Giulia Berzero

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.

Spinal hemorrhage in eosinophilic granulomatosis with polyangiitis (Churg–Strauss)

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as a Churg–Strauss syndrome [1], is a rare systemic small vessel vasculitis mainly affecting people aged 40–60 years without gender predominance [2, 3]. Asthma, eosinophilia, chronic paranasal sinusitis, nasal polyposis, non-fixed pulmonary infiltrates, and myocarditis are typical findings of EGPA [4]. Neurologic involvement is frequently observed and peripheral nervous system (PNS) is affected in 59–86 % of patients, mainly in the form of peripheral neuropathy [5]. On the contrary, central nervous system (CNS) involvement is described in less than 10 % of cases [5]. The most common CNS manifestations are cerebral infarction and diffuse encephalopathy, while cerebral hemorrhages have been seldom associated with EGPA [6] and only one case of spinal subarachnoid hemorrhage has been previously reported in the early 1980s [7]. In June of 2012, a 31-year-old pregnant Caucasian woman with a long-term history of asthma and rhinitis on the day of the delivery presented with high spiking fever (up to 39.5 C) and arthralgias, disappearing in a few hours. Further similar episodes were then observed in the subsequent months without other additional findings. In August 2012, painful paresthesias in left hand, right arm, and dorsal surface of right foot appeared, together with bilateral distal upper limbs weakness. Electromyography/ electroneurography (EMG/ENG) confirmed a severe sensory-motor axonal neuropathy, predominant in upper limbs, characterized by patchy pattern as in vasculitic mononeuritis multiplex. Laboratory investigations showed an increase of inflammatory markers (ESR 58 mm/h, CPR 6.9 mg/dl) and leukocytosis (21,000/ll) with eosinophilia (63 %). Antineutrophil cytoplasmic antibodies (ANCA) were positive both in IIF (p-ANCA pattern) and in ELISA (anti-MPO specificity). Because of headache and neck stiffness appearance, brain MRI was performed, displaying maxillary and sphenoid sinusitis without CNS pathological findings. After the exclusion of underlying infections, the patient was diagnosed with EGPA and methylprednisolone 1 mg/kg/ day i.v. was started. Despite corticosteroid treatment, headache and neck stiffness persisted, global left upper limb weakness worsened in particular arm and wrist extension, and brisk left supinator tendon reflex appeared. Lumbar puncture revealed hemorrhagic cerebrospinal fluid, with a protein value of 755 mg/dl, glucose value of 23 mg/ dl, and 205 cells (neutrophils and red blood cells). HumanCMV and HSV infections were excluded by real-time PCR on cerebrospinal fluid, as well as other infectious processes. Spinal MRI was performed showing cervical and dorsal subarachnoid bleeding with spinal cord compression and C6–C7 intramedullary hyperintensity on the left side (Figs. 1a, 2a). Intravenous steroid (methylprednisolone 1 mg/kg/day i.v. for 6 days) was administered, followed by oral prednisone (75 mg/day) with subsequent tapering until suspension at 12 weeks. L. Diamanti (&) G. Berzero P. Bini S. Ravaglia E. Marchioni Neurology Department, IRCCS National Neurological Institute C. Mondino, University of Pavia, via Mondino 2, 27100 Pavia, Italy e-mail: luca.diamanti@mondino.it

Acute late-onset encephalopathy after radiotherapy: an unusual life-threatening complication.

Unusual late-onset complications of brain irradiation, characterized by reversible neurologic focal signs, seizures, and MRI alterations, have recently been reported and classified as stroke-like migraine attacks after radiation therapy (SMART)1 and peri-ictal pseudoprogression (PIPG).2

Diagnosis and therapy of acute disseminated encephalomyelitis and its variants.

Acute disseminated encephalomyelitis (ADEM) is traditionally regarded as a monophasic demyelinating disorder of the central nervous system occurring in children after infection or vaccination. ADEM in children has a polysymptomatic presentation that includes encephalopathy, fever and meningeal signs. In adults, encephalopathy is less frequent and the clinical presentation is usually dominated by long tract involvement. Despite the initial clinical severity, the functional outcome is favorable in most cases. ADEM is a subgroup within the broader spectrum of postinfectious neurological syndromes (PINSs), which includes variants characterized by additional peripheral nervous system involvement, and variants characterized by a relapsing or chronic progressive course. The literature on the matter is scarce, mostly consisting of retrospective studies. The aims of this paper are to review the clinical and paraclinical profile of ADEM and its variants, to identify potential predictors of outcome, to summarize current treatment strategies and to outline research perspectives.

Herpes simplex encephalitis in glioma patients: a challenging diagnosis

Objectives In recent years, herpes simplex encephalitis (HSE) has been reported with increasing frequency in settings of immunosuppression, such as acquired immunodeficiency, transplantation and cancer. As observed, in immunocompromised individuals HSE presents peculiar clinical and paraclinical features, and poorer prognosis. Methods Here we describe a retrospective series of seven cases of HSE in patients with high-grade glioma (HGG), collected among three institutions in a 5-year period (during this time, a total of 1750 patients with HGG were treated). Results Diagnosis of the condition was particularly challenging due to the confounding clinical presentation and the atypical biological findings. As a result, antiviral treatment was started with a sharp delay compared with immunocompetent hosts. Prognosis was poor, with high short-term mortality and severe residual disability in survivors. Conclusions The substantial incidence of HSE observed in our centres together with the difficulty in diagnosing the condition suggest that the incidence of this complication may be highly underestimated. The aim of our report is to strengthen the observation of HSE in patients with HGG and outline the key elements that may allow its diagnosis.

Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area

Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV), calculated with Dynamic Susceptibility Contrast (DSC) Perfusion-Weighted Imaging (PWI), allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI) approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV). Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp.), the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P = 0.036). In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.

Paraneoplastic cerebellar degeneration associated with anti-ITPR1 antibodies

In recent years, the spectrum of anti-Purkinje cell autoimmunity has widened to include novel clinico-immunologic entities, a number of which have been associated with antibodies targeting intracellular antigens (protein kinase C gamma (PKCγ), carbonic anhydrase–related protein (CARP VIII), Ca/Rho GTPase activating protein 26 (ARHGAP26), inositol 1,4,5-trisphosphate receptor 1 (ITPR1), and HOMER3).1–3 Anti-ITPR1 belong to this group of newly discovered anticerebellar autoantibodies,4 but little is known regarding the exact clinical and paraclinical phenotypes associated with these antibodies and their potential association with cancer.

Safety of treatment with nivolumab after ipilimumab-related meningoradiculitis and bilateral optic neuropathy

a OncoNeuroTox Group: Center for Patients with Neurological Complications of Oncologic Treatments, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix et Hôpital Percy, Paris, France b Department of Neurology 2 (Mazarin), Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Assistance Publique Hôpitaux de Paris (APHP), Paris, France c UMR975 INSERM-UPMC, GH PitiéSalpêtrière, Paris, France d Neuroscience Consortium, Università di Pavia Monza Policlinico and Pavia Mondino, Italy e Department of Neuroradiology, Fondation Rothschild Hospital, Paris, France f INSERM U1015, Gustave Roussy, Villejuif, France g Department of Ophtalmology, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Assistance Publique Hôpitaux de Paris (APHP), Paris, France h Department of Neurology, Military Training Hospital Percy, Service de Santé des Armées, Paris, France i Military Health Service Academy of Val-de-Grâce, Service de Santé des Armées, Paris, France j Department of Oncology, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Assistance Publique Hôpitaux de Paris (APHP), Paris, France

FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas

Objective To characterize the prevalence and prognostic significance of major driver molecular alterations in adult midline diffuse gliomas (MLG). Methods Adults with histologically proven MLG diagnosed between 1996 and 2017 were identified from our tumor bank, systematically reviewed, and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A, HIST1H3B, TERTp, IDH1/2, FGFR1, p16/CDKN2A, and EGFR status. Results A total of 116 adult patients (M/F 71/45, median age 46.5 years) with MLG (17 cerebellar, 8 spinal, 30 brainstem, 57 thalamic, and 4 diencephalic nonthalamic) were identified. Most patients had high-grade disease at presentation (grade II: 11%, grade III: 15%, grade IV: 75%). Median overall survival was 17.3 months (14.5–23.8 months). Main molecular alterations observed were TERT promoter, H3F3A, and hotspot FGFR1 (N546 and K656) mutations, in 37%, 34%, and 18% of patients, respectively. IDH1 mutations only affected brainstem gliomas (6/24 vs 0/78; p = 7.5 × 10−5), were mostly non-R132H (contrasting with hemispheric gliomas, p = 0.0001), and were associated with longer survival (54 vs 12 months). TERT promoter mutation (9.1 vs 24.2 months), CDKN2A deletion (9.9 vs 23.8 months), and EGFR amplification (4.3 vs 23.8 months) were associated with shorter survival. Of interest, in contrast with pediatric MLG, H3K27M mutations were not associated with worse prognosis (23 vs 15 months). Conclusions Patients with adult MLG present with unique clinical and molecular characteristics, differing from their pediatric counterparts. The identification of potentially actionable FGFR1 mutations in a subset of adult MLG highlights the importance of comprehensive genomic analysis in this rare affection.

Motor neuron disease of paraneoplastic origin: a rare but treatable condition

Paraneoplastic motor neuron disorders (MND) are rare conditions; their exact clinical and electrophysiological phenotype have not been exhaustively described yet. The purpose of this study is to depict the main characteristics of paraneoplastic MND to highlight the features that may allow its diagnosis. Based on the description of eight original cases, and on the revision of 21 patients identified from a systematic review of the literature, the main features of paraneoplastic MND can be summarized as follows: (1) subacute; (2) lower motor neuron syndrome, associated or not with upper motor neuron involvement; (3) predominant asymmetric upper limb involvement; (4) presence of other non-motor neurological manifestations, including sensory neuronopathy; (5) signs of inflammation in the cerebrospinal fluid (CSF); (6) neurological improvement or stabilization after immunotherapy and tumor treatment. The diagnosis of paraneoplastic MND may be difficult because of its rarity, the absence of pathognomonic clinical features, and the frequent absence of prior tumor history. However, it is of capital importance to correctly identify patients with paraneoplastic MND, as this represents a potentially treatable condition. In the presence of subacute lower motor neuron impairment, especially when atypical clinical features for degenerative MND or other non-motor neurological manifestations are present, we recommend testing for onconeural antibodies. In the case, the search for onconeural antibodies is negative, but it exists a strong clinical suspicion for a paraneoplastic etiology; CSF analysis and total-body 18FDG-PET/CT imaging should be performed to circumstantiate diagnosis.