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.

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.

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.

Idiopathic familial trigeminal neuralgia: a case report.

Trigeminal neuralgia (TN) is paroxysmal, lancinant pain often described as an "electric wave" by patients, with involvement of the divisions of the fifth cranial nerve. Demyelinating, compressive, ischaemic diseases are involved in the physiopathology of TN, but there are some cases without explanation. Familial TN (FTN) is a rare condition, about 1%-2% of all TN cases, while sporadic cases are the most common. To date, there have been about 126 reports of FTN. We describe the case of a 66-year-old man who had been complaining for 3 years of right-side paroxysmal lancinating pain in the second division of the fifth cranial nerve. A brain MRI with angiographic sequences did not show neurovascular conflicts or other pathological conditions. The patient had a family history of TN, which had been diagnosed in 3 other family members (father, sister and first cousin), who had undergone medical or surgical treatment for TN. There was no family history of hypertension, metabolic disorders, neurological or traumatic diseases. Animal studies have shown a probable involvement of genes codifying for calcium channels as the starting alterations in trigeminal excitability. Our FTN could be a good model to investigate the role of gene mutations in this condition.

PRES: posterior or potentially reversible encephalopathy syndrome?

Posterior reversible encephalopathy syndrome (PRES) is an acronym that identifies a new clinico-neuroradiologic entity occurring in association with different conditions. We report a patient with eclamptic encephalopathy whose clinico-radiological picture normalised after prompt treatment. We suggest defining this condition as potentially RES, to emphasise that reversibility is not spontaneous but is usually related to an adequate treatment, and that the posterior localisation of the lesions, even if constant, may not represent the most relevant finding in some patients.

Cerebral vasculitis in a patient with HCV-related type II mixed cryoglobulinemia.

The peripheral nervous system is often involved in patients with mixed cryoglobulinemia (MC), while there are few reports of central nervous system involvement. We describe a case of HCV-related type II MC with peripheral and central nervous system involvement. A 61-year-old woman, suffering from flaccid tetraparesis, was referred to our department because of an increasing disability. The presence of delirium prompted us to also investigate the central nervous system. MMSE, EEG, EMG, brain CT-scan, color-Doppler of neck vessels, retinal fluorangiography and brain MRI were performed. These investigations suggested a cerebral vasculitis. The finding of very low C4 serum levels, together with high rheumatoid factor serum levels, suggested the search for cryoglobulins. The laboratory findings showed a HCV-related type II (IgMk) MC. A marked improvement of symptoms and of laboratory data was obtained by treatment with methylprednisolone + cyclophosphamide.