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1.  Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica 
Neurology  2013;81(14):1197-1204.
To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome.
From Mayo Clinic records (2005–2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 “seronegative” patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus.
Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly.
Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG–seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG–seropositive NMO.
PMCID: PMC3795610  PMID: 23997151
2.  Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations 
Parkinsonism & related disorders  2013;19(10):869-877.
Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11).
We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
PMCID: PMC3977389  PMID: 23787135
HDLS; CSF1R mutation; Parkinsonism; Autosomal dominant; White matter disorders
3.  Aquaporin 4 IgG Serostatus and Outcome in Recurrent Longitudinally Extensive Transverse Myelitis 
JAMA neurology  2014;71(1):48-54.
Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking.
To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG–positive rLETM.
A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from “seronegative” patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG–positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO).
AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score.
Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG–negative rLETM and 5:1 for AQP4-IgG–positive patients. The AQP4-IgG–positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG–positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG–positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG–positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG–positive and AQP4-IgG–negative patients with rLETM.
Recombinant antigen–based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG–negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG–positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.
PMCID: PMC3934000  PMID: 24248262
4.  Effects of Age and Sex on Aquaporin-4 Autoimmunity 
Archives of neurology  2012;69(8):1039-1043.
To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56 464 patient samples.
Observational analysis.
Mayo Clinic Neuroimmunology Laboratory.
Between October 1, 2005, and January 4, 2011, 56 464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive.
Main Outcome Measure
Seropositivity for AQP4-IgG.
Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P<.001). More females than males were tested (37 662 vs 16 810, respectively; P<.001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P<.001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female: male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P<.001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P<.001). The proportion of AQP4-IgG–seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years.
Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.
PMCID: PMC3746965  PMID: 22507888
5.  MRI characteristics and scoring in HDLS due to CSF1R gene mutations 
Neurology  2012;79(6):566-574.
To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan.
Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.
Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.
PMCID: PMC3413763  PMID: 22843259
6.  Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids 
Nature Genetics  2011;44(2):200-205.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominantly inherited central nervous system white matter disease with variable clinical presentations including personality and behavioral changes, dementia, depression, parkinsonism, seizures, and others1,2. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 (encoded by CSF1R) in 14 families affected by HDLS. In one kindred, the de novo occurrence of the mutation was confirmed. Follow-up sequencing analyses identified an additional CSF1R mutation in a patient clinically diagnosed with corticobasal syndrome (CBS). In vitro, CSF-1 stimulation resulted in the rapid autophosphorylation of selected tyrosine-residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from a partial loss of CSF1R function. Since CSF1R is a critical mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
PMCID: PMC3267847  PMID: 22197934

Results 1-6 (6)