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Biomedical subjects

Giuliano Avanzini

Publications and source records attributed to Giuliano Avanzini.

At least 19 recordsLinked to original sources
PubMed2006

A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression.

Unverricht-Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo, CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.

Animals↗
PubMed2006

Effects in neocortical neurons of mutations of the Na(v)1.2 Na+ channel causing benign familial neonatal-infantile seizures.

Mutations of voltage-gated Na+ channels are the most common cause of familial epilepsy. Benign familial neonatal-infantile seizures (BFNIS) is an epileptic trait of the early infancy, and it is the only well characterized epileptic syndrome caused exclusively by mutations of Na(V)1.2 Na+ channels, but no functional studies of BFNIS mutations have been done. The comparative study of the functional effects and the elucidation of the pathogenic mechanisms of epileptogenic mutations is essential for designing targeted and effective therapies. However, the functional properties of Na+ channels and the effects of their mutations are very sensitive to the cell background and thus to the expression system used. We investigated the functional effects of four of the six BFNIS mutations identified (L1330F, L1563V, R223Q, and R1319Q) using as expression system transfected pyramidal and bipolar neocortical neurons in short primary cultures, which have small endogenous Na+ current and thus permit the selective study of transfected channels. The mutation L1330F caused a positive shift of the inactivation curve, and the mutation L1563V caused a negative shift of the activation curve, effects that are consistent with neuronal hyperexcitability. The mutations R223Q and R1319Q mainly caused positive shifts of both activation and inactivation curves, effects that cannot be directly associated with a specific modification of excitability. Using physiological stimuli in voltage-clamp experiments, we showed that these mutations increase both subthreshold and action Na+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.

Action Potentials↗
PubMed2006

Vagal nerve stimulation: relationship between outcome and electroclinical seizure pattern.

In recent years, vagal nerve stimulation (VNS) has been proposed as a possible way to improve the control of refractory (partial and generalized) seizures. To date, however, there is no complete understanding of the underlying mechanism for this action nor are there any available guidelines or criteria for the selection of those candidates that might be most suitable for this kind of neuromodulating surgery. This report presents evidence that should be helpful in defining the clinical criteria for using VNS for the treatment of refractory seizures. We report on 17 patients with severe partial refractory epilepsy and polymorphous seizures, who have been operated on previously or who were excluded from epilepsy surgery and for whom, at least, one seizure type has been electrographically recorded. Sixteen of these patients also had falling seizures. Our objective was to identify responders and to correlate the outcome of their seizures with the EEGraphic onset of their seizure. Follow-up ranged from 4 to 9 years. The results of this study indicate a significant reduction of seizures in only four patients and better outcome in patients where the onset of seizure activity occurred in the temporal area. Patients with frontal or frontocentral seizures resulted in the poorest outcomes. In four patients with Lennox-Gastaut syndrome VNS produced no significant reduction of seizures, while falling seizures decreased significantly in three patients with retropulsive falls. These results of this small series of patients suggest that VNS might be more suitable in patients with temporal rather than frontal or central seizure onset. Further studies are required to support this hypothesis.

Adult↗
PubMed2006

Sensorimotor organization in double cortex syndrome.

Subcortical band heterotopia is a diffuse malformation of cortical development related to pharmacologically intractable epilepsy. On magnetic resonance imaging (MRI), patients with "double cortex" syndrome (DCS) present with a band of heterotopic gray matter separated from the overlying cortex by a layer of white matter. The function and connectivity of the subcortical heterotopic band in humans is only partially understood. We studied six DCS patients with bilateral subcortical band heterotopias and six healthy controls using functional MRI (fMRI). In controls, simple motor task elicited contralateral activation of the primary motor cortex (M1) and ipsilateral activation of the cerebellum and left supplementary motor area (SMA). All DCS patients showed task-related contralateral activation of both M1 and the underlying heterotopic band. Ipsilateral motor activation was seen in 4/6 DCS patients. Furthermore, there were additional activations of nonprimary normotopic cortical areas. The sensory stimulus resulted in activation of the contralateral primary sensory cortex (SI) and the thalamus in all healthy subjects. The left sensory task also induced a contralateral activation of the insular cortex. Sensory activation of the contralateral SI was seen in all DCS patients and secondary somatosensory areas in 5/6. The heterotopic band beneath SI became activated in 3/6 DCS patients. Activations were also seen in subcortical structures for both paradigms. In DCS, motor and sensory tasks induce an activation of the subcortical heterotopic band. The recruitment of bilateral primary areas and higher-order association normotopic cortices indicates the need for a widespread network to perform simple tasks.

Adolescent↗
PubMed2006

Rhythmic cortical myoclonus in Niemann-Pick disease type C.

We here describe a patient with late-infantile Niemann-Pick disease type C (NPC) presenting with worsening myoclonus, seizures, cerebellar symptoms, mild mental impairment, and gaze palsy. Electroencephalographic (EEG) -polymyographic examinations showed abnormally high and diffuse background alpha-activity, enhanced by intermittent photic stimulation. The electromyographic (EMG) showed quasirhythmic myoclonic jerks during motor activation. EEG-EMG frequency analysis (better than jerk-locked back-averaging) demonstrated the cortical origin of the myoclonus. Our observations indicate that cortical myoclonus may occur as the main symptom of NPC.

Adolescent↗
PubMed2006

Suppressive efficacy by a commercially available blue lens on PPR in 610 photosensitive epilepsy patients.

PURPOSE: Photosensitivity can represent a serious problem in epilepsy patients, also because pharmacologic treatment is often ineffective. Nonpharmacologic treatment using blue sunglasses is effective and safe in controlling photosensitivity, but large series of patients have never been studied. METHODS: This multicenter study was conducted in 12 epilepsy centers in northern, central, southern, and insular Italy. A commercially available lens, named Z1, obtained in a previous trial, was used to test consecutively enrolled pediatric and adult epilepsy patients with photosensitivity. Only type 4 photosensitivity (photoparoxysmal response, PPR) was considered in the study. A standardized method was used for photostimulation. RESULTS: Six hundred ten epilepsy patients were tested. Four hundred (66%) were female patients; 396 (65%) were younger than 14 years. Three hundred eighty-one (62%) subjects were pharmacologically treated at the time of investigation. Z1 lenses made PPR disappear in 463 (75.9%) patients, and PPR was considerably reduced in an additional 109 (17.9%) of them. PPR remained unchanged only in the remaining 38 (6.2%) patients. The response of PPR to Z1 lenses was not significantly influenced by the patients' age, sex, or type of epilepsy. No difference was found between pharmacologically treated and untreated patients. CONCLUSIONS: The Z1 lens is highly effective in controlling PPR in a very large number of photosensitive epilepsy patients irrespective of their epilepsy or antiepileptic drug treatment. The lens might become a valid resource in the daily activity of any clinician who cares for patients with epilepsy.

Adolescent↗
PubMed2006

Clinical and genetic findings in 26 Italian patients with Lafora disease.

PURPOSE: EPM2B mutations have been found in a variable proportion of patients with Lafora disease (LD). Genotype-phenotype correlations suggested that EPM2B patients show a slower course of the disease, with delayed age at death, compared with EPM2A patients. We herein report clinical and genetic findings of 26 Italian LD patients. METHODS: Disease progression was evaluated by means of a disability scale based on residual motor and cognitive functions and daily living and social abilities, at 4 years from the onset. Mutational analysis was performed by sequencing the coding regions of the EPM2A and EPM2B genes. RESULTS: Age at onset ranged from 8.5 to 18.5 years (mean, 13.7+/-2.6). The mean duration of follow-up was 7.1+/-3.9 years. Daily living activities and social interactions were preserved in five of 24 patients. The remaining patients showed moderate to extremely severe limitations of daily living and social abilities. Sixteen (72%) of 22 families showed mutations in the EPM2B gene, and five (22%), in the EPM2A gene. One family showed no mutations. A novel EPM2B mutation also was identified. CONCLUSIONS: In our series, EPM2B mutations occurred in 72% of families, thus indicating that EPM2B is the major gene for LD in the Italian population. Moreover, we found that six of 17 EPM2B patients preserved daily living activities and social interactions at 4 years from onset, suggesting a slow disease progression. Additional clinical and functional studies will clarify whether specific mutations may influence the course of the disease in LD patients.

Activities of Daily Living↗
PubMed2005

Semantic memory in partial epilepsy: verbal and non-verbal deficits and neuroanatomical relationships.

Semantic memory was evaluated in 124 epilepsy patients, including 84 with left (n=44) or right temporal lobe epilepsy (TLE) (n=40) and 40 with left (n=25) or right frontal lobe epilepsy (FLE) (n=15), in order to determine their verbal and visual deficits, and the neuroanatomical relationships between them. The controls were 35 healthy subjects. Semantic memory was assessed by means of Picture Naming, Picture Pointing, the verbal Pyramid and Palm Trees Test (PPTT), the visual PPTT, Object Decision Hard, and Drawing From Memory. Episodic memory was assessed by means of the Short Story, Rey's Complex Figure, the Verbal and Visual Selective Reminding Procedure and Brown-Peterson Procedure. Factor analysis of the epilepsy patients distinguished their semantic memory scores from other neuropsychological domains. The semantic memory factor was significantly related to the side of the epileptic region, with lower scores in the left hemisphere and left TLE patients. In comparison with the controls, the left TLE patients were significantly impaired on Picture Naming, Picture Pointing, and Object Decision Hard. Subsequent analyses showed that, in comparison with the controls and the right TLE patients, the left TLE patients with lateral temporal lobe lesions were impaired in Picture Naming whereas, in comparison with the controls, the left TLE patients with mesial temporal lobe lesions were impaired in Object Decision Hard. On the contrary, the episodic memory factor was not related to the side of the epileptic region, and a few material-specific tests revealed opposite impairments in the left and right hemisphere patients. These results show that left TLE may cause semantic memory deficits involving verbal and visual information. Unlike the material-specific pattern of episodic memory, this pattern of impairment is in line with the view of an amodal semantic store in which all of the information about a thing overlaps. The semantic memory impairment may reflect damage in the lateral and mesial temporal lobe regions that impair neocortical functions in storing and retrieving information or hippocampal functions in processing meaningful stimuli.

Adult↗
PubMed2004

Molecular biology of channelopathies: impact on diagnosis and treatment.

Channelopathies are genetically determined ion channel alterations that lead to acute and transient symptoms in subjects who otherwise appear to be normal. This article reviews the recent progression of biomolecular studies that have clarified the mechanisms by which gene mutations may result in alterations of excitable tissues responsible for episodic neurological, neuromuscular and cardiac disorders, defined as channelopathies. The development of technologies capable of testing pharmacological agents in vitro on mutated channels expressed in cell lines makes it possible to define a more rational use of the available drugs acting on ion channels, and to design new molecules specifically targeted to known channel dysfunctions and new ones that could be identified by future genetic studies.

Central Nervous System Diseases↗
PubMed2003

Mutations in NHLRC1 cause progressive myoclonus epilepsy.

Lafora progressive myoclonus epilepsy is characterized by pathognomonic endoplasmic reticulum (ER)-associated polyglucosan accumulations. We previously discovered that mutations in EPM2A cause Lafora disease. Here, we identify a second gene associated with this disease, NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy.

Base Sequence↗
PubMed2003

Rhythmic cortical myoclonus in a case of HIV-related encephalopathy.

We describe a 66-year-old, HIV-seropositive patient presenting with ataxia and upper limb rhythmic myoclonus activated by postural maintenance. Electromyograph (EMG) recordings of the forearm muscles showed 50-msec bursts, with a frequency of 10 Hz, concurring with frontocentral electroencephalograph (EEG) rhythmic activity. Autoregressive spectral analysis applied to the EEG-EMG traces made it possible to detect significant coherence between the rhythmic EEG discharges and EMG bursts. The amplitude of the middle-latency somatosensory evoked potentials was increased. Long-latency reflexes were enhanced. On the basis of the electrophysiological findings, the movement disorder should be considered a rhythmic variant of cortical myoclonus. In our patient, HIV infection may have caused a dysfunction in the central nervous system pathways involving the cerebellum and sensorimotor cortex, similar to that occurring in genetically determined conditions characterised by cortical myoclonus.

AIDS Dementia Complex↗
PubMed2003

Epileptic and imaging findings in perinatal hypoxic-ischemic encephalopathy with ulegyria.

Hypoxic-ischemic encephalopathy due to fetal or neonatal asphyxia is a major cause of acute mortality and chronic disability involving cerebral palsy, seizures, and mental retardation. The gestational age of the infant is one of the main variables determining the neuropathological picture of hypoxic-ischemic brain injury, and ulegyria (one of its neuropathological correlates) typically affects full-term infants. The damage usually involves the deeper sulcal portion of the convolutions while sparing the crowns, and includes subcortical white matter atrophy and gliosis. The aim of this study was to characterize the electroclinical features of hypoxic-ischemic encephalopathy when ulegyria is one of its main neuropathological features. To this end, nine patients with MRI-proven ulegyria and epilepsy underwent a complete neurological work-up. The ulegyric lesions were mainly distributed in the parasagittal watershed areas and frequently associated with other hypoxic-ischemic lesions. The neurological picture was characterized in most patients by mental retardation, motor deficits, and drug-refractory partial epilepsy. The ulegyria in our patients was associated with a complex clinical picture: epilepsy was a prominent component, and its severity directly correlated with the extent of the ulegyria and the associated hypoxic-ischemic lesions. Drug refractoriness was an almost constant correlate of this form of symptomatic epilepsy.

Adolescent↗
PubMed2003

Cellular biology of epileptogenesis.

The ionic currents that underlie the mechanisms of epileptogenesis have been systematically characterised in different experimental preparations. The recent elucidation of the molecular structures of most membrane channels and receptors has enabled structure-function analyses in both physiological and pathophysiological conditions. The neurophysiological and biomolecular features of epileptogenic mechanisms that putatively account for human epilepsies are summarised in this review. Particular emphasis is given to epilepsies that are associated with genetically determined alterations of ligand-gated and voltage-gated ion channels. Changes in ionic currents that flow through sodium, potassium, and calcium channels can lead to different types of epilepsies. Inherited or acquired changes that alter the function of receptors for acetylcholine, glutamate, and gamma-aminobutryic acid are also involved. better understanding of the role of these epileptogenic mechanisms will promote new advances in the development of selective and targeted antiepileptic drugs.

Cell Membrane↗
PubMed2003

Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families.

PURPOSE: [corrected] To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE). METHODS: A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations. RESULTS: The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures. CONCLUSIONS: Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.

Adolescent↗
PubMed2003

Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons.

The ionic mechanisms underlying the termination of action-potential (AP) bursts and postburst afterhyperpolarization (AHP) in intrinsically bursting (IB) neocortical neurons were investigated by performing intracellular recordings in thin slices of rat sensorimotor cortex. The blockade of Ca(2+)-activated K(+) currents enhanced postburst depolarizing afterpotentials, but had inconsistent and minor effects on the amplitude and duration of AHPs. On the contrary, experimental conditions resulting in reduction of voltage-dependent Na(+) entry into the cells caused a significant decrease of AHP amplitude. Slice perfusion with a modified artificial cerebrospinal fluid in which LiCl (40 mM) partially replaced NaCl had negligible effects on the properties of individual APs, whereas it consistently increased burst length and led to an approximately 30% reduction in the amplitude of AHPs following individual bursts or short trains of stimulus-induced APs. Experiments performed by partially replacing Na(+) ions with choline revealed a comparable reduction in AHP amplitude associated with an inhibition of bursting activity. Moreover, in voltage-clamp experiments carried out in both in situ and acutely isolated neurons, partial substitution of extracellular NaCl with LiCl significantly and reversibly reduced the amplitude of K(+) currents evoked by depolarizing stimuli above-threshold for Na(+)-current activation. The above effect of Na(+)-to-Li(+) substitution was not seen when voltage-gated Na(+) currents were blocked with TTX, indicating the presence of a specific K(+)-current component activated by voltage-dependent Na(+) (but not Li(+)) influx. The above findings suggest that a Na(+)-activated K(+) current recruited by the Na(+) entry secondary to burst discharge significantly contributes to AHP generation and the maintenance of rhythmic burst recurrence during sustained depolarizations in neocortical IB neurons.

Action Potentials↗