Demographic Disparities in the Incidence, Clinical Characteristics, and Outcome of Posterior Reversible Encephalopathy Syndrome in the United States.

OBJECTIVES: To estimate age-specific, sex-specific, and race-specific incidence of posterior reversible encephalopathy syndrome (PRES) in the United States. METHODS: We conducted a retrospective cohort study using the State Inpatient Database of Florida (2016-2019), Maryland (2016-2019), and New York (2016-2018). All new cases of PRES in adults (18 years or older) were combined with Census data to compute incidence. We evaluated the generalizability of incident estimates to the entire country using the 2016-2019 National Readmissions Database (NRD). RESULTS: Across the study period, there were 3,716 incident hospitalizations for PRES in the selected states. The age-standardized and sex-standardized incidence of PRES was 2.7 (95% CI 2.5-2.8) cases/100,000/y. Incidence in female patients was >2 times that of male patients (3.7 vs 1.6 cases/100,000/y, p < 0.001). Incidence increased with age in both sexes (p-trend <0.001). Similar demographic distribution of first hospitalization for PRES was also noted in the entire country using the NRD. Age-standardized and sex-standardized PRES incidence in Black patients (4.2/100,000/y) was significantly greater than in Non-Hispanic White (2.7/100,000/y) and Hispanic patients (1.2/100,000/y) (p < 0.001 for pairwise comparisons). DISCUSSION: The incidence of PRES in the United States is approximately 3/100,000/y, but incidence in female patients is >2 times that of male patients. PRES incidence is higher in Black compared with non-Hispanic White and Hispanic patients.

New-Onset Refractory Status Epilepticus (NORSE) as a Recurrence of Anti-Neuronal Nuclear Antibody 2 (ANNA-2) Encephalitis After Immune Checkpoint Inhibition Therapy.

Paraneoplastic encephalitis from anti-neuronal nuclear antibody 2 (ANNA-2), usually associated with breast cancer, can cause seizures. We report a case of recurrent paraneoplastic encephalitis due to ANNA-2 presenting with new-onset refractory status epilepticus (NORSE) one month after receiving checkpoint inhibitors therapy. A 69-year-old female was diagnosed with opsoclonus myoclonus syndrome (OMS) secondary to ANNA-2, which led to a diagnosis of breast cancer. OMS improved with surgical resection and intravenous immunoglobulin (IVIG). Three years later, she was diagnosed with metastatic cancer to the liver and spine. She underwent immune checkpoint inhibitor therapy. One month later, she was admitted with NORSE. Opsoclonus was seen at the physical exam. Brain MRI and infectious work-up were unremarkable. Cerebrospinal fluid (CSF) analysis revealed pleocytosis with lymphocytic predominance. She was treated with corticosteroids and immunoglobulins, and she had symptomatic improvement. ANNA-2 test was positive in a lower titration than three years earlier. Opsoclonus in a patient with NORSE can be the hint of ANNA-2 positivity. Immune checkpoint inhibitor therapy should be carefully reconsidered in patients with a history of paraneoplastic encephalitis for ANNA-2 as it could precipitate NORSE.

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

BACKGROUND: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. METHODS: A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. RESULTS: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. CONCLUSION: This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

Onabotulinumtoxin Type A reconstitution with preserved versus preservative-free saline in chronic migraine (B-RECON). A randomised, double-blind trial.

INTRODUCTION: Onabotulinumtoxin type A (BoNTA) is manufactured as powder that requires reconstitution with normal saline prior to injection. Previous literature has suggested that preserved saline (PS) exerts a local anaesthetic effect, and reduces the procedure discomfort when used in reconstitution in lieu of preservative-free saline (PFS). However, this was mainly studied in the aesthetics indications of BoNTA, and never in its use for the treatment of chronic migraine. The distinction is important as chronic migraine population suffers high incidence of scalp allodynia which makes it more prone to injection site pain. In addition, the pain of the procedure itself may be related to the spike of migraine frequency in the immediate postprocedural period which can occur in up to 5% of patients receiving the treatment. Our trial aimed to study the difference in procedural pain scale, and postprocedural headache rating with the use of PS vs PFS in constitution of BoNTA when used as a treatment for chronic migraine. METHODS: 68 subjects were consecutively enrolled in an outpatient setting at a large tertiary headache centre over a period of 6 months. Subjects were randomised into PS or PFS group. BoNTA was administered as per standard protocol in both groups. Injection site pain scores and frequency of headache days in the immediate following week were recorded. Wilcoxon rank sum tests were used to compare differences in between groups using SPSS software. RESULTS: Analysis (SAS V 9.4) revealed that those receiving [PF] had significantly higher procedure pain scores than those receiving [P] (5.3 vs 3.2, respectively). There was no difference in the headache or migraine frequency in the immediate postprocedural period. CONCLUSION: This study supports the use of PS (bacteriostatic) over PFS for reconstitution of BoNTA in chronic migraine as it reduces the discomfort of the injection sites.

Artificial Intelligence to Detect Papilledema from Ocular Fundus Photographs.

BACKGROUND: Nonophthalmologist physicians do not confidently perform direct ophthalmoscopy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied. METHODS: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations. Of these photographs, 14,341 from 19 sites in 11 countries were used for training and validation, and 1505 photographs from 5 other sites were used for external testing. Performance at classifying the optic-disk appearance was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity, as compared with a reference standard of clinical diagnoses by neuro-ophthalmologists. RESULTS: The training and validation data sets from 6779 patients included 14,341 photographs: 9156 of normal disks, 2148 of disks with papilledema, and 3037 of disks with other abnormalities. The percentage classified as being normal ranged across sites from 9.8 to 100%; the percentage classified as having papilledema ranged across sites from zero to 59.5%. In the validation set, the system discriminated disks with papilledema from normal disks and disks with nonpapilledema abnormalities with an AUC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormal disks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing data set of 1505 photographs, the system had an AUC for the detection of papilledema of 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3), and a specificity of 84.7% (95% CI, 82.3 to 87.1). CONCLUSIONS: A deep-learning system using fundus photographs with pharmacologically dilated pupils differentiated among optic disks with papilledema, normal disks, and disks with nonpapilledema abnormalities. (Funded by the Singapore National Medical Research Council and the SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic Clinical Program.).

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

OnabotulinumtoxinA wear-off in chronic migraine, observational cohort study.

INTRODUCTION: The current standard-of-care protocol for OnabotulinumtoxinA (BoNTA) injections consists of fixed-site injections every 12 weeks. This pattern is based on clinical practice and extrapolated from BoNTA injections for other, non-migraine-related indications. It is unclear if this protocol is optimal for chronic migraine. In clinical practice, migraine patients frequently describe a period of increased headache frequency and intensity in the few weeks preceding their next injections. In order to evaluate the duration of the clinical effect of BoNTA injections in chronic migraine, we studied the variation in headache frequency on a weekly basis during the 12-week period following treatment in a cohort of migraine patients. METHOD: 38 consecutive subjects were enrolled from an outpatient headache clinic, and asked to keep daily headache journals. 24 completed headache journals were analyzed. Headache frequency, duration and severity, as well as intake of symptomatic headache medications were recorded and compared among the different weeks. RESULTS: The time-response plot following BoNTA injection was roughly U-shaped, with 3 distinct phases: an induction phase, a maximum efficacy phase, and a wear-off phase. The time-response plot revealed that the wear-off commenced around the eighth week post injection. The mean difference in the number of headache days per week between the first and the eighth week was 1.8 (95% CI [0.670-2.830], p = 0.003). CONCLUSION: The effect of BoNTA injections on chronic migraines was not uniform throughout a 12-week period. A window of vulnerability to migraine attacks exist in the beginning and end of each cycle.

Further Evidence that Onabotulinum Toxin is a Viable Treatment Option for Pediatric Chronic Migraine Patients.

Introduction Chronic migraine is particularly devastating. It affects school work, extracurricular activities, and quality of life, including relationships with other family members, and can also influence the mental health of both the migraineurs and family members. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), chronic migraine is defined as 15 or more headache days per month for greater than three months, where at least on eight days per month, there are features of migraine headache. Although botulinum toxin type A (BoNTA) has been proven effective for treating chronic migraine in adults, little literature exists about its use in children. Here, we present the treatment response in children with chronic migraines treated with BoNTA at our institutions Duke and State University of New York (SUNY) Upstate. Method A retrospective analysis of 30 adolescent migraineurs who met ICHD-3 criteria for chronic migraine were treated with BoNTA injection according to the standardized adult protocol. Descriptive statistics and paired t-tests were performed. A total of 185 units of botulinum toxin were injected intramuscularly per patient, as in addition to the standard 31 sites for a total of 155 units, an additional 30 units were given in areas that were felt to provide further benefit. Results Participants (n=30) were 16.5 ± 1.83 years old. The headaches were precipitated by trauma in seven cases. All had failed standard pharmacotherapy, including amitriptyline and topiramate. An average of 2.47 ± 1.6 BoNTA injection cycles was performed. Migraine severity decreased significantly from 7.47 ± 1.89 on a 10-point scale to 4.34 ± 3.02 (p<.001). Additionally, headache frequency improved from 24.4 ± 7.49 painful days per month to 14.8 ± 12.52 painful days per month (p<.001). One patient developed nausea related to injections; all others tolerated it well, with no side effects. Discussion BoNTA injection was a safe and effective therapy for chronic migraine in our cohort of children recalcitrant to medical therapy. Further research with multi-centered, double-blinded, randomized, placebo-controlled trials is warranted to evaluate the long-term safety and efficacy in this population.

Headache in Idiopathic Intracranial Hypertension: Findings From the Idiopathic Intracranial Hypertension Treatment Trial.

OBJECTIVE: To characterize the phenotype, headache-related disability, medical co-morbidities, use of symptomatic headache medications, and headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Patients with untreated IIH and mild vision loss enrolled in the IIHTT and randomized to acetazolamide (ACZ) and weight loss or placebo (PLB) and weight loss had prospective assessment of headache disability using the Headache Impact Test-6 (HIT-6) questionnaire. Subjects with headache at the baseline visit were assigned a headache phenotype using the International Classification for Headache Disorders version 3 beta (ICHD-3b). Medication overuse was determined using the participants' reported medication use for the preceding month and ICHD-3b thresholds for diagnosing medication overuse headache. We investigated relationships between headache disability and various other clinical characteristics at baseline and at 6 months. RESULTS: Headache was present in 139 (84%) of the 165 enrollees at baseline. The most common headache phenotypes were migraine (52%), tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%). Fifty-one (37%) participants overused symptomatic medications at baseline, most frequently simple analgesics. A similar amount of improvement in the adjusted mean (± standard error) HIT-6 score occurred in the ACZ (-9.56 ± 1.05) and PLB groups (-9.11 ± 1.14) at 6 months (group difference -0.45, 95% CI -3.50 to 2.60, P = .77). Headache disability did not correlate with any of the studies, variables of interest, which included: the lumbar puncture opening pressure at baseline or at 6 months, body mass index, the amount of weight lost, papilledema grade, perimetric mean deviation, or the use of hormonal contraception. Headache disability was significantly associated with patient-reported quality of life in the physical, mental, and visual domains. CONCLUSIONS: Headache was common, of varied character, disabling, and associated with poorer quality of life in our cohort of patients with mild visual impairment. The lack of correlation between headache disability and cerebrospinal fluid (CSF) pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension, and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.

CSF pressure, papilledema grade, and response to acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial.

Previous reports suggest an association between the degree of optic nerve head edema and CSF pressure (CSFp) in idiopathic intracranial hypertension (IIH). We hypothesized that CSFp would be associated with Frisén papilledema grade (FPG) and other clinical features, and that FPG would modify the CSFp response to acetazolamide in participants in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). In the IIHTT, eligible patients underwent lumbar puncture (LP) prior to enrollment and were randomly assigned to one of two treatment groups: acetazolamide plus supervised diet or placebo plus supervised diet. Trial eligibility required baseline CSFp ≥250 mm H2O or ≥200 mm H2O with compelling clinical or imaging IIH findings. Associations between CSFp and FPG and other clinical features were examined at baseline. The effect of acetazolamide on 6-month change in CSFp was examined in those with low FPG (grades I-III) and those with high FPG (grades IV-V) at baseline. All 165 enrolled subjects had a baseline LP and 85 had an LP at 6 months. There was an association between CSFp and FPG at baseline: CSFp was more elevated in subjects with high FPG (378 ± 90 mm H2O, n = 50) than in subjects with low FPG (331 ± 77, n = 115, p = 0.002). At 6 months, acetazolamide had a similar effect on CSFp in subjects with high FPG (-79.9 mm H2O) and in subjects with low FPG (-50.9 mm H2O, p = 0.50). We found a modest association between CSFp and FPG. Acetazolamide had a beneficial effect on CSFp regardless of baseline FPG.

IgG4-related ophthalmic disease.

IgG4-related disease is a fibro-inflammatory condition with tendency to form tumors with inflammatory infiltrate with IgG4 rich plasma cells and elevation of IgG4 level in serum, which may affect virtually every organ and tissue in the organism. IgG4-related ophthalmic disease may present as dacryoadenitis, myositis, other orbital tissues, hypophysitis or pachymeningitis causing cranial neuropathies. The diagnosis of IgG4-related disease is based on a typical clinical scenario, supportive laboratory data, expected radiological characteristics and distinct histopathological and immunohistochemical features. Corticosteroid followed by the use of long-term immunosuppressive therapy is the most commonly attempted treatment.

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Impairment of habituation of the auditory brain stem response in migrainous vertigo.

OBJECTIVES: We evaluated the auditory brain stem response (ABR) in migrainous vertigo (MV). METHODS: Four subjects who met clinical criteria for definite MV and 4 subjects with non-vertiginous migraine (NVM) underwent ABR testing while asymptomatic and within 16 hours of a symptomatic episode. Four control subjects were also tested. A set of 4 consecutive 750-click series was administered at 50-, 60-, and 70-dB intensities. We compared the groups in terms of habituation of the amplitude of wave IV-V (habituation of IV-V) from the first through fourth series for each set. RESULTS: The habituation of IV-V amplitude to 50-dB stimuli was significantly less (p = 0.047) in the symptomatic MV group (5.08% +/- 22.32%) than in the symptomatic NVM group (-21.44% +/- 13.50%) or the control group (-26.06% +/- 9.76%). The habituation of IV-V amplitude to 70-dB stimuli in the MV group was significantly less (p = 0.031) during symptomatic testing (-3.43% +/- 8.89%) than during asymptomatic testing (-21.23% +/- 6.41%). CONCLUSIONS: The habituation of IV-V amplitude is reduced during MV attacks. This finding suggests impaired brain stem inhibition at the level of the inferior colliculus, which shares serotonergic connections with the dorsal raphe nucleus, an area hyperactive in migraine.

IgG4-related inflammatory pseudotumor of the central nervous system responsive to mycophenolate mofetil.

Orbital apex and skull base masses often present with neuro-ophthalmic signs and symptoms. Though the localization of these syndromes and visualization of the responsible lesion on imaging is typically straightforward, definitive diagnosis usually relies on biopsy. Immunohistochemistry is important for categorization and treatment planning. IgG4-related disease is emerging as a pathologically defined inflammatory process that can occur in multiple organ systems. We present two patients with extensive inflammatory mass lesions of the central nervous system with immunohistochemistry positive for IgG4 and negative for ALK-1 as examples of meningeal based IgG4-related inflammatory pseudotumors. In both patients, there was treatment response to mycophenolate mofetil.

Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-ß 1a treated multiple sclerosis patients.

Interferon-ß (IFN-ß) is a current effective treatment for multiple sclerosis (MS) and exerts its therapeutic effects by down-modulating the systemic immune response and cytokine signaling. In clinical practice there are several formulations of interferon including a low dose of IFN-ß 1a formulation of 30 µg IM once weekly (Avonex) and a high dose formulation of 44 µg SC three times weekly (Rebif). Recent studies suggest that Rebif is more efficacious compared to Avonex in preventing relapses and decreasing MRI activity in relapsing remitting MS (RRMS) patients. This study examines whether there are quantitative gene expression changes in interferon-treated RRMS patients that can explain the difference in efficacy and side effects between Rebif and Avonex. Herein, RRMS patients were treated for three months with IFN-ß 1a and the levels of plasma cytokines and gene expression in peripheral blood mononuclear cells were examined. Thirty-two normal subjects were compared to thirty-two RRMS patients, of which ten were treated with Rebif and ten with Avonex. Rebif and Avonex both significantly and equally suppressed plasma TNF-α and IL-6 levels. Rebif suppressed IL-13 significantly more than Avonex. Rebif also significantly suppressed the levels of the chemokines CCL17 and RANTES, the protease ADAM8, and COX-2 at a higher degree compared to Avonex. The STAT1-inducible genes IP-10 and caspase 1 were significantly increased with Rebif compared to Avonex. In conclusion, the higher dosed, more frequently administered IFN-ß 1a Rebif when compared to IFN-ß 1a Avonex has more potent immunomodulatory effects. These quantitative results might relate to efficacy and side-effect profile of the two IFN-ß 1a formulations and provide prospective practical clinical tools to monitor treatment and adjust dosage.

Nonvestibulocochlear cranial nerve schwannomas.

OPINION STATEMENT: Nonvestibulocochlear cranial nerve schwannomas traditionally have been managed by surgical excision. Although debulking surgery is still considered the first treatment option for larger tumors, stereotactic radiosurgery is now preferred for smaller tumors because of its high tumor control rate and low treatment-related morbidity. Furthermore, an initial period of radiologic and clinical observation following the diagnosis should be strongly considered for smaller tumors because some may not grow or may grow at a slow rate. Medical management of tumor-associated symptoms (when present) should not be ignored. Most importantly, the time has come to embark on the first randomized controlled trials comparing clinical and radiologic observation, surgery, and radiosurgery in the management of cranial nerve schwannomas.

Interferon-beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1.

Interferon-beta is a current treatment for multiple sclerosis (MS). Interferon-beta is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon beta-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-kappaB, which are known SHP-1 targets. Interferon-beta treatment in vivo resulted in decreased NF-kappaB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-beta treatment that correlated with decreased NF-kappaB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-beta treatment, indicating that SHP-1 is a predominant mediator of interferon-beta activity. In conclusion, interferon-beta treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis.