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Archives of neurology 07/2012; 69(7):819-20. · 6.31 Impact Factor
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Melih Tutuncu,
Junger Tang,
Nuhad Abou Zeid,
Nilufer Kale,
Daniel J Crusan,
Elizabeth J Atkinson,
Aksel Siva,
Sean J Pittock,
Istvan Pirko, B Mark Keegan,
Claudia F Lucchinetti,
John H Noseworthy,
Moses Rodriguez,
Brian G Weinshenker,
Orhun H Kantarci
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ABSTRACT: Background:It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases.Objective:Our aim is to confirm that onset of progressive disease course is more relevant to the patient's age than the presence or duration of a pre-progression relapsing disease course in MS.Methods:We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics (chi(2) or t-test), age-of-progression-onset (t-test) and time to Expanded Disability Status Scale of 6 (EDSS6) (Kaplan-Meier analyses).Results:Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression.Conclusions: PATIENTS: with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.
Multiple Sclerosis 06/2012; · 4.26 Impact Factor
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ABSTRACT: BackgroundAcute hemorrhagic leukoencephalitis (AHL; Hurst’s disease) is a rare, severe, inflammatory CNS disease that is typically diffuse,
multifocal and associated with petechial hemorrhage. The objective of this study is to report the clinical, radiologic, and
pathologic findings in a fatal AHL case with focal brainstem involvement and gross hemorrhage.
MethodsPatient evaluation in a tertiary neurointensive care unit with serial brain magnetic resonance imaging (MRI) and neuropathological
examination on autopsy were performed.
ResultsThe patient presented with mild, then rapidly worsening, brainstem impairment to a locked-in syndrome. Brain MRI demonstrated
an isolated gadolinium enhancing brainstem lesion that enlarged dramatically over weeks and was associated with gross hemorrhage
and necrosis. The patient died despite aggressive treatment with intravenous corticosteroids and plasma exchange. Autopsy
demonstrated the isolated severe necrotic lesion consistent with AHL.
ConclusionsAHL may present as a solitary brainstem lesion with gross hemorrhage and should be considered in patients with isolated enhancing
brainstem lesions. AHL may be fatal even despite early, aggressive immunomodulatory therapy.
Neurocritical Care 04/2012; 12(1):95-97. · 2.47 Impact Factor
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ABSTRACT: To present a case series of patients with progressive myelopathy in the setting of a solitary demyelinating lesion.
We describe 7 patients evaluated over a 6-year period. All had progressive motor impairment attributable to an MRI lesion compatible with a demyelinating plaque in the brainstem or upper cervical spinal cord. At the time of evaluation, none met the International Panel imaging criteria for dissemination in space, and none described clinical symptoms consistent with relapses affecting other portions of the CNS.
Lesions identified were in the ventral cervicomedullary junction in 4 patients, the ventral spinal cord in 2 patients, and the pons in 1 patient. Median age at onset was 43 years (range 33-51 years). Median follow-up interval was 3 years (range 2-27 years). Six patients reached an Expanded Disability Status Scale (EDSS) score of 6.0 or worse. Median time to EDSS score of 6.0 was 7.5 years (range 1.5-26 years). Four had CSF findings characteristic of multiple sclerosis (MS). None had CSF, imaging, or serologic evidence of an alternative etiology of progressive myelopathy. In 3 patients, serial MRI scans of the brain and spinal cord demonstrated no accumulation of lesions. Postmortem examination of a fourth patient demonstrated an isolated pontine demyelinating lesion.
Solitary demyelinating lesions may produce a progressive myelopathy similar to primary progressive MS. Demyelinating disease should be in the differential diagnosis of progressive myelopathy despite absence of dissemination in space.
Neurology 02/2012; 78(8):540-4. · 8.31 Impact Factor
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B Mark Keegan
The Lancet Neurology 08/2011; 10(8):677-8. · 23.46 Impact Factor
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ABSTRACT: Oculopalatal tremor is frequently accompanied by progressive ataxia. In symptomatic oculopalatal tremor the ataxia frequently is delayed in onset. Progressive ataxia is a defining clinical feature of superficial siderosis. We report 5 cases with palatal tremor and ataxia. Four cases had evidence of intraparenchymal hemosiderin deposition on T2-gradient-echo imaging. Three cases had a brainstem vascular malformation. In two cases the hemosiderin deposition was likely due to prior trauma. The significance of these associations and possible similarities between ataxia related to superficial siderosis and ataxia and intraparenchymal hemosiderin is discussed.
Parkinsonism & Related Disorders 05/2011; 17(7):565-8. · 3.80 Impact Factor
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Neurology 03/2011; 76(9):830-6. · 8.31 Impact Factor
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Brain 03/2011; · 9.46 Impact Factor
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Setty M Magaña, B Mark Keegan,
Brian G Weinshenker,
Bradley J Erickson,
Sean J Pittock,
Vanda A Lennon,
Moses Rodriguez,
Kristine Thomsen,
Stephen Weigand,
Jay Mandrekar,
Linda Linbo,
Claudia F Lucchinetti
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ABSTRACT: Plasma exchange (PLEX) is a beneficial rescue therapy for acute, steroid-refractory central nervous system inflammatory demyelinating disease (CNS-IDD). Despite the approximately 45% PLEX response rate reported among patients with CNS-IDD, determinants of interindividual differences in PLEX response are not well characterized.
To perform an exploratory analysis of clinical, radiographic, and serological features associated with beneficial PLEX response.
Historical cohort study.
Neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients All Mayo Clinic patients treated with PLEX between January 5, 1999, and November 12, 2007, for a steroid-refractory CNS-IDD attack.
The PLEX response in attack-related, targeted neurological deficit(s) assessed within the 6-month period following PLEX.
We identified 153 patients treated with PLEX for a steroid-refractory CNS-IDD, of whom 90 (59%) exhibited moderate to marked functional neurological improvement within 6 months following treatment. Pre-PLEX clinical features associated with a beneficial PLEX response were shorter disease duration (P = .02) and preserved deep tendon reflexes (P = .001); post-PLEX variables included a diagnosis of relapsing-remitting multiple sclerosis (P = .008) and a lower Expanded Disability Status Scale score (P < .001) at last follow-up. Plasma exchange was less effective for patients with multiple sclerosis who subsequently developed a progressive disease course (P = .046). Radiographic features associated with a beneficial PLEX response were presence of ring-enhancing lesions (odds ratio = 4.00; P = .03) and/or mass effect (odds ratio = 3.00; P = .02). No association was found between neuromyelitis optica-IgG serostatus and PLEX response.
We have identified clinical and radiographic features that may aid in identifying patients with fulminant, steroid-refractory CNS-IDD attacks who are more likely to respond to PLEX.
Archives of neurology 03/2011; 68(7):870-8. · 6.31 Impact Factor
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ABSTRACT: Intravascular lymphoma is a rare disorder that commonly involves the central nervous system. Neurologic involvement may be the presenting and only manifestation. Identifying intravascular lymphoma as the cause of neurologic disease is diagnostically challenging. We report an elderly woman presenting with subacute onset paraparesis due to spinal cord involvement by an intravascular lymphoma. Progressive worsening was associated with extension of a longitudinally-extensive thoracic intramedullary spinal cord lesion. Extensive investigations failed to provide a diagnosis in life and repeated empiric therapeutic trials were unsuccessful. Diagnostic confirmation was postmortem. A longitudinally-extensive spinal cord lesion has a broad differential diagnosis. Intravascular lymphoma should be considered particularly in older individuals. The presence of coexisting hematologic abnormalities should prompt consideration of a bone marrow biopsy. Early diagnosis may direct therapy and lead to a more favorable prognosis.
Journal of the neurological sciences 01/2011; 303(1-2):146-9. · 2.32 Impact Factor
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ABSTRACT: The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange. The positive response to Rituximab in Phase II clinical trials of relapsing-remitting MS confirms the role of B cells. The critical question is how B cells contribute to MS. In this paper, we discuss both the deleterious and the beneficial roles of B cells and immunoglobulins in MS lesions. We provide alternative hypotheses to explain both damaging and protective antibody responses.
Neurology research international. 01/2011; 2011:780712.
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Neurology 11/2010; 75(18 Suppl 1):S65. · 8.31 Impact Factor
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Sean J Pittock,
Joseph E Parisi,
Andrew McKeon,
Shanu F Roemer,
Claudia F Lucchinetti,
K Meng Tan, B Mark Keegan,
Samuel F Hunter,
Paul R Duncan,
Joachim M Baehring,
Joseph Y Matsumoto,
Vanda A Lennon
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ABSTRACT: Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma.
To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes.
Retrospective case series with prospective clinical follow-up.
Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota.
Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. Main Outcome
Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed.
Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset.
Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.
Archives of neurology 09/2010; 67(9):1109-15. · 6.31 Impact Factor
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Sean J Pittock,
Jan Debruyne,
Karl N Krecke,
Caterina Giannini,
Jelle van den Ameele,
Veerle De Herdt,
Andrew McKeon,
Robert D Fealey,
Brian G Weinshenker,
Allen J Aksamit,
Bruce R Krueger,
Elizabeth A Shuster, B Mark Keegan
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ABSTRACT: The classification and pathological mechanisms of many central nervous system inflammatory diseases remain uncertain. In this article we report eight patients with a clinically and radiologically distinct pontine-predominant encephalomyelitis we have named 'chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids' (CLIPPERS). The patients were assessed clinically, radiologically and pathologically at Mayo Clinic, USA and Ghent University Hospital, Belgium from 1999 to 2009. Median follow-up duration from clinical onset was 22 months (range 7-144 months). Patients underwent extensive laboratory (serum and cerebrospinal fluid), radiological and pathological testing (conjunctival, transbronchial and brain biopsies) to search for causes of an inflammatory central nervous system disorder. All eight patients (five female, three male) presented with episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and had a favourable initial response to high dose glucocorticosteroids. All patients had symmetric curvilinear gadolinium enhancement peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally spinal cord. Radiological improvement accompanied clinical response to glucocorticosteroids. Patients routinely worsened following glucocorticosteroid taper and required chronic glucocorticosteroid or other immunosuppressive therapy. Neuropathology of biopsy material from four patients demonstrated white matter perivascular, predominantly T lymphocytic, infiltrate without granulomas, infection, lymphoma or vasculitis. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a definable, chronic inflammatory central nervous system disorder amenable to immunosuppressive treatment. The T cell predominant inflammatory pathology in affected central nervous system lesions and the clinical and radiological response to immunosuppressive therapies is consistent with an immune-mediated process.
Brain 09/2010; 133(9):2626-34. · 9.46 Impact Factor
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ABSTRACT: Leucodystrophy with neuroaxonal spheroids (LNS) is rare. There have been fewer than 10 sporadic cases reported, all occurring in the fourth to sixth decades of life. Previously unreported diffusion weighted imaging (DWI) changes on brain imaging in LNS are described as well as the first neurocognitive profile of this disorder in a 24-year-old woman. Neuropsychological testing demonstrated a global cognitive decline, with deficits most representative of a frontal-subcortical dementia. Bright DWI and corresponding dark apparent diffusion coefficient changes were initially mistaken for acute cerebral infarction but then persisted for 19 weeks. Biopsy of a bright DWI lesion showed no evidence of vascular disease and confirmed this rare diagnosis. Given the number of patients with the diagnosis of cerebrovascular disease, supported by DWI findings, we propose other milder cases of LNS may be overlooked.
Journal of neurology, neurosurgery, and psychiatry 02/2010; 81(6):619-22. · 4.87 Impact Factor
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Neurology 10/2009; 73(17):1399-405. · 8.31 Impact Factor
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ABSTRACT: The aquaporin-4-specific serum autoantibody neuromyelitis optica (NMO) IgG is a validated biomarker distinguishing NMO spectrum disorders from multiple sclerosis (MS). Because fulminant attacks are more common in NMO spectrum disorders than in MS, some investigators suggest that NMO IgG may be a marker of destructive demyelination rather than a disease-specific biomarker. To our knowledge, this study is the first to compare NMO IgG serostatus among patients with fulminant central nervous system inflammatory demyelinating disease (CNS IDD).
To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD.
Descriptive historical cohort.
Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay.
Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review.
Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis.
Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.
Archives of neurology 09/2009; 66(8):964-6. · 6.31 Impact Factor
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ABSTRACT: Neuromyelitis optica (NMO) is the first inflammatory autoimmune demyelinating disease of the central nervous system for which a specific antigenic target has been identified; the marker autoantibody NMO-IgG specifically recognizes the astrocytic water channel aquaporin 4. Current evidence strongly suggests that NMO-IgG may be pathogenic. Since disability accrues incrementally related to attacks, attack prevention with immunosuppressive therapy is the mainstay of preventing disability.
To evaluate the efficacy and safety of mycophenolate mofetil therapy in NMO spectrum disorders.
Retrospective case series with prospective telephone follow-up.
Mayo Clinic Health System. Patients Twenty-four patients with NMO spectrum disorders (7 treatment-naive). Intervention Mycophenolate mofetil (median dose of 2000 mg per day).
Annualized relapse rates and disability (Expanded Disability Status Scale).
At a median follow-up of 28 months (range, 18-89 months), 19 patients (79%) were continuing treatment. The median duration of treatment was 27 months (range, 1-89 months). The median annualized posttreatment relapse rate was lower than the pretreatment rate (0.09; range, 0-1.5; and 1.3; range, 0.23-11.8, respectively; P < .001). Disability stabilized or decreased in 22 of 24 patients (91%). One patient died of disease complications during follow-up. Six patients (25%) noted adverse effects during treatment with mycophenolate.
Mycophenolate is associated with reduction in relapse frequency and stable or reduced disability in patients with NMO spectrum disorders.
Archives of neurology 09/2009; 66(9):1128-33. · 6.31 Impact Factor
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ABSTRACT: To describe the characteristics of multiple sclerosis (MS) presenting with severe cognitive impairment as its primary disabling manifestation.
Retrospective case series.
Tertiary referral center. Patients Patients were identified through the Mayo Clinic data retrieval system (1996-2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course, and radiological features.
Demographic, clinical, and radiological characteristics of the disease.
Twelve patients were men. The median age of the first clinical symptom suggestive of central nervous system demyelination was 33 years, and severe MS-related cognitive impairment developed at a median age of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n = 9) or chronic progressive (n = 14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%), and cortical symptoms and signs (eg, seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain magnetic resonance imaging demonstrated diffuse cerebral atrophy in 16 and gadolinium-enhancing lesions in 11. Asymptomatic spinal cord magnetic resonance imaging lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients.
We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be overrepresented in this phenotype.
Archives of neurology 09/2009; 66(9):1139-43. · 6.31 Impact Factor
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ABSTRACT: Gait apraxia is a gait disorder not attributable to motor, cerebellar, or sensory dysfunction. Gait impairment is common in Multiple Sclerosis (MS), but is mostly attributed to spasticity and ataxia. Impairment ratings scales are designed accordingly and do not separately evaluate apraxia.
To describe 15 patients with gait apraxia resulting from MS as their major functional impairment.
The Mayo Clinic database (1994-2007) was searched for the terms MS and gait apraxia. Inclusion criteria: Definite MS, significant gait apraxia. Exclusion criteria: alternative disorder causing apraxia, predominantly spastic/ataxic gait disorder.
9 (60%) of the patients were women, and 12 (80%) had a progressive MS course. Gait apraxia was evident at a median of 8 years (range 0-34) following MS onset. Median EDSS at recognition of gait apraxia was 6.5 (range 5-8). Cognitive dysfunction was present in 11 (73%) and neurogenic bladder dysfunction in 14 (93%). The commonest MRI findings were confluent periventricular T2 lesions, T1 hypointensity and generalized cerebral atrophy with symmetrical ex vacuo ventricular enlargement.
Gait apraxia can cause significant functional impairment in MS patients, and may be underrecognized. The natural course of the neurological deficit in such patients is unknown, and may differ from that of MS patients with other ambulatory disabilities.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 09/2009; 36(5):562-5. · 0.97 Impact Factor
