Maria Federica Pelizza

Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis

Encephalitis associated with anti-N-Methyl-D-Aspartate Receptor (NMDAR) antibodies is an autoimmune encephalopathy often associated with teratoma [1]. Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system (CNS) associated with antibodies against aquaporin 4 (AQP4) [2]. Here, we report the case of a patient who developed limbic encephalitis (LE) followed by NMO, whose serum harbored anti-NMDAR and anti-AQP4 IgG antibodies. A 50-year-old woman presented with subacute, shortterm memory loss, confusion, and behavioral changes. Routine blood tests, an infectious disease screening, an electroencephalogram (EEG) and cerebral spinal fluid (CSF) tests were all negative, whereas a brain MRI showed a T2-weighted, hyperintense medial temporal cortex. A pelvic mass was detected by computed tomography (CT) scan. Two months later, she underwent a hystero-adnexectomy with the removal of an ovarian teratoma. A diagnosis of paraneoplastic LE was made. Tests for classical onconeural antibodies (Hu, Ri, Ma2, CV2/CMRP5, amphiphysin, Yo) proved negative. Her memory deficit started to improve 4 months after surgery, when she received repeated courses of low-dose oral steroids. One month later, she had only residual retrograde amnesia (Fig. 1e). Five months later, she developed drowsiness, cervical itching, and impaired gait. Within 2 weeks, she had developed paraplegia and MRI showed multiple T2weighted hyperintense lesions in the pons, hypothalamus, medulla oblongata, and cervical spine (Fig. 1a–c). A CSF analysis proved negative (normal white cell count and proteins, and absence of IgG intrathecal synthesis). Plasmaexchange and high-dose intravenous steroids were initiated, resulting in a slow improvement of strength. Nine months later, she presented with left-eye optic neuritis. High-dose intravenous steroids were partially effective. Three months later, a relapse occurred with weakness of the right limbs. An MRI disclosed new lesions in the pons and dorsal spine (Fig. 1d). Her serum and CSF were tested for AQP4-IgG-Ab by indirect immunofluorescence on a commercial assay (Euroimmun, Lubeck, Germany) [3], proving positive on serum (titer 1:100). The test was extended to NMDAR-IgG-Ab, also proving positive on serum (1:32) and on CSF. The patient was treated with plasma-exchange and oral steroids, with benefit. Three months later, her CSF analysis revealed a normal white cell count and increased protein content (84 mg/dl); matching oligoclonal bands were detected in the CSF and serum. Human leukocyte typing disclosed the presence of the class I allele B8 and class II DR3-DQ2 (DRB1*03-DQB1*02). AQP4-IgG-Aband NMDAR-IgG-Ab-positivity were both confirmed, but a decrease in serum Ab titer was shown (both Abs serum titer 1:10; NMDAR-Ab CSF titer 1:3, 2); VGCC-, AMPAR-, GABAbR-, LGI1and CASPR2-Abs tested negative. Treatment with azathioprine was started. Eight months later, her conditions were stable. This patient presented with LE followed by NMO 1 year later, and tested positive for AQP4and NMDAR-Abs. To M. Zoccarato M. F. Pelizza B. Giometto L. Zuliani (&) Department of Neurology, Ospedale Ca’Foncello, Azienda Unita Locale Socio-Sanitaria 9 Treviso, Piazza Ospedale 1, 31100 Treviso, Italy e-mail: luigizuliani77@gmail.com

Paediatric anti-N-methyl-d-aspartate receptor encephalitis: The first Italian multicenter case series

BACKGROUND Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. METHODS To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. RESULTS Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. CONCLUSIONS Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.

Plasma exchange in pediatric anti-NMDAR encephalitis: A systematic review

OBJECTIVE To clarify the most frequent modalities of use of plasma exchange (PE) in pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis and to establish the most effective association with other immunotherapies. METHODS Systematic literature review on PE in pediatric anti-NMDAR encephalitis (2007-2015). RESULTS Seventy-one articles were included (mostly retrospective), reporting a total of 242 subjects (73.2%, 93/127 females; median age at onset 12years, range 1-18). Median time to immunotherapy was 21days (range 0-190). In most cases, PE was given with steroids and IVIG (69.5%, 89/128), or steroids only (18%, 23/128); in a minority, it was associated with IVIG only (7%, 9/128), or was the only first-line treatment (5.5%, 7/128). In 54.5% (65/119), PE was the third treatment after steroids and IVIG, in 31.1% (37/119) the second after steroids or IVIG; only in 14.3% (17/119) was it the first treatment. Second-line immunotherapies were administered in 71.9% (100/139). Higher rates of full/substantial recovery at follow-up were observed with immunotherapy given ⩽30days from onset (69.4%, 25/36) compared to later (59.2%, 16/27), and when PE was associated with steroids (66.7%, 70/105) rather than not (46.7%, 7/15). Significant adverse reactions to PE were reported in 6 patients. CONCLUSION Our review disclosed a paucity of quality data on PE in pediatric anti-NMDAR encephalitis. PE use in this condition has been increasingly reported, most often with steroids and IVIG. Despite the limited number of patients, our data seem to confirm the trend towards a better outcome when PE was administered early, and when given with steroids.

Genetic and imaging features of cerebellar abnormalities in tuberous sclerosis complex: more insights into their pathogenesis

1 Department of Medicine and Surgery, Neuroradiology, Sezione di Neuroscienze, University of Salerno, Baronissi; 2 Department of Woman and Child Health, Pediatric Neurology and Neurophysiology Unit, University Hospital of Padova, Padova; 3 Epilepsy and Sleep Medicine Center, Neuropsychiatric Unit, ASST Santi Paolo Carlo, Milan; 4 Epilepsy Center, Health Sciences Department, University of Milano, Milan, Italy.

PP13.1 – 2834: Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series

Objective Given the rarity of this condition, especially in children, there is a paucity of literature reporting large case series of paediatric anti-N-methyl-D-aspartate receptor encephalitis. Our goal is to contribute to define the features of paediatric anti-N-methyl-D-aspartate receptor encephalitis. Methods We describe a new nationwide case series of 20 children (50% females), referred by 13 Italian centers. Results Mean age at onset was 8 years (range 3–17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioral/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12–18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. Most patients recovered substantially (80%); this rate was higher among older patients, and in those receiving first immune therapy within 1 month. Conclusion Our case series confirms a symptomatologic core of paediatric anti-N-methyl-D-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of the patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. Paediatricians should consider this diagnosis for children presenting with neurological and/or behavioral or psychiatric disturbances, regardless of age and gender, especially in the absence of data suggesting other specific etiologies. Other authors: F. Beccaria, L. Giunta, C. Boniver, M.G. Natali Sora, N. Zamponi.

Tuberous sclerosis-associated neuropsychiatric disorders: a paediatric cohort study

We aimed to study tuberous sclerosis‐associated neuropsychiatric disorders (TAND) in children and adolescents with tuberous sclerosis complex (TSC).

Acute hyperkinetic movement disorders in Italian paediatric emergency departments

Introduction Limited data exist on epidemiology, clinical presentation and management of acute hyperkinetic movement disorders (AHMD) in paediatric emergency departments (pED). Methods We retrospectively analysed a case series of 256 children (aged 2 months to 17 years) presenting with AHMD to the pEDs of six Italian tertiary care hospitals over a 2-year period (January 2012 to December 2013). Results The most common type of AHMD was tics (44.5%), followed by tremors (21.1%), chorea (13.7%), dystonia (10.2%), myoclonus (6.3%) and stereotypies (4.3%). Neuropsychiatric disorders (including tic disorders, psychogenic movement disorders and idiopathic stereotypies) were the most represented cause (51.2%). Inflammatory conditions (infectious and immune-mediated neurological disorders) accounted for 17.6% of the cases whereas non-inflammatory disorders (including drug-induced AHMDs, genetic/metabolic diseases, paroxysmal non-epileptic movements and idiopathic AHMDs) accounted for 31.2%. Neuropsychiatric disorders prevailed among preschoolers and schoolers (51.9% and 25.2%, respectively), non-inflammatory disorders were more frequent in infants and toddlers (63.8%), whereas inflammatory conditions were more often encountered among schoolers (73.3%). In 5 out of 36 Sydenham’s chorea (SC) cases, tics were the presentation symptom on admission to emergency department (ED), highlighting the difficulties in early diagnosis of SC. Inflammatory disorders were associated with a longer hospital stay and a greater need of neuroimaging test compared with other disorders. Conclusions This study provides the first large sample of paediatric patients presenting to the ED for AHMDs, helping to elucidate the epidemiology, aetiology and clinical presentation of these disorders.