Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection.

Purpose: Herpes simplex virus type-1 (HSV-1) is a leading cause of neurotrophic keratitis, characterized by decreased or absent corneal sensation due to damage to the sensory corneal innervation. We previously reported the elicited immune response to infection contributes to the mechanism of corneal nerve regression/damage during acute HSV-1 infection. Our aim is to further establish the involvement of infiltrated macrophages in the mechanism of nerve loss upon infection. Methods: Macrophage Fas-Induced Apoptosis (MAFIA) transgenic C57BL/6 mice were systemically treated with AP20187 dimerizer or vehicle (VEH), and their corneas, lymph nodes, and blood were assessed for CD45+CD11b+GFP+ cell depletion by flow cytometry (FC). Mice were ocularly infected with HSV-1 or left uninfected. At 2, 4, and/or 6 days post infection (PI), corneas were assessed for sensitivity and harvested for FC, nerve structure by immunohistochemistry, viral content by plaque assay, soluble factor content by suspension array, and activation of signaling pathways by Western blot analysis. C57BL6 mice were used to compare to the MAFIA mouse model. Results: MAFIA mice treated with AP20187 had efficient depletion of CD45+CD11b+GFP+ cells in the tissues analyzed. The reduction of CD45+CD11b+GFP+ cells recruited to the infected corneas of AP20187-treated mice correlated with preservation of corneal nerve structure and function, decreased protein concentration of inflammatory cytokines, and decreased STAT3 activation despite no changes in viral content in the cornea compared to VEH-treated animals. Conclusions: Our results suggest infiltrated macrophages are early effectors in the nerve regression following HSV-1 infection. We propose the neurodegeneration mechanism involves macrophages, local up-regulation of IL-6, and activation of STAT3.

Orbital Involvement and Ocular Surface Changes in IgG4-Related Systemic Disease.

PURPOSE: To evaluate ophthalmic involvement of systemic immunoglobulin-G4-related disease (IgG4-RD) and describe the changes in both ocular surface parameters and corneal subbasal nerve plexus. MATERIALS AND METHODS: Twenty eyes of 10 patients with systemic IgG4-RD and 20 eyes of 10 control subjects were enrolled in this study. Demographic information, medical history, serum IgG4 levels, orbital imaging, and follow-up data of subjects were recorded. Ocular surface tests were carried out in the order of tear break-up time (BUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire for all participants. Corneal subbasal nerves and basal epithelial cell layer were evaluated using in vivo confocal microscopy. RESULTS: Among the 10 patients with IgG4-RD, 11 eyes of 7 patients had orbital involvement. Among these 7 patients with IgG4-related ophthalmic disease, 4 presented with painless eyelid or periorbital swelling, 2 with diplopia and restricted ocular motility, and 1 with proptosis. Patients with IgG4-RD had higher OSDI (5.9 ± 6.6 vs. 1.7 ± 2.4, P < 0.001) and LG staining scores (0.7 ± 1.0 vs. 0.0 ± 0.0, P = 0.011) and lower BUT (5.6 ± 1.4 vs. 10.2 ± 1.0, P < 0.001) and Schirmer values (11.9 ± 10.3 vs. 18.3 ± 4.4, P = 0.021) as compared with those of control subjects. Total nerve density and nerve fiber length were found to be significantly lower in patients with IgG4-RD. CONCLUSIONS: The orbit is frequently involved during the course of IgG4-RD. These patients should be evaluated in terms of ocular surface disease and dry eye, which may be associated with lacrimal gland and/or orbital nerve involvement.

Location and frequency of lesions in patients with IgG4-related ophthalmic diseases.

BACKGROUND: It is well-known that the lacrimal gland (LG) may be affected in IgG4-related ophthalmic disease (IgG4ROD). Recently, IgG4-related ophthalmic lesions other than those of the lacrimal gland have been reported. However, no study to date has revealed the details of these lesions. This study was conducted to evaluate the location and frequency of lesions found in conjunction with IgG4ROD using radiological imaging. METHODS: Radiological images and clinical records of 65 patients collected from seven institutions in Japan were reviewed retrospectively. All patients had been pathologically diagnosed with IgG4ROD. Patients of mucosa-associated lymphoid tissue lymphoma associated with IgG4-related lesions were excluded. Orbital magnetic resonance imaging or computed tomography findings were evaluated. RESULTS: Of the 65 patients, 31 (47.7 %) had lesions involving the LG alone, whereas 34 (52.3 %) had lesions involving the areas other than LG, including eight patients who had lesions without any LG involvement. IgG4-related ophthalmic lesions included LG enlargement in 57 patients (87.7 %), trigeminal nerve branch enlargement in 25 (38.5 %), extraocular muscle enlargement in 16 (24.6 %), diffuse orbital fat lesions in 15 (23.1 %), orbital mass lesions in 11 (16.9 %), eyelid lesions in eight (12.3 %), and nasolacrimal duct lesion in one (1.5 %). Six patients (9.2 %) presented with visual disturbance due to optic nerve disturbance, eight (12.3 %) with a restriction of ocular movement, and 19 (29.2 %) with exophthalmos. CONCLUSIONS: Thirty-four (52.3 %) of the 65 IgG4ROD patients had lesions in areas other than LG. Lesions were found in the trigeminal nerve branch including pterygopalatine fossa, extraocular muscles, orbital fat, eyelid, and nasolacrimal duct.

IgG4-related systemic disease as a cause of "idiopathic" orbital inflammation, including orbital myositis, and trigeminal nerve involvement.

IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been identified as the cause of tumefactive lesions in a number of tissues and organs. The role of the IgG4 remains to be clarified fully, but the histopathologic diagnosis hinges upon the finding of IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated seum IgG4. We present a 56-year-old man with orbital pseudotumor in whom, after 30 years of intractable disease, biopsy showed IgG4-RD involving the lacrimal gland, extraocular muscles, intraconal fat, and trigeminal nerve. Six months after initiating treatment with rituximab, his disease remained dormant, with improvement in his proptosis and normalization of serum IgG4 levels. We review the differential of idiopathic orbital inflammatory disease, including IgG4-RD, and emphasize the need for biopsy for accurate diagnosis and to guide appropriate treatment.

Immune trigeminal sensory neuropathy with esophageal achalasia: improvement with long-term immunotherapy.

We report a patient who developed subacute facial-predominant numbness and anhidrosis, oral incoordination, and esophageal achalasia with resultant cachexia. Great auricular nerve biopsy showed extensive epineurial perivascular inflammatory infiltrates. Sensation, sweating, and swallowing improved with pulse intravenous methylprednisolone given over 5 years. We suggest that the patient's deficits, including achalasia, were due to an immune-mediated sensory and autonomic neuropathy and that, in such cases, pathologic studies of the great auricular nerve may be diagnostically informative.

IgG4-related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease?

IgG4-related IPTs have been reported in various sites and may form part of the spectrum of systemic IgG4-related sclerosing disease. Some pseudotumors are clinically and radiologically indistinguishable from malignant tumors. We present the first case of an IgG4-related IPT of the trigeminal nerve diagnosed histopathologically without involvement of any of the common sites. The trigeminal nerve pseudotumor may represent a component of IgG4-related sclerosing disease.

Trigeminal injury causes kappa opioid-dependent allodynic, glial and immune cell responses in mice.

BACKGROUND: The dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR-/-) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ganglion (TG). RESULTS: In KOR-/- mice or norBNI-treated mice, the number of proliferating cells in the Vp was significantly less than in WT mice, whereas cell proliferation was enhanced in TREZ and TG. The majority of the proliferating cells were nestin positive stem cells or CD11b positive microglia in the Vp and macrophages in the TG. GFAP-positive astrocytes made a clear borderline between the CNS and the PNS in TREZ, and phosphorylated KOR staining (KOR-p) was detectable only in the astrocytes in CNS in WT mice but not in KOR-/- or norBNI-treated mice. CONCLUSIONS: These results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies.

Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains.

Inbred rat strains BDIX and BDIV are constitutionally susceptible and resistant, respectively, to the development of malignant peripheral nerve sheath tumors (MPNST) induced by neonatal exposure to N-ethyl-N-nitrosourea (EtNU). They represent a model system for analysis of molecular and cellular processes underlying differential cancer susceptibility. A point mutation in the Neu/ErbB-2 gene is an early marker of Schwann precursor cells at high risk of malignant conversion and is diagnostic of the resulting MPNST predominantly developing in the trigeminal nerves. Initially considerable amounts of Neu/ErbB-2-mutant cells arise in nerve tissue of both rat strains subsequently disappearing in resistant BDIV rats, but persisting and giving rise to MPNST in susceptible BDIX animals. An almost identical cellular immune response-sequentially involving macrophages, T helper- and cytotoxic T lymphocytes-is mounted in the trigeminal nerves of EtNU-treated rats of both strains. In this study, T cell maturation was prevented by neonatal thymectomy following EtNU-exposure. While resistance against MPNST development significantly decreased in BDIV rats MPNST incidence and survival time remained unaltered in thymectomized BDIX rats. Contrary to euthymic animals a number of both thymectomized BDIV and BDIX rats developed MPNST lacking the Neu/ErbB-2-mutation. This suggests that Schwann cells initiated by other genetic alterations can progress to full malignancy in immune-compromised rats only. T cell-dependent resistance against tumorigenesis originating from non-Neu/ErbB-2-mutant Schwann precursors might thus be shared by both strains while BDIV T lymphocytes additionally prevent the development of Neu/ErbB-2-mutant MPNST. Rat strain-specific differences in the interaction of T lymphocytes with (pre)malignant Neu-mutant cells may thus critically contribute to susceptibility and resistance towards EtNU-induced MPNST development.

[Trigeminal sensory neuropathy and lupus anticoagulant positive: cause or coincidence?]. / Neuropatía sensitiva del trigémino y anticoagulante lúpico positivo: ¿causa o casualidad?

INTRODUCTION: Trigeminal sensory neuropathy (TSN) is a rare entity characterised by transient sensory disorders in one or more branches of the trigeminal nerve (TN). There are (acute or chronic) idiopathic forms as well as others that are linked to inflammatory, vascular or structural lesions. CASE REPORT: We describe the case of a female aged 30 who presented two self limited episodes of left facial hypaesthesia (second branch of the TN), with no other accompanying symptoms and which lasted 3 7 days, with complete resolution. In the study, lupus anticoagulant (LAC) positive was found in two determinations conducted at a six week interval, while the rest of the findings were either negative or within values that were considered to be normal. CONCLUSIONS: Following the description of a case of what may be idiopathic TSN, we discuss the possible relation this may have with the positive result for LAC.