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Cortical demyelination is common early in the course of multiple sclerosis and is inflammatory in nature, according to an analysis of brain biopsy samples containing cortical tissue.
"These findings do not support a primary (noninflammatory) neurodegenerative process during early-stage multiple sclerosis," Dr. Claudia F. Lucchinetti of the Mayo Clinic, Rochester, Minn., and her associates wrote in the Dec. 8 issue of the New England Journal of Medicine.
Most previous studies of cortical lesions have focused on autopsy findings in patients with longstanding multiple sclerosis and "have suggested that neurodegeneration proceeds independently of parenchymal inflammation," the investigators noted.
They chose instead to study the prevalence and histopathologic features of cortical demyelination in brain biopsy samples from 563 patients who underwent the procedure to rule out other possible causes of their neurological symptoms, such as brain tumors. The cortical matter was obtained "in passing," in samples that were targeting white-matter lesions. The samples were obtained within a median of 27 days from the onset of symptoms.
A total of 138 patients’ samples contained a sufficient amount of cortex for analysis. Of these 138 patients, 77 had clinical follow-up for a median of 3.5 years. MS was eventually diagnosed in 58 (75%), and a clinically isolated syndrome was diagnosed in the remaining 19 (25%).
In all, 53 of the 138 samples (38%) showed cortical demyelination, Dr. Lucchinetti and her colleagues reported (N. Engl. J. Med. 2011;365:2188-97).
The lesions were highly inflammatory and had a high prevalence of CD3-positive and CD8-positive T-cell infiltrates as well as myelin-laden macrophages.
In addition, among patients who had sufficient meningeal tissue for analysis, meningeal inflammation was topographically adjacent to the cortical demyelination.
The researchers also found concurrent subpial and leukocortical lesions within individual tissue sections, "suggesting that superficial demyelinating disease may contribute to the generation of deeper lesions by means of cytokine diffusion."
In addition, "our findings of microglial activation, neuritic injury, pyknotic neurons, and reduced oligodendrocyte density ... are consonant with the findings in patients with progressive MS, underscoring the potential of cortical demyelination to cause irreversible injury, although inflammation may resolve rapidly."
They speculated that the mechanism of MS progression might involve "myelin-laden macrophages leaving the cortex, entering the cerebrospinal fluid, and gaining access to deep cervical lymph nodes to promote epitope spreading."
This study was supported by the National Multiple Sclerosis Society and the National Institutes of Health. Dr. Lucchinetti’s associates reported ties to numerous companies that market and develop drugs for MS, as well as receiving research funding or travel awards from research institutions or patient advocacy organizations.
The "provocative" findings of Dr. Lucchinetti and her colleagues "provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of multiple sclerosis," wrote Dr. Peter A. Calabresi.
Before now, macrophages laden with myelin – the hallmark of an active plaque – have not been seen in cortical tissue, and gray-matter lesions have been "routinely underestimated" because conventional MRI doesn’t pick up MS plaques in the cortical and deep gray structures, he said.
This study suggests that cortical neuronal loss "is directly associated with inflammatory demyelination, and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments," Dr. Calabresi added.
Dr. Calabresi is in the department of neurology at Johns Hopkins Hospital, Baltimore. He reported ties to numerous companies that market and develop drugs for MS. These remarks were adapted from his editorial comment accompanying Dr. Lucchinetti’s report (N. Engl. J. Med. 2011;365:2231-3).
The "provocative" findings of Dr. Lucchinetti and her colleagues "provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of multiple sclerosis," wrote Dr. Peter A. Calabresi.
Before now, macrophages laden with myelin – the hallmark of an active plaque – have not been seen in cortical tissue, and gray-matter lesions have been "routinely underestimated" because conventional MRI doesn’t pick up MS plaques in the cortical and deep gray structures, he said.
This study suggests that cortical neuronal loss "is directly associated with inflammatory demyelination, and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments," Dr. Calabresi added.
Dr. Calabresi is in the department of neurology at Johns Hopkins Hospital, Baltimore. He reported ties to numerous companies that market and develop drugs for MS. These remarks were adapted from his editorial comment accompanying Dr. Lucchinetti’s report (N. Engl. J. Med. 2011;365:2231-3).
The "provocative" findings of Dr. Lucchinetti and her colleagues "provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of multiple sclerosis," wrote Dr. Peter A. Calabresi.
Before now, macrophages laden with myelin – the hallmark of an active plaque – have not been seen in cortical tissue, and gray-matter lesions have been "routinely underestimated" because conventional MRI doesn’t pick up MS plaques in the cortical and deep gray structures, he said.
This study suggests that cortical neuronal loss "is directly associated with inflammatory demyelination, and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments," Dr. Calabresi added.
Dr. Calabresi is in the department of neurology at Johns Hopkins Hospital, Baltimore. He reported ties to numerous companies that market and develop drugs for MS. These remarks were adapted from his editorial comment accompanying Dr. Lucchinetti’s report (N. Engl. J. Med. 2011;365:2231-3).
Cortical demyelination is common early in the course of multiple sclerosis and is inflammatory in nature, according to an analysis of brain biopsy samples containing cortical tissue.
"These findings do not support a primary (noninflammatory) neurodegenerative process during early-stage multiple sclerosis," Dr. Claudia F. Lucchinetti of the Mayo Clinic, Rochester, Minn., and her associates wrote in the Dec. 8 issue of the New England Journal of Medicine.
Most previous studies of cortical lesions have focused on autopsy findings in patients with longstanding multiple sclerosis and "have suggested that neurodegeneration proceeds independently of parenchymal inflammation," the investigators noted.
They chose instead to study the prevalence and histopathologic features of cortical demyelination in brain biopsy samples from 563 patients who underwent the procedure to rule out other possible causes of their neurological symptoms, such as brain tumors. The cortical matter was obtained "in passing," in samples that were targeting white-matter lesions. The samples were obtained within a median of 27 days from the onset of symptoms.
A total of 138 patients’ samples contained a sufficient amount of cortex for analysis. Of these 138 patients, 77 had clinical follow-up for a median of 3.5 years. MS was eventually diagnosed in 58 (75%), and a clinically isolated syndrome was diagnosed in the remaining 19 (25%).
In all, 53 of the 138 samples (38%) showed cortical demyelination, Dr. Lucchinetti and her colleagues reported (N. Engl. J. Med. 2011;365:2188-97).
The lesions were highly inflammatory and had a high prevalence of CD3-positive and CD8-positive T-cell infiltrates as well as myelin-laden macrophages.
In addition, among patients who had sufficient meningeal tissue for analysis, meningeal inflammation was topographically adjacent to the cortical demyelination.
The researchers also found concurrent subpial and leukocortical lesions within individual tissue sections, "suggesting that superficial demyelinating disease may contribute to the generation of deeper lesions by means of cytokine diffusion."
In addition, "our findings of microglial activation, neuritic injury, pyknotic neurons, and reduced oligodendrocyte density ... are consonant with the findings in patients with progressive MS, underscoring the potential of cortical demyelination to cause irreversible injury, although inflammation may resolve rapidly."
They speculated that the mechanism of MS progression might involve "myelin-laden macrophages leaving the cortex, entering the cerebrospinal fluid, and gaining access to deep cervical lymph nodes to promote epitope spreading."
This study was supported by the National Multiple Sclerosis Society and the National Institutes of Health. Dr. Lucchinetti’s associates reported ties to numerous companies that market and develop drugs for MS, as well as receiving research funding or travel awards from research institutions or patient advocacy organizations.
Cortical demyelination is common early in the course of multiple sclerosis and is inflammatory in nature, according to an analysis of brain biopsy samples containing cortical tissue.
"These findings do not support a primary (noninflammatory) neurodegenerative process during early-stage multiple sclerosis," Dr. Claudia F. Lucchinetti of the Mayo Clinic, Rochester, Minn., and her associates wrote in the Dec. 8 issue of the New England Journal of Medicine.
Most previous studies of cortical lesions have focused on autopsy findings in patients with longstanding multiple sclerosis and "have suggested that neurodegeneration proceeds independently of parenchymal inflammation," the investigators noted.
They chose instead to study the prevalence and histopathologic features of cortical demyelination in brain biopsy samples from 563 patients who underwent the procedure to rule out other possible causes of their neurological symptoms, such as brain tumors. The cortical matter was obtained "in passing," in samples that were targeting white-matter lesions. The samples were obtained within a median of 27 days from the onset of symptoms.
A total of 138 patients’ samples contained a sufficient amount of cortex for analysis. Of these 138 patients, 77 had clinical follow-up for a median of 3.5 years. MS was eventually diagnosed in 58 (75%), and a clinically isolated syndrome was diagnosed in the remaining 19 (25%).
In all, 53 of the 138 samples (38%) showed cortical demyelination, Dr. Lucchinetti and her colleagues reported (N. Engl. J. Med. 2011;365:2188-97).
The lesions were highly inflammatory and had a high prevalence of CD3-positive and CD8-positive T-cell infiltrates as well as myelin-laden macrophages.
In addition, among patients who had sufficient meningeal tissue for analysis, meningeal inflammation was topographically adjacent to the cortical demyelination.
The researchers also found concurrent subpial and leukocortical lesions within individual tissue sections, "suggesting that superficial demyelinating disease may contribute to the generation of deeper lesions by means of cytokine diffusion."
In addition, "our findings of microglial activation, neuritic injury, pyknotic neurons, and reduced oligodendrocyte density ... are consonant with the findings in patients with progressive MS, underscoring the potential of cortical demyelination to cause irreversible injury, although inflammation may resolve rapidly."
They speculated that the mechanism of MS progression might involve "myelin-laden macrophages leaving the cortex, entering the cerebrospinal fluid, and gaining access to deep cervical lymph nodes to promote epitope spreading."
This study was supported by the National Multiple Sclerosis Society and the National Institutes of Health. Dr. Lucchinetti’s associates reported ties to numerous companies that market and develop drugs for MS, as well as receiving research funding or travel awards from research institutions or patient advocacy organizations.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: A total of 53 (38%) of 138 biopsy samples of cortical tissue showed demyelination, with a high prevalence of inflammation.
Data Source: An analysis of brain biopsy samples containing cortical tissue from 138 patients early in the course of MS, often before the disease was diagnosed.
Disclosures: This study was supported by the National Multiple Sclerosis Society and the National Institutes of Health. Dr. Lucchinetti’s associates reported ties to numerous companies that market and develop drugs for MS, as well as receiving research funding or travel awards from research institutions or patient advocacy organizations.