Luis J. Mejico

Weight gain and recurrence in idiopathic intracranial hypertension A case-control study

Objective: To determine whether weight gain is associated with recurrence in idiopathic intracranial hypertension (IIH). Methods: Medical records of adult patients with IIH seen between 1993 and 2009 at 2 university hospitals were reviewed to identify those with and without recurrence. Patients with documented height and weight at presentation and at subsequent visits were studied. The Wilcoxon rank sum test was used to compare mean body mass index (BMI) and percent weight change between the groups of patients with recurrence and without recurrence. The signed-rank test was used for comparing BMI within groups at the various time points. Results: Fifty women with IIH were included in the analyses: 26 had IIH recurrence and 24 did not. Patients with recurrence had greater BMI at the time of recurrence compared to BMI at diagnosis (p = 0.02, signed-rank test). They also demonstrated a greater degree of weight gain between initial resolution and recurrence (BMI change +2.0 kg/m2 [−1.5 to 10.8]) compared to patients without recurrence (−0.75 kg/m2 [−35 to 3.6], p = 0.0009, Wilcoxon rank sum test). Patients without recurrence demonstrated stable weights (0%[95% CI −9.6 to 10.1%]), while patients with recurrence demonstrated a 6% weight gain ([−3.5 to 40.2%], p = 0.005), with an average rate of BMI gain of 1.3 kg/m2/year vs −0.96 kg/m2/year in those without recurrence. Conclusion: Patients with IIH recurrence had significant increases in BMI compared to patients without recurrence in this cohort. Patients with resolved IIH should be advised that weight gain may be a risk factor for IIH recurrence.

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system. The present study investigates a possible similar role for SHP-1 in the human disease multiple sclerosis (MS). The levels of SHP-1 protein and mRNA in PBMCs of MS patients were significantly lower compared to normal subjects. Moreover, promoter II transcripts, expressed from one of two known promoters, were selectively deficient in MS patients. To examine functional consequences of the lower SHP-1 in PBMCs of MS patients, we measured the intracellular levels of phosphorylated STAT6 (pSTAT6). As expected, MS patients had significantly higher levels of pSTAT6. Accordingly, siRNA to SHP-1 effectively increased the levels of pSTAT6 in PBMCs of controls to levels equal to MS patients. Additionally, transduction of PBMCs with a lentiviral vector expressing SHP-1 lowered pSTAT6 levels. Finally, multiple STAT6-responsive inflammatory genes were increased in PBMCs of MS patients relative to PBMCs of normal subjects. Thus, PBMCs of MS patients display a stable deficiency of SHP-1 expression, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination.

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.

Interferon-β 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.

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

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).

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.

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

Interferon-β (IFN-β) 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-β 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-β 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-β 1a Rebif when compared to IFN-β 1a Avonex has more potent immunomodulatory effects. These quantitative results might relate to efficacy and side-effect profile of the two IFN-β 1a formulations and provide prospective practical clinical tools to monitor treatment and adjust dosage.

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.

Re: Oculomotor nerve tumors masquerading as recurrent painful ophthalmoplegic neuropathy.

Dear Editor-in-Chief, Cephalalgia We read with interest the report by Kim et al. of two cases of oculomotor nerve schwannoma that mimicked recurrent painful ophthalmoplegic neuropathy (RPON), formerly known as ‘‘ophthalmoplegic migraine’’ (1). We recently published a case series of 10 patients with cranial nerve schwannomas that included two additional, previously unreported, cases of oculomotor nerve schwannoma mimicking RPON and an update on the first published case of this phenomenon (2,3). The authors stated that incomplete recovery from RPON should raise the possibility of a tumoral etiology (1). We wish to emphasize that schwannoma may be present even when recovery from RPON is complete. Also of interest is the fact that schwannomas may be found in painless relapsing ocular cranial nerve palsies (2). Because complete remission of symptoms, as present in our cases and initially in the authors’ cases, may occur, we suggest that schwannoma may be a more common mimicker of RPON than previously recognized and concur with the authors that serial magnetic resonance imaging (MRI) scans are essential to distinguish schwannoma from other causes, such as presumed transient inflammation.

Nonvestibulocochlear Cranial Nerve Schwannomas

Opinion statementNonvestibulocochlear 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.