MRI findings in benign multiple sclerosis are variable.
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Brain↗
Biomedical subjects
Sean J Pittock
Publications and source records attributed to Sean J Pittock.
Therapeutic decision making in MS: impact of a slower disability progression.
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Decision Making↗
Neuromyelitis optica IgG status in acute partial transverse myelitis.
BACKGROUND: Neuromyelitis optica (NMO) IgG is a specific marker for NMO. Furthermore, a high proportion of patients with longitudinally extensive transverse myelitis (characterized by spinal cord lesions extending 3 vertebral segments or more on magnetic resonance imaging) are seropositive for NMO-IgG and are considered to have a limited form of NMO. The NMO-IgG status in mild cases of acute partial transverse myelitis asociated with minimal magnetic resonance imaging abnormalities (spinal cord lesions <2 vertebral segments on magnetic resonance imaging) is unknown. OBJECTIVE: To investigate the NMO-IgG status of patients with acute partial transverse myelitis and a normal cerebral magnetic resonance image. DESIGN: Observational, retrospective consecutive case series with longitudinal follow-up. SETTING: Allegheny Multiple Sclerosis Treatment Center. PATIENTS: Three groups of patients were tested for NMO-IgG. Group 1 consisted of 22 patients with acute partial transverse myelitis, group 2 consisted of 4 patients with definite NMO (by 1999 criteria of Wingerchuk et al), and group 3 consisted of 6 patients with definite multiple sclerosis. MAIN OUTCOME MEASURE: NMO-IgG status. A commercially available assay for NMO antibodies was performed at the Mayo Clinic. Testing was performed during the convalescent stage of the illness. RESULTS: Of the 22 patients with acute partial transverse myelitis, only 1 was seropositive for NMO-IgG at presentation. This patient subsequently developed recurrent episodes of longitudinally extensive transverse myelitis that are typicaly seen in association with NMO-IgG. Three of the 4 patients meeting criteria for NMO were seropositive. None of the patients with multiple sclerosis had NMO-IgG detected. CONCLUSION: NMO-IgG is rarely encountered in patients with acute partial transverse myelitis, which is in sharp contrast to the high frequency of this antibody in patients with NMO and longitudinally extensive transverse myelitis.
Follow-Up Studies↗
Brain abnormalities in neuromyelitis optica.
BACKGROUND: Neuromyelitis optica (NMO) is a severe demyelinating disease defined principally by its tendency to selectively affect optic nerves and the spinal cord causing recurrent attacks of blindness and paralysis. Contemporary diagnostic criteria require absence of clinical disease outside the optic nerve or spinal cord. We have, however, frequently encountered patients with a well-established diagnosis of NMO in whom either asymptomatic or symptomatic brain lesions develop suggesting that the diagnostic criteria for NMO should be revised. OBJECTIVE: To describe the magnetic resonance image (MRI) brain findings in NMO. DESIGN: Observational, retrospective case series. Patients We ascertained patients through a clinical biospecimens database of individuals with definite or suspected NMO. We included patients who (1) satisfied the 1999 criteria of Wingerchuk et al for NMO except for the absolute criterion of lacking symptoms beyond the optic nerve and spinal cord and the supportive criterion of having a normal brain MRI at onset; (2) had MRI evidence of a spinal cord lesion extending 3 vertebral segments or more (the most specific nonserological feature to differentiate NMO from MS); and (3) were evaluated neurologically and by brain MRI at the Mayo Clinic. MAIN OUTCOME MEASURES: Magnetic resonance images were classified as normal or as abnormal with either nonspecific, multiple sclerosis-like or atypical abnormalities. We evaluated whether brain lesions were symptomatic and analyzed the neuropathologic features of a single brain biopsy specimen. RESULTS: Sixty patients (53 women [88%]) fulfilled these inclusion criteria. The mean +/- SD age at onset was 37.2 +/- 18.4 years and the mean +/- SD duration of follow-up was 6.0 +/- 5.6 years. Neuromyelitis optica-IgG was detected in 41 patients (68%). Brain MRI lesions were detected in 36 patients (60%). Most were nonspecific, but 6 patients (10%) had multiple sclerosis-like lesions, usually asymptomatic. Another 5 patients (8%), mostly children, had diencephalic, brainstem or cerebral lesions, atypical for multiple sclerosis. When present, symptoms of brain involvement were subtle, except in 1 patient who was comatose and had large cerebral lesions. CONCLUSIONS: Asymptomatic brain lesions are common in NMO, and symptomatic brain lesions do not exclude the diagnosis of NMO. These observations justify revision of diagnostic criteria for NMO to allow for brain involvement.
Adult↗
Not every patient with multiple sclerosis should be treated at time of diagnosis.
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Clinical Protocols↗
Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.
BACKGROUND: Neuromyelitis optica (NMO)-IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE: To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN: Observational, retrospective case series. SETTING: Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS: We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE: Magnetic resonance imaging abnormalities. RESULTS: In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION: The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.
Adolescent↗
Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.
OBJECTIVE: We investigated whether neuromyelitis optica (NMO) IgG seropositivity at the initial presentation of longitudinally extensive transverse myelitis (LETM) predicts relapse of myelitis or development of optic neuritis. METHODS: Prospective study of patients with initial LETM who were tested for the presence of NMO-IgG. RESULTS: Eleven of 29 patients (37.9%) were seropositive after a first attack of LETM spanning three or more vertebral segments on magnetic resonance imaging. Of 23 patients followed up for 1 year, none of 14 who were seronegative experienced a relapse or developed optic neuritis. Of 9 seropositive patients, 5 developed a second event: 4 of 9 (44%) developed recurrent transverse myelitis and 1 of 9 (11%) developed optic neuritis (p = 0.004). INTERPRETATION: LETM represents an inaugural or limited form of NMO in a high proportion of patients. The 40% of patients who are seropositive for NMO-IgG are at high risk for relapse.
Adult↗
Inflammatory transverse myelitis: evolving concepts.
PURPOSE OF REVIEW: Acute transverse myelitis is a pathogenetically heterogeneous inflammatory disorder of the spinal cord. Here we describe recent advances in inflammatory non-infectious transverse myelitis. Particular attention will be paid to the serum autoantibody marker NMO-IgG and its application to acute transverse myelitis. RECENT FINDINGS: The recent identification of neuromyelitis optica-IgG, a novel marker of neuromyelitis optica spectrum disorders (including longitudinally extensive transverse myelitis), contributes to an evolving understanding of acute transverse myelitis. Other serological markers, such as collapsin response-mediator protein-5 -IgG and amphiphysin-IgG, predict specific cancers in the setting of a paraneoplastic acute transverse myelitis. Furthermore, novel inflammatory markers such as interleukin-6 or other proteins in their signaling pathways may represent markers of disease severity and potential therapeutic targets. Additional cerebrospinal fluid biomarkers, such as protein 14-3-3 and neuron-specific enolase, may be useful prognostic indicators in transverse myelitis. Acute transverse myelitis in children, in contrast to adults, is more likely to be longitudinally extensive, and has a better prognosis and lower likelihood of recurrence. Prognostic factors in pediatric transverse myelitis are reviewed. SUMMARY: The recent identification of novel biomarkers associated with acute transverse myelitis has led to a better understanding of the spectrum of disorders associated with inflammatory transverse myelitis, as well as a greater appreciation of its diverse and complex pathogenetic basis.
Aquaporins↗
NMO-IgG: a specific biomarker for neuromyelitis optica.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system's predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients' spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.
Autoantibodies↗
Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
OBJECTIVE: To describe novel neurological manifestations associated with glutamic acid decarboxylase (GAD65) autoimmunity. PATIENTS AND METHODS: This retrospective study (1987-2003) describes 62 patients Incidentally found to have a serum autoantibody that bound selectively to synapse-rich central nervous system tissues. The immunostaining pattern was determined to be GAD65-specific by radiolmmunoprecipitation assay. These cases were identified among samples submitted for paraneoplastic autoantibody evaluation using indirect immunofluorescence. In no case had GAD65 or any other islet cell antibody testing been requested. RESULTS: In most cases, the patients' presentations were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic). Median age at onset was 50 years, and 77% were women. Of the 44 patients seen at the Mayo Clinic, 23% were African American; in contrast, less than 10% of Mayo Clinic's neurology patients are African American. Median follow-up was 24 months. The radioimmunoprecipitation assay values for GAD65 antibody were extremely high (median, 1429 nmol/L; Interquartile range, 643-3078 nmol/L) and correlated significantly with immunofluorescence titers (median, 3840; interquartile range, 1920-15,360; r = 0.81; P < .001). Neurological manifestations were multifocal in 41 patients and included cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff-man phenomena (26%), extrapyramidal signs (16%), and myelopathy (8%). One third of the patients had type 1 diabetes mellitus, 53% had thyroid autoantibodies, and 16% had vitiligo. Eleven of 20 patients identified as African American had brainstem involvement. Some patients appeared to benefit from short-term immunosuppression (none received long-term therapy). CONCLUSIONS: The neurological spectrum of GAD65 autoimmunity includes brainstem, extrapyramidal, and spinal cord syndromes. In our experience, African American patients were disproportionately affected. A patient with a presumed neurodegenerative disorder of new onset, with high levels of GAD65 antibody (>20 nmol/L), merits consideration of immunotherapy.
Black or African American↗
IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.
Animals↗
Amphiphysin autoimmunity: paraneoplastic accompaniments.
Amphiphysin-IgG was identified in 71 patients among 120,000 evaluated serologically for paraneoplastic autoantibodies. Clinical information was available for 63 patients. Cancer was detected in 50 (mostly limited), proven histologically in 46, and was imaged intrathoracically in 4 patients (lung, small-cell [27] and non-small cell [1]), breast [16] and melanoma [2]). Neurological accompaniments included (decreasing frequency): neuropathy, encephalopathy, myelopathy, stiff-man phenomena, and cerebellar syndrome. In a case examined neuropathologically, parenchymal T-lymphocyte infiltration (predominantly CD8(+)) was prominent in lower brainstem, spinal cord, and dorsal root ganglion. Coexisting paraneoplastic autoantibodies, identified in 74% of patients, predicted a common neoplasm and indicated other neuronal autoantigen targets that plausibly explained several neurological manifestations; for example, P/Q-type Ca(2+)-channel antibody with Lambert-Eaton syndrome (n = 5), anti-neuronal nuclear antibody type 1 with sensory neuronopathy (n = 7), K(+)-channel antibody with limbic encephalitis (n = 1) or neuromyotonia (n = 1), and collapsin response-mediator protein-5-IgG with optic neuritis (n = 3). Patients with isolated amphiphysin-IgG (n = 19) were more likely to be women (with breast cancer, p < 0.05) and to have myelopathy or stiff-man phenomena (p < 0.01). Overall, a minority of women (39%) and men (12%) had stiff-man phenomena. Only 10% of women (some with lung carcinoma) and 4% of men fulfilled diagnostic criteria for stiff-man syndrome.
Aged↗
Quality of life is favorable for most patients with multiple sclerosis: a population-based cohort study.
BACKGROUND: Quality of life (QOL) is becoming an increasingly important factor in measurement of disease impact as well as an outcome measure in clinical trials. OBJECTIVES: To study the QOL of patients with multiple sclerosis (MS) in a population-based prevalence cohort and compare it with the general US population. DESIGN: Population-based prevalence cohort. SETTING: Olmsted County, Minn, population. PARTICIPANTS: All patients with definite MS (N = 201) alive and residing in Olmsted County on December 1, 2000. INTERVENTION: None. MAIN OUTCOME MEASURES: The expanded disability status scale (EDSS) and the Multiple Sclerosis Quality of Life Health Survey (MSQOL-54), which consisted of Short Form 36 (SF-36) with an additional 18 items pertinent to MS. RESULTS: The MSQOL-54 form was completed by 185 patients. Patients with MS had worse scores than the general US population with respect to physical functioning, vitality, and general health dimensions of the SF-36 QOL measure. Many QOL domains (pain, role emotional, mental health, and social functioning) were, however, similar for the 2000 MS cohort compared with the general US population. Duration of MS and EDSS score correlated significantly with physical functioning (P<.001). The QOL correlation with EDSS score was less than expected. No significant difference in the scores for the 8 QOL dimensions were found for patients with quick vs slow progression (quick progression defined as <5 years from onset to EDSS score of 3). The majority of patients with MS (77%) were mostly satisfied or delighted with their QOL. CONCLUSION: Though MS can cause significant disability, most patients with MS in the Olmsted County prevalence cohort continue to report a good QOL.
Activities of Daily Living↗
Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study.
In 2001, we followed up all patients from the 1991 Olmsted County Multiple Sclerosis (MS) prevalence cohort. We found that the longer the duration of MS and the lower the disability, the more likely a patient is to remain stable and not progress. This is particularly powerful for patients with benign MS with Expanded Disability Status Scale score of 2 or lower for 10 years or longer who have a greater than 90% chance of remaining stable. This is important because these patients represent 17% of the entire prevalence cohort. These data should assist in the shared therapeutic decision-making process of whether to start immunomodulatory medications.
Cohort Studies↗
Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome.
We investigated coexisting autoantibodies in sera of 553 patients with a neurological presentation and one or more paraneoplastic neuronal nuclear or cytoplasmic autoantibodies: antineuronal nuclear autoantibody type 1 (ANNA-1), ANNA-2, ANNA-3; Purkinje cell cytoplasmic autoantibody type 1 (PCA-1), PCA-2; and CRMP-5-immunoglobulin G or amphiphysin-immunoglobulin G. Except for PCA-1, which occurred alone, 31% of sera had more than one of these autoantibodies. In addition, 25% of sera had neuronal calcium channel (P/Q-type or N-type), potassium channel, ganglionic acetylcholine receptor, muscle acetylcholine receptor, or striational antibodies. The autoantibody profiles observed in patients with paraneoplastic disorders imply the targeting of multiple onconeural antigens and predict the patient's neoplasm, but not a specific neurological syndrome.
Antibodies, Antinuclear↗
Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology.
The neuroanatomical substrate for restless legs syndrome (RLS) is unknown. We identified 4 patients with idiopathic RLS who came to post-mortem examination, where brain and spinal cord tissue were available for neuropathological assessment. Lewy bodies were not identified and alpha-synuclein immunohistochemistry was uniformly negative. Neurofibrillary tangle pathology was variable and nonspecific. These findings suggest that tau- or alpha-synuclein brain pathology is not a component of primary RLS. Although chronic ischemic changes were found in all 4 cases, these were probably incidental. The absence of diagnostic microscopic brain or spinal cord pathology suggests that the pathologic substrate may be neurochemical or receptor based.
Aged↗
Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population.
We applied a clinical tremor rating scale and measures of disability to 200 of 201 multiple sclerosis patients from a prevalence cohort in Olmsted County, Minnesota. In a community-based sample, tremor was found clinically in 51 (25%) patients, although only 6 (3%) patients had severe tremor. Within the population as a whole, tremor was strongly associated with impairment disability and handicap.
Adolescent↗