Background Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. Methods In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×106, 1×106, or 3×106 IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. Results A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×106 IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Conclusions Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana–Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.)
A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.
SEE MCKAY AND FURL DOI101093/AWW323 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.
Purpose To estimate the proportion of patients presenting with isolated third, fourth or sixth cranial nerve palsies of presumed microvascular origin versus other causes. Design Prospective, multi-center observational case series. Participants One hundred and nine patients, 50 years of age or older with acute isolated ocular motor nerve palsy. Testing Magnetic resonance imaging (MRI) of the brain Main outcome measures Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. Results Among 109 patients enrolled in the study, there were 22 patients with cranial nerve III palsy, 25 patients with cranial nerve IV palsy and 62 patients with cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5 %, 95% confidence interval (CI): 10.7–24.6%). The presence of one or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke and smoking) was significantly associated with a presumed microvascular cause (p=0.003, Fisher’s exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes including midbrain infarction, neoplasms, inflammation, pituitary apoplexy and giant cell arteritis (GCA). Excluding patients with third cranial nerve palsies and those with GCA the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). Conclusions In our series of patients with acute isolated ocular motor nerve palsies, substantial proportion of patients had other causes including neoplasm, GCA and brainstem infarction. Brain MRI and laboratory work–up has a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present or not.
Many structural and functional brain alterations accompany blindness, with substantial individual variation in these effects. In normally sighted people, there is correlated individual variation in some visual pathway structures. Here we examined if the changes in brain anatomy produced by blindness alter the patterns of anatomical variation found in the sighted. We derived eight measures of central visual pathway anatomy from a structural image of the brain from 59 sighted and 53 blind people. These measures showed highly significant differences in mean size between the sighted and blind cohorts. When we examined the measurements across individuals within each group we found three clusters of correlated variation, with V1 surface area and pericalcarine volume linked, and independent of the thickness of V1 cortex. These two clusters were in turn relatively independent of the volumes of the optic chiasm and lateral geniculate nucleus. This same pattern of variation in visual pathway anatomy was found in the sighted and the blind. Anatomical changes within these clusters were graded by the timing of onset of blindness, with those subjects with a post-natal onset of blindness having alterations in brain anatomy that were intermediate to those seen in the sighted and congenitally blind. Many of the blind and sighted subjects also contributed functional MRI measures of cross-modal responses within visual cortex, and a diffusion tensor imaging measure of fractional anisotropy within the optic radiations and the splenium of the corpus callosum. We again found group differences between the blind and sighted in these measures. The previously identified clusters of anatomical variation were also found to be differentially related to these additional measures: across subjects, V1 cortical thickness was related to cross-modal activation, and the volume of the optic chiasm and lateral geniculate was related to fractional anisotropy in the visual pathway. Our findings show that several of the structural and functional effects of blindness may be reduced to a smaller set of dimensions. It also seems that the changes in the brain that accompany blindness are on a continuum with normal variation found in the sighted.
Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.
Delusional misidentification syndromes (DMSs) are persistent delusions of hyper- or hypofamiliarity for meaningful persons and places in one's environment. This study set to determine the clinical course, neuroanatomical localization, neuropsychological abnormalities, and delusional content in patients with DMSs occurring after focal neurological injuries. Sixty-one patients were identified: 28 with hypofamiliar delusions, 27 with hyperfamiliar delusions, and, most surprisingly, six patients with both hypo- and hyperfamiliar delusions. Recognition is often delayed by months from the time of injury, and the delusions are self-limited. Patients with DMSs had right hemisphere (92%) injuries (specifically right frontal injuries in 63%), prominent memory impairment (73%), and multiple concurrent DMSs (29%).
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