Cranial Base Manifestations of Granulomatosis with Polyangiitis.

OBJECTIVE: Although granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) is classically characterized by systemic disease involving the kidneys and airway, approximately 10% of patients who have it present with isolated central nervous system disease. When involving the skull base, GPA frequently mimics more common pathology, resulting in diagnostic challenges and delay. The primary objective of this study is to characterize the cranial base manifestations of GPA, highlighting aspects most relevant to the skull base surgeon. STUDY DESIGN: Retrospective review. SETTING: Tertiary academic referral center. SUBJECTS AND METHODS: Retrospective analysis of all patients with skull base GPA treated at a tertiary referral center from January 1, 1996, to May 1, 2018. RESULTS: Twenty-nine patients met inclusion criteria. Twenty-one (72%) initially presented with skull base symptomatology as their cardinal manifestation of GPA. Twenty-four (82%) presented with cranial neuropathy at some point in their disease course. The trigeminal nerve was most commonly involved (12 of 24, 50%), followed by the facial (11 of 24, 46%) and optic (8 of 24, 33%) nerves. Eighteen patients reported hearing loss attributed to the GPA disease process, presenting as conductive, sensorineural, or mixed. The most common locations for GPA-derived inflammatory skull base disease on imaging included the cavernous sinus (12 of 29, 41%) and the orbit (7 of 29, 24%). CONCLUSION: Establishing the diagnosis of skull base GPA remains challenging. Cranial neuropathy is diverse in presentation and often mimics more common conditions. Imaging findings are also unpredictable and frequently nonspecific. Careful review of patient history, clinical presentation, serology and biopsy results, and imaging can reveal important clues toward the diagnosis.

Correlation between ADAMTS13 activity and neurological impairment in acute thrombotic microangiopathy patients.

Differential diagnosis between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMA) is usually difficult because of frequently overlapping clinical presentations. Severely depressed ADAMTS13 activity (<10 %) seems distinctive for TTP because of its pathogenetic role. However a long debate exists in the literature about its sensibility and specificity. Our aim was to search for clinical differences between TMA patients referred to our laboratory, comparing them for protease activity <10 versus ≥10 %. ADAMTS13 activity ≥10 % patients (n = 73) showed a higher prevalence of drug- (p = 0.005) and cancer-associated (p < 0.001) TMA. Mean platelet count and renal dysfunction prevalence was lower (p < 0.001), while neurological impairment was more frequent (p = 0.001) in the <10 % ADAMTS13 activity group (n = 109), confirming previous literature findings. When taken neurological manifestations singularly, epilepsy (p = 0.04), focal motor deficit (p < 0.001) and cranial nerve palsy (p = 0.007) were more frequent in the <10 % activity group. In our case series, a <10 % ADAMTS13 activity depicts a group of patients with clinical features similar to TTP patients. Focal motor impairment or epileptic manifestations could further address toward a TTP diagnosis. Studies about treatment efficacy and follow-up are advised to determine whether laboratory findings can guide therapeutic decisions.

Multiple cranial nerve palsy revealing hypertrophic pachymeningitis with positive myeloperoxidase-antineutrophil cytoplasmic antibody.

Pachymeningitis is a progressive disease resulting in a diffuse thickening of dura mater due to inflammation, tumor or autoimmune diseases, but most cases are idiopathic. Here, we report the case of a 60-year old man who had a progressive sensorineural hearing loss, visual disturbance and others cranial nerve involvement with an accompanying headache over several months. Brain magnetic resonance imaging showed diffusely thickened dura mater, highly enhanced after gadolinium administration, which was consistent with pachymeningitis. It was assumed to be related to autoimmune pathogenesis on the basis of elevated serum myeloperoxidase-antineutrophil cytoplasmic antibody titers. After empirical steroid and cyclophosphamide therapy, the neurological problems were partially improved. Therefore, in the case of atypical sensorineural hearing loss accompanied by cranial nerve palsy or headache, pachymeningitis should be considered in the differential diagnosis.

Clinical characteristics and associated comorbidities in diabetic patients with cranial nerve palsies.

BACKGROUND: Cranial mononeuropathy is one of the not so common forms of diabetic neuropathy that often appears to be a serious problem from a diagnostic and therapeutic point of view. AIM: Objective of this study was to determine the incidence, the clinical characteristics, and risk factors associated with cranial nerve palsies among persons with diabetes. METHODS: We have performed a retrospective study of all diabetic patients with cranial nerve palsies who were hospitalized in a metabolic department over a 12-yr period. RESULTS: During the period of the survey, a total of 8150 diabetic subjects were hospitalized and cranial nerve palsies were identified in 61 patients (0.75%). Isolated III nerve palsies accounted for the majority of patients (0.35%), with VII nerve palsies (0.21%) occurring more frequently than VI (0.15%) and multiple palsies (0.04%). Peripheral neuropathy was present in only 24% of patients. Patients with VII nerve palsies showed a tendency toward a lower coexistence of diabetic complications and cardiovascular risk factors than those with III and VI nerve palsies. CONCLUSIONS: Cranial nerve palsies are a not common problem among patients with diabetes; diagnosis of diabetic mononeuropathy should be considered even in the absence of peripheral neuropathy; the oculomotor nerve was most frequently affected in our case report. The coexistence of diabetic complications and cardiovascular risk factors was slightly lower in patients with VII nerve palsy: this fact is compatible with the hypotesis that this event is less closely related to diabetes and metabolic factors in its pathogenesis.

Acute leukemia presenting with blasts first found in the cerebrospinal fluid but not in the peripheral blood.

Acute leukemia presenting with central nervous system (CNS) signs and symptoms is uncommon and prone to be misdiagnosed. Here, we report nine patients with acute leukemia, including five patients with acute lymphoblastic leukemia (ALL) and four patients with acute myeloid leukemia (AML). These patients presented with symptoms suggestive of involvement of multiple cranial nerves, the spinal cord, and meningeal involvement. Moreover, we found that all these patients unexpectedly showed the presence of blasts in the cerebrospinal fluid (CSF) but not in the peripheral blood despite repeated examinations. Bone marrow examination confirmed the presence of acute leukemia in these patients. Seven patients died within 18months of diagnosis and two patients developed stable disease. Our findings show a novel presenting feature of acute leukemia and highlight the importance of CSF cytology in the diagnosis of acute leukemia.

A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia.

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA(B) receptor (GABA(B)R). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA(B)R1 and rat GABA(B)R2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA(B)R1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA(B)R antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA(B)R that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.

Application of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis.

PURPOSE: To investigate the efficacy of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis. DESIGN: Prospective noncomparative case series. PARTICIPANTS: Twenty-eight eyes of 28 patients with neurotrophic keratitis who were refractory to conventional treatment. METHODS: The patients with neurotrophic keraitis were treated with 20% umbilical cord serum eyedrops 6 to 10 times a day. Ophthalmic examinations including best-corrected visual acuity (VA) measurement, corneal sensitivity test, corneal fluorescein staining, and anterior segment photography were performed before and after the treatment. Concentrations of substance P, insulinlike growth factor 1 (IGF-1), and nerve growth factor (NGF) in umbilical cord serum, normal peripheral blood serum, and tears were measured. MAIN OUTCOME MEASURES: Epithelial healing time; changes of VA and corneal sensitivity after treatment; and levels of substance P, IGF-1, and NGF in umbilical cord serum, normal peripheral blood serum, and tears. RESULTS: The epithelial defect healed completely in all eyes, with a mean healing time of 4.4+/-4.0 weeks. The epithelial defect healed within 2 weeks in 8 eyes (28.6%), between 2 and 4 weeks in 14 eyes (50.0%), and after 4 weeks in 6 eyes (21.4%). After treatment, VA improved by >2 lines in 17 eyes (60.7%). Mean pretreatment corneal sensitivity was 21.1+/-10.5 mm, and mean posttreatment corneal sensitivity was 24.3+/-11.7 mm (P<0.01). Mean concentrations of substance P, IGF-1, and NGF were 245.3+/-53.9 pg/ml, 239.0+/-77.1 ng/ml, and 729.7+/-72.0 pg/ml in umbilical cord serum; 169.5+/-81.0 pg/ml, 375.5+/-51.3 ng/ml, and 401.7+/-98.1 pg/ml in peripheral blood serum; and 69.8+/-24.9 pg/ml, 75.7+/-50.5 ng/ml, and 107.5+/-70.9 pg/ml in tears, respectively. CONCLUSIONS: Umbilical cord serum contains many neurotrophic factors, and umbilical cord serum eyedrops appeared to be effective for the treatment of neurotrophic keratitis.

Autologous serum application in the treatment of neurotrophic keratopathy.

OBJECTIVE: To evaluate the effect of autologous serum application for epithelial disorders in neurotrophic keratopathy (NK). DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Fourteen eyes of 11 patients with NK seen at Tokyo Dental College, Ichikawa General Hospital, Department of Ophthalmology, were studied. INTERVENTION: Twenty percent topical autologous serum eye drops were applied 5 to 10 times daily until resolution of the NK. Patients underwent routine ophthalmic examinations, including slit-lamp examination, corneal fluorescein dye testing, Cochet-Bonnet corneal sensitivity (Luneau, France), and best-corrected visual acuity (BCVA) measurements before and at the end of the treatment. Moreover, serum samples from 10 healthy volunteers were studied for the levels of substance P (SP), insulinlike growth factor (IGF-1), and nerve growth factor (NGF) by using radioimmunoassay and enzyme-linked immunosorbent assay techniques. Tear samples from 3 healthy subjects also were analyzed for NGF and IGF-1 levels by the same techniques. MAIN OUTCOME MEASURES: The changes in corneal disease state, corneal sensitivity, and BCVA with treatment were evaluated. The levels of neural healing factors like SP, IGF-1, and NGF in serum as well as NGF and IGF-1 in tears of healthy subjects also were examined. RESULTS: The epithelial disorders healed completely in all eyes within 6 to 32 days (mean, 17.1+/-8.0 days), with a decrease in corneal scarring. The mean pretreatment corneal sensitivity was 11.8+/-11.6 mm, which increased to 30.0+/-22.9 mm after treatment at the last follow-up. Five eyes attained normal corneal sensitivity with treatment. The BCVA improved by >2 Landolt lines in 78.6% of the eyes. The mean concentrations of SP in diluted and undiluted serum were 31.4+/-8.4 pg/ml and 157.0+/-42.1 pg/ml, respectively. The mean respective concentrations of IGF-1 in diluted and undiluted serum were 31.4+/-14.8 ng/ml and 157.0+/-73.9 ng/ml. The mean concentrations for NGF were 93.6+/-63.5 pg/ml and 468.3+/-317.4 pg/ml in serum samples with and without dilution, respectively. The mean concentration of NGF in tears was found to be 54 pg/ml. Insulinlike growth factor 1 was not detected in tears in this study. CONCLUSIONS: Autologous serum harbors neurotrophic factors. Autologous serum treatment may provide neural healers to the compromised ocular surface and seems promising for the restoration of the ocular surface epithelial integrity in patients with NK.

Rheumatoid factor positive hypertrophic cranial pachymeningitis in association with hypopituitarism and multiple cranial nerve palsies.

This is the first report of a patient presenting with rheumatoid factor (RF) positive hypertrophic cranial pachymeningitis (HCP) in association with hypopituitarism and multiple cranial nerve palsies. Our patient developed palsies of the left II and III, bilateral VI and VII, and right IX, X, and XII cranial nerves. A stimulation test showed hypopituitarism due to hypothalamic failure. The patient was seropositive for RF but had no multiple joint pain or deformities. Magnetic resonance imaging (MRI) showed thickened dura of the sellar and parasellar region, hypothalamus, bilateral cavernous sinuses and the tentorium all of which were enhanced by gadolinium (Gd). Treatment with prednisone improved clinical symptoms and MRI findings concomitant with reduction of RF titer. Although the exact mechanism of HCP has not been clearly elucidated, the present case suggests an autoimmune mechanism associated with RF.

Role of vagal neuropathy in the hyponatraemia of alcoholic cirrhosis.

The hyponatraemia common in decompensated cirrhosis arises in part from secretion of antidiuretic hormone attributed to a decrease in effective blood volume. Baroreceptors send inhibitory impulses to the midbrain and hypothalamus through the vagus and glossopharyngeal nerves. Since vagal neuropathy often occurs in chronic alcoholism, this might theoretically contribute to the inappropriate secretion of antidiuretic hormone, which might in turn induce hyponatraemia. In a prospective study including 34 patients with cirrhosis a high incidence of vagal neuropathy was found in the alcoholics (64%) and a clear cut increase in the incidence of hyponatraemia in patients with evidence of vagal damage and ascites (seven of eight patients (88%); p = 0.02). Results of a retrospective study of 64 patients with cirrhosis and ascitic decompensation showed hyponatraemia in 17 (50%) of 34 alcoholics but in only four (13%) of 30 patients with non-alcoholic disease (p = 0.006). Vagal neuropathy in alcoholic cirrhosis may contribute to the low serum sodium concentrations commonly found in these patients.

[Kinetics of peripheral leukocyte count and leukocyte adhesion to pulmonary capillary endothelium in experimental vagal neuritis]. / Kinetika soderzhaniia leikotsitov v perifericheskoi krovi i ikh adgezii k éndoteliiu kapilliarov legkogo pri éksperimental'nom nevrite bluzhdaiushchego nerva.

It was disclosed in chronic experiments on rats with dextral vagus neuritis that reactive leucocytosis is wave-like in character. Variations in leucocytosis were inversely proportional to adhesiveness of the lung capillary endothelium with respect to leucocytes. The relationship between the number of circulatory leucocytes and adhesiveness of the capillary endothelium is not so pronounced in intact animals as compared to controls.