Patient-reported outcome measures in patients with familial cerebral cavernous malformations: results from the Treat_CCM trial.

Background: The Phase 1/2 Treat_CCM randomized controlled trial for people with familial cerebral cavernous malformations (FCCMs) confirmed the safety of propranolol and suggested beneficial effects on intracerebral hemorrhage or new focal neurological deficits, but the effects on patient-reported outcome measures have not been reported. Methods: Participants completed self-reported questionnaires at baseline, 1 and 2 years. Depression was assessed with the Beck Depression Inventory-II (BDI-2); Anxiety with the State-Trait Anxiety Inventory X1 and X2 (STAI X-1 and STAI X-2); and Quality of Life with the Short Form 36 (SF-36), split into the physical and mental component scales (PCS and MCS). Differences between treatment groups and the general population were assessed. Change over time by treatment was assessed by means of mixed models. Results: In total, 71 participants (48 propranolol and 23 standard care) were enrolled, of whom 61 (73%) completed questionnaires at baseline and 2-year FU. At baseline, no differences between treatment groups for any of the questionnaires were present. Twenty (31.7%) patients were considered depressed at baseline, while this proportion was lower in the propranolol group after 2 years (28.6% vs. 55.5%, p = 0.047). The STAI X-1 and X-2 scores were stable over time. PCS was lower in FCCM patients as compared with the general Italian population, while the MCS was similar to the general population. No effect of propranolol was found for both PCS and MCS. Conclusion: Depression is common among patients with FCCM. Patients randomized to propranolol had a lower proportion of participants with depression after 2 years.Clinical trial registration: https://clinicaltrials.gov/, identifier (NCT03589014).

Circulating biomarkers in familial cerebral cavernous malformation.

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. METHODS: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FINDINGS: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. INTERPRETATION: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

Intravenous thrombolysis + endovascular thrombectomy versus thrombolysis alone in large vessel occlusion mild stroke: a propensity score matched analysis.

BACKGROUND AND PURPOSE: The best reperfusion treatment for patients with mild acute ischaemic stroke harbouring proximal anterior circulation large vessel occlusion (LVO) is unknown. The aim was to compare the safety and efficacy of intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus IVT alone in LVO patients with mild symptoms. METHODS: From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis and Thrombectomy Register (SITS-ISTR), were included: (i) consecutive acute ischaemic stroke patients, (ii) treated within 4.5 h from symptoms onset, (iii) baseline National Institutes of Health Stroke Scale (NIHSS) score ≤5 and (iv) intracranial internal carotid artery [ICA], M1 or T occlusion [defined as occlusion of ICA terminal bifurcation]. After propensity score matching, 3-month functional outcomes (modified Rankin Scale [mRS] 0-1 and 0-2) and safety outcomes (symptomatic intracerebral haemorrhage and death) were compared (via univariable and multivariable logistic [and ordinal] regression analyses) in patients treated with IVT + EVT versus IVT alone. RESULTS: In all, 1037 patients were included. After propensity score matching (n = 312 per group), IVT + EVT was independently associated with poor functional outcomes (adjusted odds ratio [aOR] 0.46 for mRS 0-1, 95% confidence interval [CI] 0.30-0.72, p = 0.001; aOR 0.52 for mRS 0-2, 95% CI 0.32-0.84, p = 0.007; aOR 1.61 for 1-point shift in mRS score, 95% CI 1.12-2.32, p = 0.011), with no significant differences in safety outcomes compared to IVT alone, despite numerically higher rates of symptomatic intracerebral haemorrhage (3.3% vs. 1.1%; p = 0.082), a higher rate of any haemorrhagic transformation (17.6% vs. 7.3%; p < 0.001) and subarachnoid haemorrhage (7.9% vs. 1.5%; p = 0.002) in the IVT + EVT group. DISCUSSION: In anterior circulation LVO patients presenting with NIHSS score ≤5, IVT + EVT (vs. IVT alone) was associated with poorer 3-month functional outcome. Randomized controlled trials are needed to elucidate the best treatments in mild LVO patients.

Magnetic susceptibility as a 1-year predictor of outcome in familial cerebral cavernous malformations: a pilot study.

OBJECTIVES: To test whether quantitative susceptibility mapping (QSM) of cerebral cavernous malformations (CCMs) assessed at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. METHODS: Familial CCM patients were enrolled in the longitudinal multicentre study Treat-CCM. The 3-T MRI scan allowed performing a semi-automatic segmentation of CCMs and computing the maximum susceptibility in each segmented CCM (QSMmax) at baseline. CCMs were classified as haemorrhagic and non-haemorrhagic at baseline and then subclassified according to the 1-year (t1) evolution. Between-group differences were tested, and the diagnostic accuracy of QSMmax in predicting the presence or absence of haemorrhagic signs in CCMs was calculated with ROC analyses. RESULTS: Thirty-three patients were included in the analysis, and a total of 1126 CCMs were segmented. QSMmax was higher in haemorrhagic CCMs than in non-haemorrhagic CCMs (p < 0.001). In haemorrhagic CCMs at baseline, the accuracy of QSMmax in differentiating CCMs that were still haemorrhagic from CCMs that recovered from haemorrhage at t1 calculated as area under the curve (AUC) was 0.78 with sensitivity 62.69%, specificity 82.35%, positive predictive value (PPV) 93.3% and negative predictive value (NPV) 35.9% (QSMmax cut-off ≥ 1462.95 ppb). In non-haemorrhagic CCMs at baseline, AUC was 0.91 in differentiating CCMs that bled at t1 from stable CCMs with sensitivity 100%, specificity 81.9%, PPV 5.1%, and NPV 100% (QSMmax cut-off ≥ 776.29 ppb). CONCLUSIONS: The QSMmax in CCMs at baseline showed high accuracy in predicting the presence or absence of haemorrhagic signs at 1-year follow-up. Further effort is required to test the role of QSM in follow-up assessment and therapeutic trials in multicentre CCM studies. KEY POINTS: • QSM in semi-automatically segmented CCM was feasible. • The maximum magnetic susceptibility in a single CCM at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. • Multicentric studies are needed to enforce the role of QSM in predicting the CCMs' haemorrhagic evolution in patients affected by familial and sporadic forms.

Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial.

BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the ß-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations. METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment. FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness). INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.

Clinical, neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting the central nervous system. CCM might be asymptomatic or cause cerebral hemorrhage, seizures, recurrent headaches and focal neurologic deficits. Causative mutations underlining CCM have been reported in three genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Therapeutic avenues are limited to surgery. Here we present clinical, neuroradiological and molecular findings in a cohort of familial and sporadic CCM patients. Thirty subjects underwent full clinical and radiological assessment. Molecular analysis was performed by direct sequencing and MLPA analysis. Twenty-eight of 30 subjects (93%) experienced one or more typical CCM disturbances with cerebral/spinal hemorrhage being the most common (43%) presenting symptom. A molecular diagnosis was achieved in 87% of cases, with three novel mutations identified. KRIT1/CCM1 patients displayed higher risk of de novo CCMs appearance and bleedings. Magnetic Resonance Imaging (MRI) showed that infratentorial region was more frequently affected in mutated subjects while brainstem was often spared in patients with negative genetic testing.

Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants.

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147-7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C-terminal regions and involved in protein-protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder.

Clinical features and disease course of patients with acute ischaemic stroke just before the Italian index case: Was COVID-19 already there?

Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19.

Safety and efficacy of rt-PA treatment for acute stroke in pseudoxanthoma elasticum: the first report.

Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum-related stroke undergoing intravenous thrombolysis.

Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1). CASE PRESENTATION: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient's mother and in his younger brother who displayed cortical dysplasia type 2. CONCLUSIONS: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin.

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. METHODS: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). DISCUSSION: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. TRIAL REGISTRATION: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

A Rare Cause of Juvenile Stroke: Extracranial Carotid Artery Aneurysm with Venous Complete Reconstruction of the Carotid Bifurcation.

Extracranial carotid artery aneurysms (ECAA) are a rare cause of embolic stroke. The underlying etiology is variable, with atherosclerosis being the most common entity in older subjects. Several treatments have been developed over the last 20 years, but the preferred method remains unknown. Notwithstanding the widespread use of endovascular techniques, surgical reconstruction by means of a bifurcated venous bypass graft should be applied in younger patients. In this way, it is possible to avoid major concerns about the development of long-term intrastent restenosis, and also to spare the external carotid artery which represents the main branch for the ipsilateral cerebral and facial perfusion. We propose ECAA resection and interposition of the inverted great saphenous vein to both the internal and external carotid artery by means the use of a tributary, i.e., the Giacomini vein.

Paroxysmal Nocturnal Hemoglobinuria (Pnh): Brain Mri Ischemic Lesions In Neurologically Asymtomatic Patients.

This study investigated for the first time brain ischemic involvement in 19 consecutive neurologically asymptomatic PNH patients by non-enhanced cerebral MRI, and by intracranial arterial and venous angio-MRI. Eleven cases (58%, 7 aged <65) showed pathological findings: 9 white matter (WM) abnormalities related to chronic ischemic small vessel disease, 2 a focal abnormality >5 mm, and 5 cases a score >4 by the age-related white matter changes (ARWMC) scale. Compared with age and sex-matched controls (1:2 ratio), patients showed an increased frequency of periventricular WM vascular degeneration (32% versus 5.2%, p = 0.04) and of severe lesions (ARWMC scale score >4) (26% versus 2.6%, p = 0.05), and a higher overall ARWMC scale score (3.5 ± 1.07 versus 2.0 ± 0.8, mean ± SD, p < 0.0001). Notably, vascular abnormalities suspected for prior partial venous thrombosis, were observed in PNH cases only. MRI lesions were not related to blood counts, hemolytic markers, clone size, disease duration, and therapy with eculizumab. Neurological examination was unremarkable in all patients but one (Parkinson disease). Psychiatric assessment revealed a case of generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder. In conclusion, brain MRI may be useful at diagnosis and during the course of the disease to explore subclinical neurological involvement.

Progressive Encephalomyelitis with Rigidity and Myoclonus Associated With Anti-GlyR Antibodies and Hodgkin's Lymphoma: A Case Report.

INTRODUCTION: A 60-year-old man presented with a 6-month history of low back pain and progressive rigidity of the trunk and lower limbs, followed by pruritus, dysphonia, hyperhydrosis, and urinary retention. Brain and spinal imaging were normal. EMG showed involuntary motor unit hyperactivity. Onconeural, antiglutamic acid decarboxylase (anti-GAD), voltage-gated potassium channel, and dipeptidyl peptidase-like protein 6 (DPPX) autoantibodies were negative. CSF was negative. Symptoms were partially responsive to baclofen, gabapentin, and clonazepam, but he eventually developed severe dysphagia. Antiglycine receptor (anti-GlyR) antibodies turned out positive on both serum and CSF. A plasmapheresis cycle was completed with good clinical response. A PET scan highlighted an isolated metabolically active axillary lymphnode that turned out to be a classic type Hodgkin lymphoma (HL), in the absence of bone marrow infiltration nor B symptoms. Polychemotherapy with ABVD protocol was completed with good clinical response and at 1-year follow-up the neurological examination is normal. BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and severe neurological syndrome characterized by muscular rigidity and spasms as well as brain stem and autonomic dysfunction. It can be associated with anti-GAD, GlyR, and DPPX antibodies. All of these autoantibodies may be variably associated with malignant tumors and their response to immunotherapy, as well as to tumor removal, is not easily predictable. CONCLUSION: Progressive encephalomyelitis with rigidity and myoclonus has already been described in association with HL, but this is the first case report of a HL manifesting as anti-GlyR antibodies related PERM. Our report highlights the importance of malignancy screening in autoimmune syndromes of suspected paraneoplastic origin.

Red cell distribution width and the risk of cerebral vein thrombosis: A case-control study.

BACKGROUND: Red cell distribution width (RDW) is a marker of cardiovascular diseases and venous thromboembolism, but its role in cerebral vein thrombosis (CVT) is unknown. AIMS: To investigate whether high values of RDW are associated with an increased risk of CVT. METHODS: A case-control study of CVT patients (≥18years-old) referred to our center contrasted with healthy individuals. Odds ratios (ORs) were calculated for RDW values >90th percentile by multivariable logistic regression and adjusted for demographic characteristics, hemorheological parameters, renal function, fibrinogen and CRP. Quartiles based on the distribution of RDW values were used in an additional model to assess a dose-response relationship. The risk of CVT associated with the combined presence of high RDW and either thrombophilia abnormalities or oral contraceptive use was also estimated. RESULTS: 143 cases (median age 36years, 18-79) and 352 controls (42years, 18-80) were investigated. RDW values >90th percentile (>14.6%) were associated with an increased risk of CVT (OR 2.44, 95% CI 1.39-4.28). The association remained after further adjustment for hemorheological parameters (OR 3.73, 95% CI 1.72-8.09), inflammatory markers (OR 3.77, 95% CI 1.72-8.25) and renal function (OR 3.62, 95% CI 1.53-8.55). The risk appeared restricted to these extreme levels (>14.6%), as there was no graded association between values of RDW and CVT risk over quartiles. There was a synergistic effect on the risk of CVT for the combination of high RDW and thrombophilia abnormalities (OR 33.20, 95% CI 6.95-158.55) or oral contraceptive use (OR 37.99, 95% CI 8.78-164.45). CONCLUSIONS: Values of RDW >90th percentile are associated with CVT.

Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.