Peculiar CADASIL phenotype in monozygotic twins carrying a novel NOTCH3 pathogenetic variant.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease caused by Neurogenic locus notch homolog protein 3 (NOTCH3) gene mutations. The main clinical features include migraine with aura, recurrent ischemic strokes and dementia. Brain MRI typically shows multiple small lacunar infarcts and severe, diffuse, symmetrical white matter hyperintensities (WMHs), with characteristic involvement of the anterior temporal pole, external capsule, and superior frontal gyrus. Reports of twins with CADASIL are scarce. Herein we describe a pair of monozygotic twins with peculiar CADASIL phenotype, carrying a new NOTCH3 variant. CASE PRESENTATION: Twin A was a 45-year-old male suffering from migraine, obesity, arterial hypertension, and polycythemia (with negative genetic analysis), who complained of a transient, short-lasting (~ 5 minutes) episode of speech difficulties. Brain MRI showed diffuse, symmetrical, confluent periventricular WMHs involving frontal, parietal, and temporal lobes and external capsules, with sparing of anterior temporal poles. Genetic analysis of NOTCH3 gene demonstrated the presence of missense c.3329G>A, p.(Cys1110Tyr) variant, confirming CADASIL diagnosis. Twin B, affected by migraine and polycythemia, as well as his monozygotic twin, presented with a 2-month history of trigeminal neuralgia. Brain MRI demonstrated diffuse WMHs with a pattern of distribution like his twin. Genetic analysis revealed the same NOTCH3 pathogenic variant. CONCLUSIONS: Our monozygotic twins have a strikingly similar neuroimaging picture with sparing of anterior temporal poles. They also have a peculiar phenotype, both presenting polycythemia without genetically confirmed cause. Twin B had trigeminal neuralgia, that is unusual in CADASIL. The possible association of the peculiar findings with the newly reported NOTCH3 variant needs to be confirmed with further observations.

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

The relevance of MRI blood-sensitive sequences in the diagnostic assessment of late-onset epilepsy.

OBJECTIVE: Sporadic cerebral amyloid angiopathy (CAA) is a degenerative brain small vessel disease of ageing resulting from progressive amyloid deposition in small arteries and arterioles of the cortex and leptomeninges. CAA may be diagnosed by the mean of Boston criteria, particularly with the use of the blood-sensitive T2* MRI sequences (GRE and SWI). Epileptic seizures have rarely been reported in CAA. PATIENTS AND METHODS: We describe two patients with late-onset unprovoked seizures due to CAA. A short literature review on this topic is presented. RESULTS: In our two patients with late-onset unprovoked seizures as the first manifestation of CAA, only GRE and SWI sequences lead to a correct diagnosis. In literature, only 15 patients with CAA presenting with seizures have been reported. In these subjects, data on seizures semiology and prognosis are scarce. CONCLUSIONS: Our report highlights the importance to perform blood-sensitive sequences in all subjects with LOE of otherwise unknown etiology, not to miss a diagnosis of CAA.

Functional convergence spasm: an unexpected finding in a patient with focal epilepsy.

OBJECTIVE: Convergence spasm is a clinical condition characterized by transient episodes of convergence, miosis and accommodation with strabismus and diplopia and it is usually a manifestation of a functional neurological disorder. We describe a patient with a challenging diagnosis of convergence spasm in the setting of occipital lobe epilepsy. CASE REPORT: A 52-year-old woman came for the assessment of focal epilepsy due to left occipital cortical dysplasia. During ocular motility tests, she presented with episodes of short duration (~10-30 seconds) of convergent strabismus. Neuropsychological evaluation showed a severe mixed anxiety-depressive disorder with a tendency toward somatization. RESULTS: Convergence spasm was recorded during video-EEG examination and no ictal activity was present. CONCLUSIONS: To our knowledge, no other report of functional convergence spasm in the context of focal epilepsy associated with cortical dysplasia has been described in literature.

Novel COL4A2 mutation causing familial malformations of cortical development.

OBJECTIVE: This article aimed to describe a novel COL4A2 mutation and the phenotypic features of two family members presenting with epilepsy and cortical development malformations. PATIENTS AND METHODS: The first patient is a 65-year-old woman with hematuria and adult-onset seizures. Brain MRI showed closed lip schizencephaly of right lateral sulcus associated with polymicrogyria of the surrounding cortex and areas of subcortical heterotopia. The second patient is a 40-year-old man, her son. He was born post-term with neonatal distress and psychomotor developmental delay with congenital left leg paresis and strabismus, as well as childhood-onset focal motor seizures. Brain MRI showed a right nucleus-capsular porencephalic cavitation with enlargement of the homolateral ventricle and a focal right occipital cortico-subcortical encephalomalacia. A small heterotopic band was also present in the frontal left subcortical region. RESULTS: We tested both patients with a NGS panel for genetic epilepsies, which evidenced a missense mutation in COL4A2 gene (c.2972G>A, causing the aminoacidic substitution Gly991Glu). CONCLUSIONS: The phenotypic spectrum associated with COL4A2 mutations has not been extensively described in the literature. Testing for COL4A mutations is indicated in patients with malformations of cortical development, particularly in the presence of familial conditions, even in the absence of porencephaly or early hemorrhagic strokes.

Insight into epileptic and physiological déjà vu: from a multicentric cohort study.

BACKGROUND AND PURPOSE: The presence of a continuum between physiological déjà vu (DV) and epileptic DV is still not known as well as epidemiological data in the Italian population. The aim was to identify the epidemiological distribution of DV in Italy, and secondly to look for specific features of DV able to discriminate between epileptic and non-epileptic DV. METHODS: In all, 1000 individuals, 543 healthy controls (C) (313 women; age 40 ± 15 years) and 457 patients with epilepsy (E) (260 women; age 39 ± 14 years), were prospectively recruited from 10 outpatient neurological clinics throughout Italy. All populations were screened using the Italian Inventory for Déjà Vu Experiences Assessment (I-IDEA) test and E and pairwise C underwent a comprehensive epilepsy interview. RESULTS: Of E, 69% stated that they experienced 'recognition' and 13.2% reported that this feeling occurred from a few times a month to at least weekly (versus 7.7% of the control group). Furthermore, a greater percentage of E (6.8% vs. 2.2%) reported that from a few times a month to at least weekly they felt that it seemed as though everything around was not real. In E, the feeling of recognition raised fright (22.3% vs. 13.2%) and a sense of oppression (19.4% vs. 9.4%). A fifth of E felt recognition during epileptic seizures. CONCLUSION: Only E regardless of aetiology firmly answered that they had the feeling of recognition during an epileptic seizure; thus question 14 of the I-IDEA test part 2 discriminated E from C. Paranormal activity, remembering dreams and travel frequency were mostly correlated to DV in E suggesting that the visual-memory network might be involved in epileptic DV.

Management of psychogenic non-epileptic seizures: a multidisciplinary approach.

The International League against Epilepsy (ILAE) proposed a diagnostic scheme for psychogenic non-epileptic seizure (PNES). The debate on ethical aspects of the diagnostic procedures is ongoing, the treatment is not standardized and management might differ according to age group. The objective was to reach an expert and stakeholder consensus on PNES management. A board comprising adult and child neurologists, neuropsychologists, psychiatrists, pharmacologists, experts in forensic medicine and bioethics as well as patients' representatives was formed. The board chose five main topics regarding PNES: diagnosis; ethical issues; psychiatric comorbidities; psychological treatment; and pharmacological treatment. After a systematic review of the literature, the board met in a consensus conference in Catanzaro (Italy). Further consultations using a model of Delphi panel were held. The global level of evidence for all topics was low. Even though most questions were formulated separately for children/adolescents and adults, no major age-related differences emerged. The board established that the approach to PNES diagnosis should comply with ILAE recommendations. Seizure induction was considered ethical, preferring the least invasive techniques. The board recommended looking carefully for mood disturbances, personality disorders and psychic trauma in persons with PNES and considering cognitive-behavioural therapy as a first-line psychological approach and pharmacological treatment to manage comorbid conditions, namely anxiety and depression. Psychogenic non-epileptic seizure management should be multidisciplinary. High-quality long-term studies are needed to standardize PNES management.

Value of clinical features to differentiate refractory epilepsy from mimics: a prospective longitudinal cohort study.

BACKGROUND AND PURPOSE: Misdiagnosis of refractory epilepsy (rE) is common and such patients experience a long diagnostic delay. Our aim was to identify key clinical/laboratory factors in order to obtain an alternative diagnosis in patients referred for rE. METHODS: Between January 2010 and December 2015, 125 consecutive patients with a diagnosis of rE were prospectively enrolled. All patients underwent a comprehensive neurological, neuropsychiatric and cardiological evaluation, and had an observation time of at least 1 year after the study entry. RESULTS: Diagnosis of rE was confirmed in 104/125 (83.2%) patients (55 women, mean age 38.8 ± 14.3 years). Thirteen/125 patients (10.4%, seven women, mean age 50.8 ± 20.9) were diagnosed with syncope, which was cardiac/cardio inhibitory in 9/13 (69%). The remaining 8/125 patients (6.4%, six women, mean age 41.2 ± 14.6 years) were diagnosed with psychogenic non-epileptic seizures. Age at onset had a high accuracy in differentiating patients with syncope from others, with the best cut-off age at 35 years and above. Abnormal brain magnetic resonance imaging (MRI) had a significant yield of about 70% in rE. A diagnostic model including age at onset and brain MRI was highly accurate in differentiating patients with syncope from others. In patients with cardiac/cardio inhibitory syncope, the point score of historical features was ≥1 and falsely favoured the diagnosis of epileptic seizures. CONCLUSIONS: This prospective cohort study identifies rE mimics who are at high risk of morbidity and mortality. rE starting in adulthood should raise a high suspicion of cardiac syncope. Brain MRI is accurate in differentiating rE from other conditions.

3-T magnetic resonance imaging simultaneous automated multimodal approach improves detection of ambiguous visual hippocampal sclerosis.

BACKGROUND AND PURPOSE: To evaluate if an automatic magnetic resonance imaging (MRI) processing system may improve detection of hippocampal sclerosis (Hs) in patients with mesial temporal lobe epilepsy (MTLE). METHODS: Eighty consecutive patients with a diagnosis of MTLE and 20 age- and sex-matched controls were prospectively recruited and included in our study. The entire group had 3-T MRI visual assessment of Hs analysed by two blinded imaging epilepsy experts. Logistic regression was used to evaluate the performances of neuroradiologists and multimodal analysis. RESULTS: The multimodal automated tool gave no evidence of Hs in all 20 controls and classified the 80 MTLE patients as follows: normal MRI (54/80), left Hs (14/80), right Hs (11/80) and bilateral Hs (1/80). Of note, this multimodal automated tool was always concordant with the side of MTLE, as determined by a comprehensive electroclinical evaluation. In comparison with standard visual assessment, the multimodal automated tool resolved five ambiguous cases, being able to lateralize Hs in four patients and detecting one case of bilateral Hs. Moreover, comparing the performances of the three logistic regression models, the multimodal approach overcame performances obtained with a single image modality for both the hemispheres, reaching a global accuracy value of 0.97 for the right and 0.98 for the left hemisphere. CONCLUSIONS: Multimodal quantitative automated MRI is a reliable and useful tool to depict and lateralize Hs in patients with MTLE, and may help to lateralize the side of MTLE especially in subtle and uncertain cases.

Previous infection and the risk of ischaemic stroke in Italy: the IN2 study.

BACKGROUND AND PURPOSE: There is an increasing interest in new risk factors for ischaemic stroke. Acute and chronic infections could contribute to different aetiological mechanisms of atherosclerosis that lead to cerebrovascular disease. The aim of this study was to investigate the hypothesis that previous infections and Chlamydia pneumoniae in particular increase the risk of ischaemic stroke in the population. METHODS: This was a prospective case-control study involving 11 Italian stroke units. Controls were age- and sex-matched with cases, represented by patients admitted to hospital for acute ischaemic stroke. For each participant classical vascular risk factors and previous inflammatory and infectious events up to 1 month before were registered. Blood samples were collected to analyse inflammatory markers and titres of antibodies against C. pneumoniae. RESULTS: A total of 1002 participants were included (mean age 69 years) with 749 ischaemic stroke patients. Infections occurred within 1 month previously in 12% of the entire sample with a higher prevalence in the case group (14.4% vs. 3.9%). At multivariate analysis of the seropositivity of IgA antibodies against C. pneumoniae increased the risk of stroke significantly (relative risk 2.121; 95% confidence interval 1.255-3.584) and an early previous infection (up to 7 days before the event) contributed to a rise in probability of acute cerebral ischaemia (relative risk 3.692; 95% confidence interval 1.134-6.875). CONCLUSIONS: Early previous infections and persistent chronic infection of C. pneumoniae could contribute to increase the risk of ischaemic stroke significantly, in the elderly especially.

Advanced MRI morphologic study shows no atrophy in healthy individuals with hippocampal hyperintensity.

We have already shown that brain MR imaging of healthy individuals frequently reveals either unilateral or bilateral Hh, which is considered a hallmark of hippocampal sclerosis. We performed a follow-up (5-year interval) clinical and advanced imaging study of these individuals to address whether Hh may have masked occult brain atrophy or contributed to a later onset of epilepsy. Subjects with Hh (n = 13) underwent a detailed clinical-imaging protocol, with a 3T scan and were studied with automated hippocampal segmentation (FreeSurfer), whole brain voxel-based morphometry, and shape analysis. All 13 subjects with Hh had normal neurologic examination findings with no cognitive impairment. Multimodal structural neuroimaging methods did not show clear evidence of significant volumetric changes between subjects with or without Hh. We clearly showed that Hh is not associated with any occult brain atrophy; furthermore, none of the healthy subjects with MR imaging evidence of Hh developed epilepsy or trouble with cognition.

Usefulness of rectal biopsy for the diagnosis of Kufs disease: a controlled study and review of the literature.

BACKGROUND AND PURPOSE: Rectal biopsy is usually performed for in vivo diagnosis of Kufs disease (KD). We evaluated the usefulness of rectal biopsy in the diagnosis of such condition by comparing ultrastructural data of patients with suspicion of KD with those of control subjects. Furthermore, we reviewed literature data concerning the value of such a diagnostic procedure in the diagnosis of KD. METHODS: Sixty-five subjects were enrolled and underwent rectal biopsy. Of these, 13 had a clinical picture in keeping with KD, whereas 52, affected by Irritable Bowel Syndrome, constituted the control group. RESULTS: Ultrastructural analysis evidenced fingerprint (FP) inclusions in 12 subjects, 4/13 with suspicion of KD and 8/52 controls. In patients, FPs were mainly located in vascular smooth muscle cells (VSMC) while in controls they were mostly found in pericytes and VSMC. No FPs were found in one patient with genetically confirmed KD. In literature, we identified 14 KD patients who underwent rectal biopsy. In most reports, ultrastructural features were not systematically analyzed or described. CONCLUSIONS: Fingerprints are the most common ultrastructural finding in rectal biopsy in patients with suspicion of KD. However, their presence in pericytes and VSMC is not specific for KD because they may be found in controls subjects. Our literature review revealed that data on the value of rectal biopsy in the diagnosis of KD are scarce. In light of these findings, the relevance of rectal biopsy in such condition should be re-evaluated.

Temporal lobe abnormalities on brain MRI in healthy volunteers: a prospective case-control study.

OBJECTIVE: To prospectively assess the frequency of mesiotemporal abnormalities seen on brain MRI in healthy subjects in comparison with patients with temporal lobe epilepsy (TLE). METHODS: Ninety-nine consecutive patients (48 women, mean age 36.1 +/- 16.1 years; range 10 to 75) with TLE and 51 healthy volunteers (26 women, mean age 39.3 +/- 10.8 years) prospectively underwent the same MRI protocol, specific for TLE. Images were reviewed independently by 2 neuroradiologists blinded to clinical information. Cortical atrophy and signal intensities in the amygdala, hippocampus, cingulate gyrus, subcallosal area, insula, temporal parietal, and occipital lobe were graded relative to cortical signal intensity in the frontal lobe. Intrarater and interrater reliability were also assessed. RESULTS: Interrater and intrarater measurements demonstrated consistent and repeatable results. Forty-seven of 99 (47.5%) patients showed either unilateral or bilateral major T2/fluid-attenuated inversion recovery hyperintensities of the hippocampus, and 19 patients (19.2%) showed hippocampal atrophy seen at T1/inversion recovery sequences. In the controls, 15/51 (29.4%) individuals had unilateral or bilateral hyperintensities, which did not differ from the rate of occurrence in patients (p = 0.08). Conversely, unilateral hippocampal atrophy was found in 1 control, which was significantly different (p = 0.005) from the rate of occurrence in patients. Hyperintensity plus structural hippocampal atrophy were only seen in patients. CONCLUSIONS: On brain MRI, either unilateral or bilateral hippocampal hyperintensities are frequently encountered in healthy volunteers. Conversely, hippocampal atrophy, especially when associated with concomitant hyperintensity, was seen exclusively in the epilepsy group, indicating that the combination of these 2 variables represents the strongest and most reliable indicator of epilepsy.

Hippocampal and thalamic atrophy in mild temporal lobe epilepsy: a VBM study.

BACKGROUND: Patients with temporal lobe epilepsy (TLE) often have mild drug-responsive epilepsy which is frequently associated with MRI detectable mesial temporal sclerosis (MTS), indicating that MTS is not necessarily related to seizure severity. To better define the anatomic substrates associated with TLE, we applied voxel-based morphometry (VBM) analysis to patients with mild TLE. METHODS: Optimized VBM was applied to the MRI brain images of 95 consecutive unrelated patients who were diagnosed with mild TLE and to 37 healthy controls. We complemented the investigation by calculating the gray matter volume of regions of interest (ROIs) in the bilateral hippocampus. Standard MRI scans revealed evidence of MTS (pTLE) in 34 patients, and no evidence of MTS in the remaining 61 (nTLE). RESULTS: The VBM analysis provided evidence of a reduction in gray matter volume in the hippocampus and thalami. The gray matter volume reduction in the thalamic and hippocampal networks was significantly more severe in patients with pTLE than in the nTLE or the control groups (at a threshold of FWE-corrected p < 0.05). Patients with nTLE showed the same gray matter abnormalities at an uncorrected statistical threshold (p < 0.001) compared to normal controls. ROI analysis confirmed the ipsilateral hippocampal atrophy that was detected in routine MRI scans. CONCLUSIONS: The structural abnormalities seen in patients with mild temporal lobe epilepsy (TLE) demonstrate that a temporo-limbic pathway, which includes the thalamus, plays a major role in the pathogenesis of TLE. It is likely that other factors, especially genetic ones, play a major role in the causation and severity of TLE.

Limited chronic focal encephalitis: another variant of Rasmussen syndrome?

OBJECTIVE: To describe a more limited and less malignant form of Rasmussen encephalitis (RE). METHODS: Three subjects (all women; 37, 31, and 32 years of age) developed childhood or late onset chronic focal encephalitis, with a relatively nonprogressive form of the disorder. RESULTS: In our patients, clinical features were dominated by partial seizures without marked focal motor deficit and in two with choreo-dystonic movements. The diagnosis of RE was supported by histologic examination and anatomic and functional MRI. CONCLUSIONS: These cases extend the phenotypic presentations of Rasmussen encephalitis and confirm Theodore Rasmussen's suggestion that there may be mild and nonprogressive forms of the disease.

MRI evidence of mesial temporal sclerosis in sporadic "benign" temporal lobe epilepsy.

OBJECTIVE: To determine whether there is MRI-detectable mesial temporal sclerosis (MTS) in patients with sporadic benign temporal lobe epilepsy (BTLE). METHODS: Brain MRIs were obtained from 101 consecutive, unrelated patients (51 women; mean age 37.3 +/- 17.5 years; range 10 to 83 years) with BTLE, who reported rarely or never having had seizures at the time of long-term (> 2 years) follow-up. The mean age at seizure onset was 22.3 +/- 17.4 years; the mean duration of epilepsy was 16.4 +/- 14.1 years. MRI diagnosis of MTS was based on the occurrence of hippocampal formation atrophy on T1 slices, an increased mesial temporal signal intensity alteration on fluid-attenuated inversion-recovery (FLAIR) or T2 images, or both. RESULTS: Thirty-nine of 101 patients (38.6%) had MRI evidence of unilateral MTS (19/39 left MTS, 20/39 right MTS), which correlated with the epileptiform activity. Hyperintense FLAIR and T2 signal with or without atrophy was observed in 24 of 39 individuals. There was no difference between patients with or without MRI-detected MTS in age at onset and duration of epilepsy. Family history of epilepsy or febrile convulsions (FCs) was more frequent in patients with MRI-detected MTS (36%) as compared with patients with normal MRI (22.7%), but the difference was not significant. Antecedent FCs were more frequent (p = 0.03) in patients with MRI-detected MTS (9/39; 23%) vs those with normal MRI (5/62; 8%). CONCLUSIONS: MRI-detected mesial temporal sclerosis is often encountered in patients with sporadic benign temporal lobe epilepsy.