Valeria Barcella

Evidence for retrochiasmatic tissue loss in Leber's hereditary optic neuropathy

Patients with Lebers hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small‐caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel‐based morphometry (VBM). The correlation of such changes with neuro‐ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual‐echo and fast‐field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro‐ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans‐synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction. Hum Brain Mapp, 2010.

Central nervous system dysregulation extends beyond the pain-matrix network in cluster headache

Introduction: In this study, we investigated whether abnormalities of the brain resting-state networks (RSNs) occur in patients with episodic cluster headache (CH), outside the attacks of the disease. Patients and methods: RS fMRI scans were acquired from 13 CH patients and 15 healthy controls. RS fMRI data were analyzed using both independent component analysis (ICA) and a seed correlation analysis, starting from the hypothalamus and the thalamus. Results: The seed correlation analysis revealed increased functional connectivity within the networks identified starting from the hypothalami and thalami in CH patients versus controls. ICA analysis detected 11 RSNs with potential functional relevance. Among these networks, CH patients had decreased fluctuations within the sensorimotor and the primary visual network compared to controls (P-values 0.03–0.007). RSN abnormalities were significantly correlated with disease duration. Conclusions: In CH patients a diffuse abnormality of brain functional connectivity is present, which extends beyond the antinoceptive system.

Erythroblastaemia in natalizumab-treated patients with multiple sclerosis

BACKGROUND Natalizumab is a monoclonal antibody that significantly reduces the occurrence of relapses in relapse-remitting multiple sclerosis (RRMS) patients. Early papers on the clinical use of natalizumab in RRMS patients reported erythroblastemia as occasional and transient. OBJECTIVES to determine the prevalence and absolute count of erythroblasts (nucleated red blood cells, NRBCs) in peripheral blood of RRMS patients in different treatment groups and healthy controls from the same geographic area using the same equipment for laboratory analysis. METHODS We retrospectively evaluated the samples of 203 consecutive RRMS patients including 26 subjects on natalizumab, 17 on fingolimod, 72 on interferon, 41 on glatiramer acetate, 47 treatment-naïve and 240 healthy controls from the same geographic area. Blood samples were processed using an XN-9000-Hematology Analyzer and subsequent microscopic verification. In the natalizumab-treated patients we performed an additional analysis in order to detect the expression of CD34+ cells in peripheral blood, as confirmation of a bone marrow mobilization. RESULTS The prevalence of patients with NRBCs positivity was significantly higher in natalizumab-treated patients (92%) compared with the other treatment groups and healthy controls (0%) (p<0.0005). The median absolute NRBCs count was significantly higher in natalizumab-treated patients (median 0.020, p<0.0005) than in the other treatment groups and healthy controls. Natalizumab-treated patients also had higher levels of white blood cells than all other groups and lower haemoglobin levels than healthy subjects (p<0.01), but no morphologic alterations were evident at a subsequent review of red blood cells, platelets and white blood cells. CD34+ cells levels were consistent with mobilization of haematopoietic stem cells from the bone marrow (median 8 cells/µL, IQR 5-12). CONCLUSIONS We confirm erythroblastaemia as a frequent finding of natalizumab treatment in RRMS patients. More extended knowledge and adequate long-term observation of this phenomenon are essential to better understand any pathological implication.

Incidence of orolingual angioedema after intravenous thrombolysis for stroke

IntroductionOrolingual angioedema (OA) is a known adverse effect of intravenous (i.v.) alteplase. We analyzed all patients treated with i.v. alteplase for stroke at our hospital since approval of i.v. thrombolysis in Italy in 2004 to assess the incidence of this complication.Patients and resultsFour hundred thirty-three patients received alteplase for stroke from April 2004 to May 2017. Two women developed OA (0.4%; 95% confidence interval 0.1 to 1.6%). Angioedema was mild in one case and severe in the other, with massive swelling of the lips, tongue, and oropharyngeal mucosa, and oropharyngeal bleeding, requiring intubation. Neither patient used ACE-inhibitors.DiscussionThe incidence of orolingual angioedema was very low in our series. Although OA is usually mild, anaphylactoid reactions may rarely occur, because of the variable degree of activation of the complement system and kinin cascade caused by alteplase. In such instances, admission to neurointensive care may be required. Specific bradykinin antagonists or drugs that target the kallikrein-kinin system are beginning to be used in the more severe cases. Thus, doctors and nurses caring for acute stroke patients need to be able to recognize and treat this complication.

No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study

In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a “free-of-charge” protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials.

Natalizumab-withdrawal-in-multiple-sclerosis-RR-patients-what-to-expect

Background: Postmarketing studies have shown a considerable efficacy of natalizumab (NAT) in RRMS, while progressive multifocal leukoencephalopathy (PML) is a well-known risk associated with long-term therapy. To minimize this risk, treatment with NAT is often stopped after 2years. However, the features of clinical and radiological disease activity after NAT withdrawal are still unknown. Objective: To evaluate effects of NAT discontinuation on clinical and radiological disease activity within twelve months after discontinuation. Methods: We retrospectively analyzed clinical and radiological data of 30 patients with MS who discontinued NAT between 2006 and 2013. Results: 14/29 patients had relapses after discontinuation of NAT, 1 patient experienced a rebound phenomenon and 14 patients were relapse-free 12 months after withdrawal. Patients in the relapse group had a higher 1-year pre-NAT treatment ARR (2.44) than the relapse-free group (1.66) (p = 0.0129), while no significant differences were observed comparing EDSS and MRI scores between both groups (p = 0.738 and 0.633 respectively). Conclusion: Our data suggest that ARR during the year previous NAT treatment start could be a predictor of relapses after NAT withdrawal. Correspondence to: Margherita Gardinetti, Papa Giovanni XXIII Hospital Piazza OMS, 24127 Bergamo Italy. E-mail: marghe.gardinetti@gmail.com

Subacute visual loss and bilateral fixed mydriasis: an atypical case of giant cell arteritis

Giant cell arteritis (GCA) is an immune-mediated chronic vasculitis of largeand medium-sized vessels, usually occurring in individuals aged over 50 years [1]. Characteristic findings include headache, jaw claudication, visual loss and constitutional symptoms. The pathological hallmark of GCA is granulomatous inflammation of the involved vessels, and temporal artery biopsy (TAB) remains the gold standard for diagnosis. Additional diagnostic tests include blood tests [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelets (PLT)] and imaging modalities [ultrasound of the arteries, fluorescein angiography, computed tomography (CT) and magnetic resonance imaging (MRI)] [2]. Since the prognosis for visual recovery is poor, the goal of treatment is to prevent ischemic damage and halt progression of visual loss [3]. A 67-year-old woman, with a history of hypertension, diabetes mellitus and with a pacemaker due to atrial fibrillation, presented to the emergency room of our hospital because of subacute and progressive visual loss. In 5 days, the patient became completely blind in her left eye (OS) and just able to distinguish light and shadow with the right one (OD). Simultaneously, her pupils became and remained mydriatic bilaterally. She was admitted to our neurological department, where the neurological examination revealed no abnormalities, except for the fixed bilateral mydriasis. Routine blood tests showed an increase of PLT (589 9 10/l), ESR (58 mm/h), CRP (98.7 mg/l), fibrinogen (774 mg/dl) and alkaline phosphatase (AP) (161 U/l). A CT scan of orbits with contrast revealed no changes in optic nerves volume, morphology and/or pathological enhancement. The cerebrospinal fluid (CSF) examination was normal. A visual acuity of 0/10 in OS and fingers counting in OD, a fixed bilateral mydriasis and a bilateral optic disc edema were demonstrated at the neurophthalmological examination. A myotic response of the pupils was observed with the pilocarpine test at 2 %, but also with a lower pilocarpine concentration (0.125 %), suggesting a pupil denervation pattern (Fig. 1).