circle of Willis, according to Dr. Nikolaos Scarmeas, of the Taub Institute at Columbia University, New York, and his colleagues.

Lewy bodies were present in roughly a quarter of the brains (26%). Patients with Lewy bodies died at an older age on average than did those without the pathology—78 years vs. 75 years. Those with Lewy bodies were also slightly more educated—16 years vs. 14 years. Lewy bodies were more likely to be found in men (66%). Changes associated with Alzheimer's disease (AD) were found in roughly half of those with and without Lewy bodies.

Cerebral atherosclerosis was classified as not present, mild, or moderate to severe. No atherosclerosis was found in 31%, mild atherosclerosis in 36%, and moderate to severe in 33%. Atherosclerosis appeared more frequently with increasing age—68 years for those without, 76 years for those with mild, and 82 years for those with moderate to severe.

The presence of AD-related changes increased with increasing cerebral atherosclerosis—44% of those with none, 56% of those with mild, and 64% of those with moderate to severe, they reported.

The researchers used logistic regression analysis to determine if the presence of mild or moderate to severe cerebral atherosclerosis was predictive of the presence of Lewy bodies in the brain. In the unadjusted model, those with both mild (OR 1.25) and moderate to severe (OR 2.38) atherosclerosis were more likely to have Lewy bodies, versus patients without atherosclerosis, as seen in this study presented as a poster at the annual meeting of the American Neurological Association.

After adjustment for gender, age at death, and AD pathologic changes, those with mild atherosclerosis were only slightly more likely to have Lewy bodies (OR 1.07). Those with moderate to severe atherosclerosis were still more than twice as likely to have them (OR 2.20).

In addition, “stratified analyses indicated that the association between Lewy bodies and atherosclerosis was stronger in women and in patients without AD pathological changes,” the researchers wrote.

The researchers also examined the effect of restricting their analyses to include only more recent cases—those cases that used α-synuclein immunostaining. However, this restriction did not affect the associations.

The boy had back pain for more than a year. Neither physical therapy nor anti-inflammatory drugs had helped. He had no significant history of injury and no family history of lower back pain. He had no skin rashes, colitis, or other complaints. He previously had an MRI of his lumbar spine, which appeared normal, and a normal CT scan of his pelvis,

When he presented to a neurosurgeon, he had lower back pain and significant limitation of movement in his lumbar spine. An MRI of the sacroiliac revealed significant inflammation on both sides of the joint (see images), compatible with sacroiliitis, a finding highly suggestive of ankylosing spondylitis (AS). He was referred to Dr. Norman B. Gaylis, a rheumatologist in Miami.

Patients withAS tend to present with sacroiliitis, especially when they are human leukocyte antigen B27-positive. “Many patients with back pain have their diagnosis missed,” he said, because either physicians don't think of AS or the x-ray is negative. If an MRI is done, it is typically on the lumbar spine.

The differential diagnosis for lower back pain includes disk damage, trauma, or muscle strain, but sometimes patients are dismissed as imagining the pain.

Historically, diagnosis of AS has depended on the radiographic finding of sacroiliitis. “The findings on MRI [for AS], similar to those for rheumatoid arthritis, occur far earlier than you will see on x-ray,” said Dr. Gaylis. MRI findings of AS—synovitis and intense enhancing bone marrow edema/osteitis, as in this case—can precede x-ray evidence by 3 years (J. Rheumatol. 1999;26:1953–8).

MRIs show synovitis and intense enhancing bone marrow edema/osteitis.

The boy had back pain for more than a year. Neither physical therapy nor anti-inflammatory drugs had helped. He had no significant history of injury and no family history of lower back pain. He had no skin rashes, colitis, or other complaints. He previously had an MRI of his lumbar spine, which appeared normal, and a normal CT scan of his pelvis,

When he presented to a neurosurgeon, he had lower back pain and significant limitation of movement in his lumbar spine. An MRI of the sacroiliac revealed significant inflammation on both sides of the joint (see images), compatible with sacroiliitis, a finding highly suggestive of ankylosing spondylitis (AS). He was referred to Dr. Norman B. Gaylis, a rheumatologist in Miami.

Patients withAS tend to present with sacroiliitis, especially when they are human leukocyte antigen B27-positive. “Many patients with back pain have their diagnosis missed,” he said, because either physicians don't think of AS or the x-ray is negative. If an MRI is done, it is typically on the lumbar spine.

The differential diagnosis for lower back pain includes disk damage, trauma, or muscle strain, but sometimes patients are dismissed as imagining the pain.

Historically, diagnosis of AS has depended on the radiographic finding of sacroiliitis. “The findings on MRI [for AS], similar to those for rheumatoid arthritis, occur far earlier than you will see on x-ray,” said Dr. Gaylis. MRI findings of AS—synovitis and intense enhancing bone marrow edema/osteitis, as in this case—can precede x-ray evidence by 3 years (J. Rheumatol. 1999;26:1953–8).

MRIs show synovitis and intense enhancing bone marrow edema/osteitis.

The boy had back pain for more than a year. Neither physical therapy nor anti-inflammatory drugs had helped. He had no significant history of injury and no family history of lower back pain. He had no skin rashes, colitis, or other complaints. He previously had an MRI of his lumbar spine, which appeared normal, and a normal CT scan of his pelvis,

When he presented to a neurosurgeon, he had lower back pain and significant limitation of movement in his lumbar spine. An MRI of the sacroiliac revealed significant inflammation on both sides of the joint (see images), compatible with sacroiliitis, a finding highly suggestive of ankylosing spondylitis (AS). He was referred to Dr. Norman B. Gaylis, a rheumatologist in Miami.

Patients withAS tend to present with sacroiliitis, especially when they are human leukocyte antigen B27-positive. “Many patients with back pain have their diagnosis missed,” he said, because either physicians don't think of AS or the x-ray is negative. If an MRI is done, it is typically on the lumbar spine.

The differential diagnosis for lower back pain includes disk damage, trauma, or muscle strain, but sometimes patients are dismissed as imagining the pain.

Historically, diagnosis of AS has depended on the radiographic finding of sacroiliitis. “The findings on MRI [for AS], similar to those for rheumatoid arthritis, occur far earlier than you will see on x-ray,” said Dr. Gaylis. MRI findings of AS—synovitis and intense enhancing bone marrow edema/osteitis, as in this case—can precede x-ray evidence by 3 years (J. Rheumatol. 1999;26:1953–8).

MRIs show synovitis and intense enhancing bone marrow edema/osteitis.

WASHINGTON — Vague presenting symptoms in combination with lack of accurate tests hamper the diagnosis of central nervous system vasculitis, while likely contributing to its overdiagnosis, according to Dr. David B. Hellmann, chairman of the department of medicine and the vice dean at the Johns Hopkins Bayview Medical Center in Baltimore.

Speaking at the annual meeting of the American Neurological Association, Dr. Hellmann discussed a few common myths about CNS vasculitis—also known as primary angiitis of the central nervous system (PACNS)—and offered clinical pearls.

Myths

▸ CNS vasculitis is common. In fact, CNS vasculitis accounts for only 1% all biopsy-proven cases of vasculitis. “CNS vasculitis is one of the greatest diagnostic challenges that any of us can face,” said Dr. Hellmann, who is also the executive director of the Johns Hopkins Vasculitis Center. Most of the common presenting features of CNS vasculitis are shared by a variety of other conditions. While there is a cluster of symptoms that is highly suggestive of this disease, a full range of CNS abnormalities is possible. No imaging tests are specific and even brain biopsy can be falsely negative.

▸ Angiograms are sensitive and specific. The sensitivity of magnetic resonance (MR) angiography ranges from 40% to 80%, and the specificity is quite low at around 25%. The main abnormality apparent on MR angiography is a beading pattern of alternating constriction and dilatation. Posterior circulation is less likely to be affected.

▸ Stroke presentation is common. While focal abnormalities are seen in about 50% of CNS vasculitis cases, very rarely do they present as stroke. “Focal [cerebral] abnormalities are pretty common by the time that you make the diagnosis but in retrospect, very few patients describe a strokelike presentation,” said Dr. Hellmann.

▸ Systemic signs are common. “Systemic symptoms are overrated. One of the myths of CNS vasculitis is that people have fevers and many other symptoms. They may, but it's actually the minority of patients who have systemic signs,” said Dr. Hellmann.

Pearls

▸ Definitive diagnosis takes biopsy. The criterion for making a possible diagnosis of CNS vasculitis is a newly acquired neurologic deficit, exclusive of other causes. A positive biopsy allows for definitive diagnosis. The diagnosis of possible CNS vasculitis is made when there is no biopsy but the clinical picture and imaging, along with the exclusion of other causes, is suggestive.

Brain biopsy is falsely negative about 25%-40% of the time. “More atrophy is biopsied in the nondominant temporal lobe,” said Dr. Hellmann.

Biopsy specimens should be taken from of the leptomeninges or parenchyma to produce a greater yield. Studies suggest that biopsy is positive in 9%-36% of suspected cases. “It seems to be worth doing, as another diagnosis is often found,” said Dr. Hellmann. However in 25%-35% of patients, biopsy produces no diagnosis.

▸ Prescribe no cyclophosphamide without a definitive diagnosis. “In the absence of biopsy-proven case, I get nervous about using cyclophosphamide,” said Dr. Hellmann. “For someone who has biopsy-proven disease, I think that … most rheumatologists would use prednisone and cyclophosphamide,” said Dr. Hellmann. For a patient who is rapidly deteriorating, 1 g/day Solu-Medrol (methylprednisolone sodium succinate) should be given intravenously for the first few days, followed by 60 mg/day for a month, then taper the dose over the next 2–6 months. Oral cyclophosphamide can be used for 3–12 months.

▸ The most common presentation is insidious cognitive decline with headache. Studies have shown that the two most common presenting symptoms are diffuse cortical dysfunction (in an estimated 95% of cases) and headache (seen in roughly 70% of cases). Associated headaches are marked by an insidious rather than thunderclap onset. Seizures are also common.

▸ Lumbar puncture and MRI are sensitive but not specific. In terms of diagnostic testing, lumbar puncture and MRI are very sensitive but sensitivity is very low. In fact, patients with CNS vasculitis may have perfectly normal-appearing MRIs. Cerebral spinal fluid (CSF) findings are abnormal in 85%-90% of cases. This includes modestly elevated protein levels and modest mononuclear pleocytosis.

In terms of imaging, MRI is much more sensitive than CT. However, there is no specific pattern to look for on MRI.

Speed of Onset Key to Differential

The differential diagnosis of CNS vasculitis or PACNS includes rheumatic diseases, infections, drugs, and vasculopathies, said Dr. Hellmann. In particular, consider reversible cerebral vasoconstriction (RCVS), lupus, HIV, histoplasmosis, tuberculosis, intravascular lymphoma, and cerebral amyloid angiopathy (distinguished by an average age of onset that is 30 years greater than for PACNS).

RCVS consists of a group of diverse conditions that are characterized by reversible multifocal narrowing of the cerebral arteries. The first symptom of RCVS is sudden (thunderclap), severe headaches with or without associated neurologic deficits. Drugs, such as phenylpropanolamine, pseudoephedrine, and others, are frequently behind RCVS.

RCVS and PACNS do have some distinguishing features. RCVS is more common among women, while PACNS is more common among men. RCVS is marked by a thunderclap-type headache, whereas PACNS is more insidious. Patients with RCVS have floridly positive angiograms.

Current suggestions for the treatment of RCVS include observation for mild cases, calcium channel blockers (nimodipine, verapamil), or high-dose steroids.

WASHINGTON — Vague presenting symptoms in combination with lack of accurate tests hamper the diagnosis of central nervous system vasculitis, while likely contributing to its overdiagnosis, according to Dr. David B. Hellmann, chairman of the department of medicine and the vice dean at the Johns Hopkins Bayview Medical Center in Baltimore.

Speaking at the annual meeting of the American Neurological Association, Dr. Hellmann discussed a few common myths about CNS vasculitis—also known as primary angiitis of the central nervous system (PACNS)—and offered clinical pearls.

Myths

▸ CNS vasculitis is common. In fact, CNS vasculitis accounts for only 1% all biopsy-proven cases of vasculitis. “CNS vasculitis is one of the greatest diagnostic challenges that any of us can face,” said Dr. Hellmann, who is also the executive director of the Johns Hopkins Vasculitis Center. Most of the common presenting features of CNS vasculitis are shared by a variety of other conditions. While there is a cluster of symptoms that is highly suggestive of this disease, a full range of CNS abnormalities is possible. No imaging tests are specific and even brain biopsy can be falsely negative.

▸ Angiograms are sensitive and specific. The sensitivity of magnetic resonance (MR) angiography ranges from 40% to 80%, and the specificity is quite low at around 25%. The main abnormality apparent on MR angiography is a beading pattern of alternating constriction and dilatation. Posterior circulation is less likely to be affected.

▸ Stroke presentation is common. While focal abnormalities are seen in about 50% of CNS vasculitis cases, very rarely do they present as stroke. “Focal [cerebral] abnormalities are pretty common by the time that you make the diagnosis but in retrospect, very few patients describe a strokelike presentation,” said Dr. Hellmann.

▸ Systemic signs are common. “Systemic symptoms are overrated. One of the myths of CNS vasculitis is that people have fevers and many other symptoms. They may, but it's actually the minority of patients who have systemic signs,” said Dr. Hellmann.

Pearls

▸ Definitive diagnosis takes biopsy. The criterion for making a possible diagnosis of CNS vasculitis is a newly acquired neurologic deficit, exclusive of other causes. A positive biopsy allows for definitive diagnosis. The diagnosis of possible CNS vasculitis is made when there is no biopsy but the clinical picture and imaging, along with the exclusion of other causes, is suggestive.

Brain biopsy is falsely negative about 25%-40% of the time. “More atrophy is biopsied in the nondominant temporal lobe,” said Dr. Hellmann.

Biopsy specimens should be taken from of the leptomeninges or parenchyma to produce a greater yield. Studies suggest that biopsy is positive in 9%-36% of suspected cases. “It seems to be worth doing, as another diagnosis is often found,” said Dr. Hellmann. However in 25%-35% of patients, biopsy produces no diagnosis.

▸ Prescribe no cyclophosphamide without a definitive diagnosis. “In the absence of biopsy-proven case, I get nervous about using cyclophosphamide,” said Dr. Hellmann. “For someone who has biopsy-proven disease, I think that … most rheumatologists would use prednisone and cyclophosphamide,” said Dr. Hellmann. For a patient who is rapidly deteriorating, 1 g/day Solu-Medrol (methylprednisolone sodium succinate) should be given intravenously for the first few days, followed by 60 mg/day for a month, then taper the dose over the next 2–6 months. Oral cyclophosphamide can be used for 3–12 months.

▸ The most common presentation is insidious cognitive decline with headache. Studies have shown that the two most common presenting symptoms are diffuse cortical dysfunction (in an estimated 95% of cases) and headache (seen in roughly 70% of cases). Associated headaches are marked by an insidious rather than thunderclap onset. Seizures are also common.

▸ Lumbar puncture and MRI are sensitive but not specific. In terms of diagnostic testing, lumbar puncture and MRI are very sensitive but sensitivity is very low. In fact, patients with CNS vasculitis may have perfectly normal-appearing MRIs. Cerebral spinal fluid (CSF) findings are abnormal in 85%-90% of cases. This includes modestly elevated protein levels and modest mononuclear pleocytosis.

In terms of imaging, MRI is much more sensitive than CT. However, there is no specific pattern to look for on MRI.

Speed of Onset Key to Differential

The differential diagnosis of CNS vasculitis or PACNS includes rheumatic diseases, infections, drugs, and vasculopathies, said Dr. Hellmann. In particular, consider reversible cerebral vasoconstriction (RCVS), lupus, HIV, histoplasmosis, tuberculosis, intravascular lymphoma, and cerebral amyloid angiopathy (distinguished by an average age of onset that is 30 years greater than for PACNS).

RCVS consists of a group of diverse conditions that are characterized by reversible multifocal narrowing of the cerebral arteries. The first symptom of RCVS is sudden (thunderclap), severe headaches with or without associated neurologic deficits. Drugs, such as phenylpropanolamine, pseudoephedrine, and others, are frequently behind RCVS.

RCVS and PACNS do have some distinguishing features. RCVS is more common among women, while PACNS is more common among men. RCVS is marked by a thunderclap-type headache, whereas PACNS is more insidious. Patients with RCVS have floridly positive angiograms.

Current suggestions for the treatment of RCVS include observation for mild cases, calcium channel blockers (nimodipine, verapamil), or high-dose steroids.

WASHINGTON — Vague presenting symptoms in combination with lack of accurate tests hamper the diagnosis of central nervous system vasculitis, while likely contributing to its overdiagnosis, according to Dr. David B. Hellmann, chairman of the department of medicine and the vice dean at the Johns Hopkins Bayview Medical Center in Baltimore.

Speaking at the annual meeting of the American Neurological Association, Dr. Hellmann discussed a few common myths about CNS vasculitis—also known as primary angiitis of the central nervous system (PACNS)—and offered clinical pearls.

Myths

▸ CNS vasculitis is common. In fact, CNS vasculitis accounts for only 1% all biopsy-proven cases of vasculitis. “CNS vasculitis is one of the greatest diagnostic challenges that any of us can face,” said Dr. Hellmann, who is also the executive director of the Johns Hopkins Vasculitis Center. Most of the common presenting features of CNS vasculitis are shared by a variety of other conditions. While there is a cluster of symptoms that is highly suggestive of this disease, a full range of CNS abnormalities is possible. No imaging tests are specific and even brain biopsy can be falsely negative.

▸ Angiograms are sensitive and specific. The sensitivity of magnetic resonance (MR) angiography ranges from 40% to 80%, and the specificity is quite low at around 25%. The main abnormality apparent on MR angiography is a beading pattern of alternating constriction and dilatation. Posterior circulation is less likely to be affected.

▸ Stroke presentation is common. While focal abnormalities are seen in about 50% of CNS vasculitis cases, very rarely do they present as stroke. “Focal [cerebral] abnormalities are pretty common by the time that you make the diagnosis but in retrospect, very few patients describe a strokelike presentation,” said Dr. Hellmann.

▸ Systemic signs are common. “Systemic symptoms are overrated. One of the myths of CNS vasculitis is that people have fevers and many other symptoms. They may, but it's actually the minority of patients who have systemic signs,” said Dr. Hellmann.

Pearls

▸ Definitive diagnosis takes biopsy. The criterion for making a possible diagnosis of CNS vasculitis is a newly acquired neurologic deficit, exclusive of other causes. A positive biopsy allows for definitive diagnosis. The diagnosis of possible CNS vasculitis is made when there is no biopsy but the clinical picture and imaging, along with the exclusion of other causes, is suggestive.

Brain biopsy is falsely negative about 25%-40% of the time. “More atrophy is biopsied in the nondominant temporal lobe,” said Dr. Hellmann.

Biopsy specimens should be taken from of the leptomeninges or parenchyma to produce a greater yield. Studies suggest that biopsy is positive in 9%-36% of suspected cases. “It seems to be worth doing, as another diagnosis is often found,” said Dr. Hellmann. However in 25%-35% of patients, biopsy produces no diagnosis.

▸ Prescribe no cyclophosphamide without a definitive diagnosis. “In the absence of biopsy-proven case, I get nervous about using cyclophosphamide,” said Dr. Hellmann. “For someone who has biopsy-proven disease, I think that … most rheumatologists would use prednisone and cyclophosphamide,” said Dr. Hellmann. For a patient who is rapidly deteriorating, 1 g/day Solu-Medrol (methylprednisolone sodium succinate) should be given intravenously for the first few days, followed by 60 mg/day for a month, then taper the dose over the next 2–6 months. Oral cyclophosphamide can be used for 3–12 months.

▸ The most common presentation is insidious cognitive decline with headache. Studies have shown that the two most common presenting symptoms are diffuse cortical dysfunction (in an estimated 95% of cases) and headache (seen in roughly 70% of cases). Associated headaches are marked by an insidious rather than thunderclap onset. Seizures are also common.

▸ Lumbar puncture and MRI are sensitive but not specific. In terms of diagnostic testing, lumbar puncture and MRI are very sensitive but sensitivity is very low. In fact, patients with CNS vasculitis may have perfectly normal-appearing MRIs. Cerebral spinal fluid (CSF) findings are abnormal in 85%-90% of cases. This includes modestly elevated protein levels and modest mononuclear pleocytosis.

In terms of imaging, MRI is much more sensitive than CT. However, there is no specific pattern to look for on MRI.

Speed of Onset Key to Differential

The differential diagnosis of CNS vasculitis or PACNS includes rheumatic diseases, infections, drugs, and vasculopathies, said Dr. Hellmann. In particular, consider reversible cerebral vasoconstriction (RCVS), lupus, HIV, histoplasmosis, tuberculosis, intravascular lymphoma, and cerebral amyloid angiopathy (distinguished by an average age of onset that is 30 years greater than for PACNS).

RCVS consists of a group of diverse conditions that are characterized by reversible multifocal narrowing of the cerebral arteries. The first symptom of RCVS is sudden (thunderclap), severe headaches with or without associated neurologic deficits. Drugs, such as phenylpropanolamine, pseudoephedrine, and others, are frequently behind RCVS.

RCVS and PACNS do have some distinguishing features. RCVS is more common among women, while PACNS is more common among men. RCVS is marked by a thunderclap-type headache, whereas PACNS is more insidious. Patients with RCVS have floridly positive angiograms.

Current suggestions for the treatment of RCVS include observation for mild cases, calcium channel blockers (nimodipine, verapamil), or high-dose steroids.

BALTIMORE — Secondary syphilis does not always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” Dr. McCalmont said. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a diagnosis confirmed by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%); however, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%), however, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. “If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis,” Dr. McCalmont said.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” he said. The organism load is usually high.

Secondary syphilis can have a variety of patterns, Dr. McCalmont said. In addition to the lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

BALTIMORE — Secondary syphilis does not always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” Dr. McCalmont said. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a diagnosis confirmed by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%); however, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%), however, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. “If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis,” Dr. McCalmont said.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” he said. The organism load is usually high.

Secondary syphilis can have a variety of patterns, Dr. McCalmont said. In addition to the lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

BALTIMORE — Secondary syphilis does not always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, a professor of clinical pathology at the University of California, San Francisco.

“There's been a resurgence in syphilis. Keep it on your differential diagnosis short list,” Dr. McCalmont said. “The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side,” he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a diagnosis confirmed by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not demonstrate the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was present in 11 of the specimens (48%), whereas psoriasiform epidermal hyperplasia was present in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%); however, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%), however, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. “If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis,” Dr. McCalmont said.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. “They often tend to have a coiled morphology that is easily picked up on staining,” he said. The organism load is usually high.

Secondary syphilis can have a variety of patterns, Dr. McCalmont said. In addition to the lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, professor of clinical pathology at the University of California, San Francisco.

"There's been a resurgence in syphilis. Keep it on your differential diagnosis short list," said Dr. McCalmont. "The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side," he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. Confirmation was made by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not exhibit the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was seen in 11 of the specimens (48%), while psoriasiform epidermal hyperplasia was seen in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. "If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis," said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. "They often tend to have a coiled morphology that is easily picked up on staining," said Dr. McCalmont. The organism load is usually high.

A variety of patterns can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

This "lichenoid-psoriasiform" configuration is common in syphilis. Immunoperoxidase staining readily reveals T. pallidum (inset). Courtesy Dr. Timothy H. McCalmont

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, professor of clinical pathology at the University of California, San Francisco.

"There's been a resurgence in syphilis. Keep it on your differential diagnosis short list," said Dr. McCalmont. "The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side," he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. Confirmation was made by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not exhibit the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was seen in 11 of the specimens (48%), while psoriasiform epidermal hyperplasia was seen in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. "If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis," said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. "They often tend to have a coiled morphology that is easily picked up on staining," said Dr. McCalmont. The organism load is usually high.

A variety of patterns can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

This "lichenoid-psoriasiform" configuration is common in syphilis. Immunoperoxidase staining readily reveals T. pallidum (inset). Courtesy Dr. Timothy H. McCalmont

BALTIMORE — Secondary syphilis doesn't always have the textbook lichenoid-psoriasiform appearance, said Dr. Timothy H. McCalmont, professor of clinical pathology at the University of California, San Francisco.

"There's been a resurgence in syphilis. Keep it on your differential diagnosis short list," said Dr. McCalmont. "The microscopy of this disease is highly varied and the textbook descriptions that are out there are perhaps a little bit on the simplistic side," he said at the annual meeting of the American Society of Dermatopathology.

Dr. McCalmont and his colleagues reviewed their experience with syphilis, which included 23 specimens from 22 patients with a confirmed diagnosis of syphilis. Confirmation was made by immunohistochemistry, polymerase chain reaction-based assay, or serology.

Histopathologically, most of the 23 samples did not exhibit the textbook lichenoid-psoriasiform pattern. A lichenoid infiltrate was seen in 11 of the specimens (48%), while psoriasiform epidermal hyperplasia was seen in only 8 (35%). Clear involvement of the epidermal-dermal junction was found in 18 (78%). However, 5 (22%) showed wholly dermal involvement.

The dermal infiltrate included histiocytes in all specimens, neutrophils in 11 (48%), and plasmacytes in 22 (96%). However, plasmacytes were conspicuous in only 7 specimens (30%). Eosinophils are generally not found in syphilis, and none were found in any of these specimens. "If you see a juxtaposition of eosinophils and plasma cells, it's probably not syphilis," said Dr. McCalmont.

When using immunoperoxidase staining for Treponema pallidum, look for organisms at the perijunctional zone. "They often tend to have a coiled morphology that is easily picked up on staining," said Dr. McCalmont. The organism load is usually high.

A variety of patterns can be seen with secondary syphilis, said Dr. McCalmont. In addition to the prototypic lichenoid-psoriasiform pattern, granulomatous, sarcoidlike, and lupus-like patterns can be seen.

This "lichenoid-psoriasiform" configuration is common in syphilis. Immunoperoxidase staining readily reveals T. pallidum (inset). Courtesy Dr. Timothy H. McCalmont

Functional MRI, single-photon emission computed tomography, PET, and magnetic resonance spectroscopy have identified brain structures activated by pain. These include the primary and secondary somatosensory cortices, the insula, the anterior cingulate, the thalamus, the dorsal lateral prefrontal cortex, and the basal ganglia.

Similar studies have indicated fibromyalgia patients have abnormal activation in these regions, both at baseline and in response to painful stimuli.

Diffusion-weighted imaging (DWI) measures the restriction of water diffusion (the apparent diffusion coefficient or ADC) in the brain. Diffusion tensor imaging (DTI) measures the directional diffusion properties of water (fractional anisotropy or FA), and therefore, the integrity of organized tissue microstructures.

Dr. Pia C. Sundgren and Dr. Daniel J. Clauw, with colleagues at the University of Michigan in Ann Arbor, used DWI and DTI to look for cerebral abnormalities in fibromyalgia patients, versus healthy controls (Acad. Radiol. 2007;14:839–46).

The researchers studied 19 fibromyalgia patients (16 women), aged 20–57 years, and 25 pain-free controls (19 women). All subjects underwent MRI (1.5 T) including pre- and postcontrast enhanced axial and sagittal T1-weighted images, axial T-2 weighted images (with fat saturation), axial fluid attenuated inversion recovery (FLAIR) images, diffusion-weighted images, and postcontrast coronal T1-weighted images. The images were evaluated for brain volume loss, abnormal signal, abnormal contrast enhancement, abnormal diffusion, the presence of hemorrhage or mineralization, or other abnormalities.

First, the researchers developed whole-brain, gray matter-only, and white matter-only ADC histograms for each patient and control. Then histograms by group (fibromyalgia patients and controls) were calculated. ADC and FA maps also were calculated. Both ADC and FA are quantitative, with normal brain values of ADC around 0.7 × 10–3 mm

DTI maps were registered with postcontrast axial T1-weighted images. Standardized 50 mm

Clinical pain was assessed immediately before the DWI and DTI scans using a 10-cm visual analog scale. Pressure pain threshold was assessed before the DWI and DTI scans. Discrete pressure stimuli were applied to the subject's left thumbnail. Pain intensity ratings were recorded. Patients with fibromyalgia also were given the Center for Epidemiologic Studies Depression Scale questionnaire and the Spielberger's State-Trait Personality Inventory anxiety questionnaire. Specific cognitive beliefs about pain and control over pain were assessed using the Beliefs About Pain Control Questionnaire.

FA values were significantly less in the right thalamus for fibromyalgia patients, compared with controls. No differences were found in any other locations.

The differences in FA in the thalamus prompted the researchers to examine the relationship between the severity of fibromyalgia and FA within the group. Patients with more severe pain had lower FA values. Fibromyalgia patients tend to attribute their pain to an external event like minor trauma. The investigators found a negative correlation between the belief in an “external” cause of their pain and the FA values. This indicates these low right-thalamic values also were tied to a cognition known to be negatively associated with prognosis in chronic pain. Lower right-thalamic FA values also were tied to greater numbers of tender points, higher levels of depression, and a low pain threshold.

“The abnormalities that we've identified using this technique are actually less pronounced than what you'd find with [functional MRI] or PET or proton spectroscopy or other modalities. All of those modalities identify objective differences between fibromyalgia patients and controls with respect to pain processing regions,” said Dr. Clauw. “What you really find with all of those functional imaging techniques—this one included—they all give you different and somewhat complementary information. … There really is something wrong going on in the brains of these patients with fibromyalgia,” said Dr. Clauw.

The focal nature of these findings suggest these abnormalities are caused by ongoing demyelination or axonal injury but are rather due to neuronal dysfunction.

“If the tissue is less organized or the axons are dysfunctional, it might be seen as a reduction in the main directionality combined with alterations in the other diffusion directions resulting in a more round and less sphere/ellipsoid appearance of the diffusion directionality as can be seen in a more isotropic environment. This idea can be supported by the normal ADC value found here in the same region,” they wrote.

ADC and FA maps (top left and right) of a fibromyalgia patient: On the same FA map (bottom left), red white matter tracts indicate greater anisotropy. On another FA map (bottom right), there is less anisotropy in the dorsomedial aspect of right thalamus. IMAGES COURTESY DR. PIA C. SUNDGREN

Functional MRI, single-photon emission computed tomography, PET, and magnetic resonance spectroscopy have identified brain structures activated by pain. These include the primary and secondary somatosensory cortices, the insula, the anterior cingulate, the thalamus, the dorsal lateral prefrontal cortex, and the basal ganglia.

Similar studies have indicated fibromyalgia patients have abnormal activation in these regions, both at baseline and in response to painful stimuli.

Diffusion-weighted imaging (DWI) measures the restriction of water diffusion (the apparent diffusion coefficient or ADC) in the brain. Diffusion tensor imaging (DTI) measures the directional diffusion properties of water (fractional anisotropy or FA), and therefore, the integrity of organized tissue microstructures.

Dr. Pia C. Sundgren and Dr. Daniel J. Clauw, with colleagues at the University of Michigan in Ann Arbor, used DWI and DTI to look for cerebral abnormalities in fibromyalgia patients, versus healthy controls (Acad. Radiol. 2007;14:839–46).

The researchers studied 19 fibromyalgia patients (16 women), aged 20–57 years, and 25 pain-free controls (19 women). All subjects underwent MRI (1.5 T) including pre- and postcontrast enhanced axial and sagittal T1-weighted images, axial T-2 weighted images (with fat saturation), axial fluid attenuated inversion recovery (FLAIR) images, diffusion-weighted images, and postcontrast coronal T1-weighted images. The images were evaluated for brain volume loss, abnormal signal, abnormal contrast enhancement, abnormal diffusion, the presence of hemorrhage or mineralization, or other abnormalities.

First, the researchers developed whole-brain, gray matter-only, and white matter-only ADC histograms for each patient and control. Then histograms by group (fibromyalgia patients and controls) were calculated. ADC and FA maps also were calculated. Both ADC and FA are quantitative, with normal brain values of ADC around 0.7 × 10–3 mm

DTI maps were registered with postcontrast axial T1-weighted images. Standardized 50 mm

Clinical pain was assessed immediately before the DWI and DTI scans using a 10-cm visual analog scale. Pressure pain threshold was assessed before the DWI and DTI scans. Discrete pressure stimuli were applied to the subject's left thumbnail. Pain intensity ratings were recorded. Patients with fibromyalgia also were given the Center for Epidemiologic Studies Depression Scale questionnaire and the Spielberger's State-Trait Personality Inventory anxiety questionnaire. Specific cognitive beliefs about pain and control over pain were assessed using the Beliefs About Pain Control Questionnaire.

FA values were significantly less in the right thalamus for fibromyalgia patients, compared with controls. No differences were found in any other locations.

The differences in FA in the thalamus prompted the researchers to examine the relationship between the severity of fibromyalgia and FA within the group. Patients with more severe pain had lower FA values. Fibromyalgia patients tend to attribute their pain to an external event like minor trauma. The investigators found a negative correlation between the belief in an “external” cause of their pain and the FA values. This indicates these low right-thalamic values also were tied to a cognition known to be negatively associated with prognosis in chronic pain. Lower right-thalamic FA values also were tied to greater numbers of tender points, higher levels of depression, and a low pain threshold.

“The abnormalities that we've identified using this technique are actually less pronounced than what you'd find with [functional MRI] or PET or proton spectroscopy or other modalities. All of those modalities identify objective differences between fibromyalgia patients and controls with respect to pain processing regions,” said Dr. Clauw. “What you really find with all of those functional imaging techniques—this one included—they all give you different and somewhat complementary information. … There really is something wrong going on in the brains of these patients with fibromyalgia,” said Dr. Clauw.

The focal nature of these findings suggest these abnormalities are caused by ongoing demyelination or axonal injury but are rather due to neuronal dysfunction.

“If the tissue is less organized or the axons are dysfunctional, it might be seen as a reduction in the main directionality combined with alterations in the other diffusion directions resulting in a more round and less sphere/ellipsoid appearance of the diffusion directionality as can be seen in a more isotropic environment. This idea can be supported by the normal ADC value found here in the same region,” they wrote.

ADC and FA maps (top left and right) of a fibromyalgia patient: On the same FA map (bottom left), red white matter tracts indicate greater anisotropy. On another FA map (bottom right), there is less anisotropy in the dorsomedial aspect of right thalamus. IMAGES COURTESY DR. PIA C. SUNDGREN

Functional MRI, single-photon emission computed tomography, PET, and magnetic resonance spectroscopy have identified brain structures activated by pain. These include the primary and secondary somatosensory cortices, the insula, the anterior cingulate, the thalamus, the dorsal lateral prefrontal cortex, and the basal ganglia.

Similar studies have indicated fibromyalgia patients have abnormal activation in these regions, both at baseline and in response to painful stimuli.

Diffusion-weighted imaging (DWI) measures the restriction of water diffusion (the apparent diffusion coefficient or ADC) in the brain. Diffusion tensor imaging (DTI) measures the directional diffusion properties of water (fractional anisotropy or FA), and therefore, the integrity of organized tissue microstructures.

Dr. Pia C. Sundgren and Dr. Daniel J. Clauw, with colleagues at the University of Michigan in Ann Arbor, used DWI and DTI to look for cerebral abnormalities in fibromyalgia patients, versus healthy controls (Acad. Radiol. 2007;14:839–46).

The researchers studied 19 fibromyalgia patients (16 women), aged 20–57 years, and 25 pain-free controls (19 women). All subjects underwent MRI (1.5 T) including pre- and postcontrast enhanced axial and sagittal T1-weighted images, axial T-2 weighted images (with fat saturation), axial fluid attenuated inversion recovery (FLAIR) images, diffusion-weighted images, and postcontrast coronal T1-weighted images. The images were evaluated for brain volume loss, abnormal signal, abnormal contrast enhancement, abnormal diffusion, the presence of hemorrhage or mineralization, or other abnormalities.

First, the researchers developed whole-brain, gray matter-only, and white matter-only ADC histograms for each patient and control. Then histograms by group (fibromyalgia patients and controls) were calculated. ADC and FA maps also were calculated. Both ADC and FA are quantitative, with normal brain values of ADC around 0.7 × 10–3 mm

DTI maps were registered with postcontrast axial T1-weighted images. Standardized 50 mm

Clinical pain was assessed immediately before the DWI and DTI scans using a 10-cm visual analog scale. Pressure pain threshold was assessed before the DWI and DTI scans. Discrete pressure stimuli were applied to the subject's left thumbnail. Pain intensity ratings were recorded. Patients with fibromyalgia also were given the Center for Epidemiologic Studies Depression Scale questionnaire and the Spielberger's State-Trait Personality Inventory anxiety questionnaire. Specific cognitive beliefs about pain and control over pain were assessed using the Beliefs About Pain Control Questionnaire.

FA values were significantly less in the right thalamus for fibromyalgia patients, compared with controls. No differences were found in any other locations.

The differences in FA in the thalamus prompted the researchers to examine the relationship between the severity of fibromyalgia and FA within the group. Patients with more severe pain had lower FA values. Fibromyalgia patients tend to attribute their pain to an external event like minor trauma. The investigators found a negative correlation between the belief in an “external” cause of their pain and the FA values. This indicates these low right-thalamic values also were tied to a cognition known to be negatively associated with prognosis in chronic pain. Lower right-thalamic FA values also were tied to greater numbers of tender points, higher levels of depression, and a low pain threshold.

“The abnormalities that we've identified using this technique are actually less pronounced than what you'd find with [functional MRI] or PET or proton spectroscopy or other modalities. All of those modalities identify objective differences between fibromyalgia patients and controls with respect to pain processing regions,” said Dr. Clauw. “What you really find with all of those functional imaging techniques—this one included—they all give you different and somewhat complementary information. … There really is something wrong going on in the brains of these patients with fibromyalgia,” said Dr. Clauw.

The focal nature of these findings suggest these abnormalities are caused by ongoing demyelination or axonal injury but are rather due to neuronal dysfunction.

“If the tissue is less organized or the axons are dysfunctional, it might be seen as a reduction in the main directionality combined with alterations in the other diffusion directions resulting in a more round and less sphere/ellipsoid appearance of the diffusion directionality as can be seen in a more isotropic environment. This idea can be supported by the normal ADC value found here in the same region,” they wrote.

ADC and FA maps (top left and right) of a fibromyalgia patient: On the same FA map (bottom left), red white matter tracts indicate greater anisotropy. On another FA map (bottom right), there is less anisotropy in the dorsomedial aspect of right thalamus. IMAGES COURTESY DR. PIA C. SUNDGREN

WASHINGTON – Not only does duloxetine appear to reduce the severity of pain, especially during the night, but it may also help patients with diabetic peripheral neuropathy get a better night's sleep, according to a poster presentation at the annual meeting of the American Pain Society.

After 12 weeks of treatment, patients on 60 mg of duloxetine once or twice daily had improvements in average daily pain severity, night pain severity, and pain-related sleep interference, wrote Dr. David A. Fishbain, professor of psychiatry and behavioral sciences at the University of Miami, and his colleagues at Eli Lilly, maker of duloxetine (Cymbalta).

Although causality cannot be demonstrated between duloxetine and better sleep, the findings suggest that improvements in pain will be associated with less interference in sleep, the authors wrote.

The researchers pooled data from three double-blind, placebo-controlled trials of duloxetine in patients with diabetic peripheral neuropathic pain (DPNP). In the first study, 457 patients were randomized to receive 20 mg of duloxetine once daily, 60 mg of duloxetine once or twice daily, or placebo. In studies two and three, 334 and 348 patients, respectively, were randomized to receive 60 mg of duloxetine once daily, 60 mg of duloxetine twice daily, or placebo. Although the primary efficacy measure for the studies was the reduction in the weekly mean of the 24-hour average pain score, secondary end points included average daily night pain severity (measured on an 11-point Likert scale) and the Brief Pain Inventory sleep interference item.

Patients were included in the trials if they were 18 years or older with pain because of bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. Pain had to have begun in the feet with relatively symmetric onset. Diagnosis was confirmed by a score of at least three on the Michigan Neuropathy Screening Instrument. Daily pain had to be present for at least 6 months. Patients also had to have at least a 4 on the 24-hour average pain severity (11-point Likert) scale and stable glycemic control. Notably, patients with a current or recent (within the last year) diagnosis of major depressive disorder as defined by the DSM-IV were excluded from the studies.

The researchers identified a subset of nonsomnolent patients by excluding those who reported treatment-emergent somnolence or who were on concomitant sedating medications. Treatment-emergent somnolence included reports of daytime sleepiness, drowsiness, being drowsy upon awakening, excessive daytime sleepiness, a feeling of residual sleepiness, groggy, groggy and sluggish, groggy on awakening, hard to awaken, less alert on rising, sleepiness, sleepy, and somnolence.

In all three studies, 339 patients received placebo. Of these, 307 met the criteria for the nonsomnolent subset. A total of 685 patients received 60 mg or 120 mg per day of duloxetine in all three studies. Of these, 607 met the criteria for the nonsomnolent subset. Patients in the nonsomnolent/nonsedating subgroup who were on duloxetine showed improvements in daily average pain and night pain severity, compared with those on placebo. The improvements started as early as 1 week and were maintained for 12 weeks. At 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in daily average pain severity of 47% and 50%, compared with 29% for those on placebo.

Also at 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in night pain severity of 47% and 51%, respectively, compared with 34% for those on placebo.

WASHINGTON – Not only does duloxetine appear to reduce the severity of pain, especially during the night, but it may also help patients with diabetic peripheral neuropathy get a better night's sleep, according to a poster presentation at the annual meeting of the American Pain Society.

After 12 weeks of treatment, patients on 60 mg of duloxetine once or twice daily had improvements in average daily pain severity, night pain severity, and pain-related sleep interference, wrote Dr. David A. Fishbain, professor of psychiatry and behavioral sciences at the University of Miami, and his colleagues at Eli Lilly, maker of duloxetine (Cymbalta).

Although causality cannot be demonstrated between duloxetine and better sleep, the findings suggest that improvements in pain will be associated with less interference in sleep, the authors wrote.

The researchers pooled data from three double-blind, placebo-controlled trials of duloxetine in patients with diabetic peripheral neuropathic pain (DPNP). In the first study, 457 patients were randomized to receive 20 mg of duloxetine once daily, 60 mg of duloxetine once or twice daily, or placebo. In studies two and three, 334 and 348 patients, respectively, were randomized to receive 60 mg of duloxetine once daily, 60 mg of duloxetine twice daily, or placebo. Although the primary efficacy measure for the studies was the reduction in the weekly mean of the 24-hour average pain score, secondary end points included average daily night pain severity (measured on an 11-point Likert scale) and the Brief Pain Inventory sleep interference item.

Patients were included in the trials if they were 18 years or older with pain because of bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. Pain had to have begun in the feet with relatively symmetric onset. Diagnosis was confirmed by a score of at least three on the Michigan Neuropathy Screening Instrument. Daily pain had to be present for at least 6 months. Patients also had to have at least a 4 on the 24-hour average pain severity (11-point Likert) scale and stable glycemic control. Notably, patients with a current or recent (within the last year) diagnosis of major depressive disorder as defined by the DSM-IV were excluded from the studies.

The researchers identified a subset of nonsomnolent patients by excluding those who reported treatment-emergent somnolence or who were on concomitant sedating medications. Treatment-emergent somnolence included reports of daytime sleepiness, drowsiness, being drowsy upon awakening, excessive daytime sleepiness, a feeling of residual sleepiness, groggy, groggy and sluggish, groggy on awakening, hard to awaken, less alert on rising, sleepiness, sleepy, and somnolence.

In all three studies, 339 patients received placebo. Of these, 307 met the criteria for the nonsomnolent subset. A total of 685 patients received 60 mg or 120 mg per day of duloxetine in all three studies. Of these, 607 met the criteria for the nonsomnolent subset. Patients in the nonsomnolent/nonsedating subgroup who were on duloxetine showed improvements in daily average pain and night pain severity, compared with those on placebo. The improvements started as early as 1 week and were maintained for 12 weeks. At 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in daily average pain severity of 47% and 50%, compared with 29% for those on placebo.

Also at 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in night pain severity of 47% and 51%, respectively, compared with 34% for those on placebo.

WASHINGTON – Not only does duloxetine appear to reduce the severity of pain, especially during the night, but it may also help patients with diabetic peripheral neuropathy get a better night's sleep, according to a poster presentation at the annual meeting of the American Pain Society.

After 12 weeks of treatment, patients on 60 mg of duloxetine once or twice daily had improvements in average daily pain severity, night pain severity, and pain-related sleep interference, wrote Dr. David A. Fishbain, professor of psychiatry and behavioral sciences at the University of Miami, and his colleagues at Eli Lilly, maker of duloxetine (Cymbalta).

Although causality cannot be demonstrated between duloxetine and better sleep, the findings suggest that improvements in pain will be associated with less interference in sleep, the authors wrote.

The researchers pooled data from three double-blind, placebo-controlled trials of duloxetine in patients with diabetic peripheral neuropathic pain (DPNP). In the first study, 457 patients were randomized to receive 20 mg of duloxetine once daily, 60 mg of duloxetine once or twice daily, or placebo. In studies two and three, 334 and 348 patients, respectively, were randomized to receive 60 mg of duloxetine once daily, 60 mg of duloxetine twice daily, or placebo. Although the primary efficacy measure for the studies was the reduction in the weekly mean of the 24-hour average pain score, secondary end points included average daily night pain severity (measured on an 11-point Likert scale) and the Brief Pain Inventory sleep interference item.

Patients were included in the trials if they were 18 years or older with pain because of bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. Pain had to have begun in the feet with relatively symmetric onset. Diagnosis was confirmed by a score of at least three on the Michigan Neuropathy Screening Instrument. Daily pain had to be present for at least 6 months. Patients also had to have at least a 4 on the 24-hour average pain severity (11-point Likert) scale and stable glycemic control. Notably, patients with a current or recent (within the last year) diagnosis of major depressive disorder as defined by the DSM-IV were excluded from the studies.

The researchers identified a subset of nonsomnolent patients by excluding those who reported treatment-emergent somnolence or who were on concomitant sedating medications. Treatment-emergent somnolence included reports of daytime sleepiness, drowsiness, being drowsy upon awakening, excessive daytime sleepiness, a feeling of residual sleepiness, groggy, groggy and sluggish, groggy on awakening, hard to awaken, less alert on rising, sleepiness, sleepy, and somnolence.

In all three studies, 339 patients received placebo. Of these, 307 met the criteria for the nonsomnolent subset. A total of 685 patients received 60 mg or 120 mg per day of duloxetine in all three studies. Of these, 607 met the criteria for the nonsomnolent subset. Patients in the nonsomnolent/nonsedating subgroup who were on duloxetine showed improvements in daily average pain and night pain severity, compared with those on placebo. The improvements started as early as 1 week and were maintained for 12 weeks. At 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in daily average pain severity of 47% and 50%, compared with 29% for those on placebo.

Also at 12 weeks, subset patients on 60 mg of duloxetine once and twice daily had improvements in night pain severity of 47% and 51%, respectively, compared with 34% for those on placebo.

BALTIMORE – The lack of diagnostic criteria has hamstrung attempts to diagnose involuntary emotional expression disorder, Dr. Sharon Handel said at a meeting on Alzheimer's disease and related disorders sponsored by Johns Hopkins University.

Even when they make the diagnosis with certainty, physicians have little to offer by way of Food and Drug Administration-approved therapy, said Dr. Handel, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. Part of the problem with identifying this condition has been the numerous names under which it is known, she noted. Involuntary emotional expression disorder (IEED) is also known as pseudobulbar affect and pathologic laughing or crying.

It's estimated that more than 1 million people in the United States have IEED. The disorder has been associated with cerebrovascular accident, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.

The hallmark of IEED is episodes of crying or laughing that are unrelated to or out of proportion with the eliciting stimulus. There is a disconnection between emotional experience and expression.

Emotional outbursts in IEED are involuntary, episodic, and incongruent with baseline mood. The outbursts are intense, but are followed by a return to baseline.

Disorders of affect–which IEED appears to be–involve impairment of the moment-to-moment regulation of emotion. “There's a disconnection of the neural networks in this condition from the experienced emotion to the display of emotion,” Dr. Handel said.

The neural networks of emotion involve the frontal lobes, the limbic system, the brainstem, the cerebellum, and white-matter tracts. In particular, the prefrontal cortex integrates complex sensory and limbic information that determines the emotional valence of a stimulus and modulates motor and autonomic responses involved in emotional expression. It's not clear where the neural interruption occurs in IEED.

For now, the current diagnostic criteria include:

▸ Episodes of involuntary crying, laughing, or related displays.

▸ Origin in brain injury or disease.

▸ A change in the patient's emotional behavior from that prior to the disease or injury.

▸ Incongruent or exaggerated mood.

▸ A response that is excessive or unrelated to the stimulus.

▸ Significant distress or impairment.

The differential diagnosis should include epilepsy; facial dystonia or dyskinesias; vocal tics; axis I disorders (such as major depression or bipolar disorder); axis II disorders (such as borderline personality disorder); and substance abuse.

“These patients often have major depression, and while specific treatment is often the same, I think it's important to differentiate the two conditions,” Dr. Handel said.

The differential diagnosis should also include affective lability, essential crying, and witzelsucht. With affective lability, the subjective and objective dimensions of affect are not dissociated. Essential crying is a hereditary and lifelong tendency to cry easily. Witzelsucht is an addiction to trivial joking, which can take the form of an inappropriate giddy affect and irritability or aggressiveness.

In terms of clinical course, IEED frequently remits spontaneously within 6 months. Others may have remission with treatment within 3 months. Resolution of IEED can be independent of the resolution of depression. However, in some cases the disorder is chronic and persistent without treatment.

Treatment of IEED is still evolving. At present, there is no FDA-approved treatment for IEED. “What are typically used–at least up to this point–are SSRIs. They tend to work quite quickly,” said Dr. Handel, who has no disclosures.

Dextromethorphan, in combination with quinidine, is being studied to treat patients who have IEED. Dextromethorphan is a nonopioid antitussive, but it also has a number of other neuropharmacologic properties. It is a potent sigma1 agonist (inhibiting the release of the excitatory neurotransmitter, glutamate) and is also an N-methyl-D-aspartic acid glutamate receptor antagonist.

Dextromethorphan undergoes significant first-pass metabolism by the cytochrome P450 isoenzyme CYP2D6. Quinidine is a potent inhibitor of this isoenzyme, thereby increasing and sustaining dextromethorphan levels.

BALTIMORE – The lack of diagnostic criteria has hamstrung attempts to diagnose involuntary emotional expression disorder, Dr. Sharon Handel said at a meeting on Alzheimer's disease and related disorders sponsored by Johns Hopkins University.

Even when they make the diagnosis with certainty, physicians have little to offer by way of Food and Drug Administration-approved therapy, said Dr. Handel, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. Part of the problem with identifying this condition has been the numerous names under which it is known, she noted. Involuntary emotional expression disorder (IEED) is also known as pseudobulbar affect and pathologic laughing or crying.

It's estimated that more than 1 million people in the United States have IEED. The disorder has been associated with cerebrovascular accident, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.

The hallmark of IEED is episodes of crying or laughing that are unrelated to or out of proportion with the eliciting stimulus. There is a disconnection between emotional experience and expression.

Emotional outbursts in IEED are involuntary, episodic, and incongruent with baseline mood. The outbursts are intense, but are followed by a return to baseline.

Disorders of affect–which IEED appears to be–involve impairment of the moment-to-moment regulation of emotion. “There's a disconnection of the neural networks in this condition from the experienced emotion to the display of emotion,” Dr. Handel said.

The neural networks of emotion involve the frontal lobes, the limbic system, the brainstem, the cerebellum, and white-matter tracts. In particular, the prefrontal cortex integrates complex sensory and limbic information that determines the emotional valence of a stimulus and modulates motor and autonomic responses involved in emotional expression. It's not clear where the neural interruption occurs in IEED.

For now, the current diagnostic criteria include:

▸ Episodes of involuntary crying, laughing, or related displays.

▸ Origin in brain injury or disease.

▸ A change in the patient's emotional behavior from that prior to the disease or injury.

▸ Incongruent or exaggerated mood.

▸ A response that is excessive or unrelated to the stimulus.

▸ Significant distress or impairment.

The differential diagnosis should include epilepsy; facial dystonia or dyskinesias; vocal tics; axis I disorders (such as major depression or bipolar disorder); axis II disorders (such as borderline personality disorder); and substance abuse.

“These patients often have major depression, and while specific treatment is often the same, I think it's important to differentiate the two conditions,” Dr. Handel said.

The differential diagnosis should also include affective lability, essential crying, and witzelsucht. With affective lability, the subjective and objective dimensions of affect are not dissociated. Essential crying is a hereditary and lifelong tendency to cry easily. Witzelsucht is an addiction to trivial joking, which can take the form of an inappropriate giddy affect and irritability or aggressiveness.

In terms of clinical course, IEED frequently remits spontaneously within 6 months. Others may have remission with treatment within 3 months. Resolution of IEED can be independent of the resolution of depression. However, in some cases the disorder is chronic and persistent without treatment.

Treatment of IEED is still evolving. At present, there is no FDA-approved treatment for IEED. “What are typically used–at least up to this point–are SSRIs. They tend to work quite quickly,” said Dr. Handel, who has no disclosures.

Dextromethorphan, in combination with quinidine, is being studied to treat patients who have IEED. Dextromethorphan is a nonopioid antitussive, but it also has a number of other neuropharmacologic properties. It is a potent sigma1 agonist (inhibiting the release of the excitatory neurotransmitter, glutamate) and is also an N-methyl-D-aspartic acid glutamate receptor antagonist.

Dextromethorphan undergoes significant first-pass metabolism by the cytochrome P450 isoenzyme CYP2D6. Quinidine is a potent inhibitor of this isoenzyme, thereby increasing and sustaining dextromethorphan levels.

BALTIMORE – The lack of diagnostic criteria has hamstrung attempts to diagnose involuntary emotional expression disorder, Dr. Sharon Handel said at a meeting on Alzheimer's disease and related disorders sponsored by Johns Hopkins University.

Even when they make the diagnosis with certainty, physicians have little to offer by way of Food and Drug Administration-approved therapy, said Dr. Handel, of the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. Part of the problem with identifying this condition has been the numerous names under which it is known, she noted. Involuntary emotional expression disorder (IEED) is also known as pseudobulbar affect and pathologic laughing or crying.

It's estimated that more than 1 million people in the United States have IEED. The disorder has been associated with cerebrovascular accident, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.

The hallmark of IEED is episodes of crying or laughing that are unrelated to or out of proportion with the eliciting stimulus. There is a disconnection between emotional experience and expression.

Emotional outbursts in IEED are involuntary, episodic, and incongruent with baseline mood. The outbursts are intense, but are followed by a return to baseline.

Disorders of affect–which IEED appears to be–involve impairment of the moment-to-moment regulation of emotion. “There's a disconnection of the neural networks in this condition from the experienced emotion to the display of emotion,” Dr. Handel said.

The neural networks of emotion involve the frontal lobes, the limbic system, the brainstem, the cerebellum, and white-matter tracts. In particular, the prefrontal cortex integrates complex sensory and limbic information that determines the emotional valence of a stimulus and modulates motor and autonomic responses involved in emotional expression. It's not clear where the neural interruption occurs in IEED.

For now, the current diagnostic criteria include:

▸ Episodes of involuntary crying, laughing, or related displays.

▸ Origin in brain injury or disease.

▸ A change in the patient's emotional behavior from that prior to the disease or injury.

▸ Incongruent or exaggerated mood.

▸ A response that is excessive or unrelated to the stimulus.

▸ Significant distress or impairment.

The differential diagnosis should include epilepsy; facial dystonia or dyskinesias; vocal tics; axis I disorders (such as major depression or bipolar disorder); axis II disorders (such as borderline personality disorder); and substance abuse.

“These patients often have major depression, and while specific treatment is often the same, I think it's important to differentiate the two conditions,” Dr. Handel said.

The differential diagnosis should also include affective lability, essential crying, and witzelsucht. With affective lability, the subjective and objective dimensions of affect are not dissociated. Essential crying is a hereditary and lifelong tendency to cry easily. Witzelsucht is an addiction to trivial joking, which can take the form of an inappropriate giddy affect and irritability or aggressiveness.

In terms of clinical course, IEED frequently remits spontaneously within 6 months. Others may have remission with treatment within 3 months. Resolution of IEED can be independent of the resolution of depression. However, in some cases the disorder is chronic and persistent without treatment.

Treatment of IEED is still evolving. At present, there is no FDA-approved treatment for IEED. “What are typically used–at least up to this point–are SSRIs. They tend to work quite quickly,” said Dr. Handel, who has no disclosures.

Dextromethorphan, in combination with quinidine, is being studied to treat patients who have IEED. Dextromethorphan is a nonopioid antitussive, but it also has a number of other neuropharmacologic properties. It is a potent sigma1 agonist (inhibiting the release of the excitatory neurotransmitter, glutamate) and is also an N-methyl-D-aspartic acid glutamate receptor antagonist.

Dextromethorphan undergoes significant first-pass metabolism by the cytochrome P450 isoenzyme CYP2D6. Quinidine is a potent inhibitor of this isoenzyme, thereby increasing and sustaining dextromethorphan levels.