Surgical and radiosurgical treatment of hypothalamic hamartoma: The Italian experience between 2011 and 2021.

OBJECTIVE: To investigate the Italian experience on the surgical and radiosurgical treatment of drug-resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011-2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. METHODS: We collected pseudo-anonymized patient's data with at least 12 months of follow-up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post-operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann-Whitney or Chi-squared test were used to assess the presence of an association between variables (p < 0.05). RESULTS: Full presurgical and postoperative data about 42 patients from 6 epilepsy surgery centers were gathered. Engel class I was reached in the 65.8% and 66.6% of patients with gelastic and non-gelastic seizures, respectively. Other than daily non-gelastic seizures were associated with seizure freedom (p = 0.01), and the radiological type presented a trend toward significance (p = 0.12). SIGNIFICANCE: Endoscopic disconnection and laser interstitial thermal therapy are effective in the treatment of HH-related epilepsy, with a tolerable safety profile. Both gelastic and non-gelastic seizures can be treated, also in patients with a long history of seizures. PLAIN LANGUAGE SUMMARY: This study collected data about 42 patients with HH-related epilepsies. Endoscopic disconnection and laser therapy are both effective and safe in the treatment of hypothalamic hamartoma-related epilepsies.

Visual integration across fixation: automatic processes are split but conscious processes remain unified in the split-brain.

The classic view holds that when "split-brain" patients are presented with an object in the right visual field, they will correctly identify it verbally and with the right hand. However, when the object is presented in the left visual field, the patient verbally states that he saw nothing but nevertheless identifies it accurately with the left hand. This interaction suggests that perception, recognition and responding are separated in the two isolated hemispheres. However, there is now accumulating evidence that this interaction is not absolute; for instance, split-brain patients are able to detect and localise stimuli anywhere in the visual field verbally and with either hand. In this study we set out to explore this cross-hemifield interaction in more detail with the split-brain patient DDC and carried out two experiments. The aim of these experiments is to unveil the unity of deliberate and automatic processing in the context of visual integration across hemispheres. Experiment 1 suggests that automatic processing is split in this context. In contrast, when the patient is forced to adopt a conscious, deliberate, approach, processing seemed to be unified across visual fields (and thus across hemispheres). First, we looked at the confidence that DDC has in his responses. The experiment involved a simultaneous "same" versus "different" matching task with two shapes presented either within one hemifield or across fixation. The results showed that we replicated the observation that split brain patients cannot match across fixation, but more interesting, that DDC was very confident in the across-fixation condition while performing at chance-level. On the basis of this result, we hypothesised a two-route explanation. In healthy subjects, the visual information from the two hemifields is integrated in an automatic, unconscious fashion via the intact splenium, and this route has been severed in DDC. However, we know from previous experiments that some transfer of information remains possible. We proposed that this second route (perhaps less visual; more symbolic) may become apparent when he is forced to use a deliberate, consciously controlled approach. In an experiment where he is informed, by a second stimulus presented in one hemifield, what to do with the first stimulus that was presented in the same or the opposite hemifield, we showed that there was indeed interhemispheric transfer of information. We suggest that this two-route model may help in clarifying some of the controversial issues in split-brain research.

Fear-specific enhancement of tactile perception is disrupted after amygdala lesion.

Tactile perception on one's own face is enhanced when viewing a fearful face being touched - as opposed to just approached - by fingers, compared to viewing other expressions, a phenomenon known as the emotional modulation of Visual Remapping of Touch (eVRT). This effect seems to be related to a preferential activation of the somatosensory system in response to threat. To test the contribution of the amygdala to this mechanism, a group of patients with unilateral lesions to the amygdala, a control group of patients with lesions in the extra-temporal regions, and a group of healthy participants completed an eVRT paradigm. They were required to detect bilateral tactile stimulation on their own cheeks, while viewing fearful, happy, or neutral faces being touched or just approached by fingers. Healthy participants and control patients confirmed that viewing a neutral face being touched - as opposed to just approached - by fingers increases tactile detection on one's own face (i.e., the typical VRT effect) and that this effect is enhanced for fearful faces, compared to neutral and happy faces. However, in patients with amygdala lesion, although the standard VRT effect was preserved for neutral faces, this was disrupted for fearful faces. This result indicates that the preferential activation of the somatosensory cortices in response to threat relies on structural integrity of the amygdala.

Microsurgical endoscopy-assisted anterior corpus callosotomy for drug-resistant epilepsy in an adult unresponsive to vagus nerve stimulation.

Because most of the corpus callosotomy (CC) series available in literature were published before the advent of vagus nerve stimulation (VNS), the efficacy of CC in patients with inadequate response to VNS remains unclear, especially in adult patients. We present the case of a 21-year-old female with medically refractory drop attacks that began at the age of 8 years, which resulted in the patient being progressively unresponsive to vagus nerve stimulation implanted at the age of 14 years. Corpus callosotomy was recommended to reduce the number of drop attacks. However, the patient had only mild cognitive impairments and no neurological deficits. For this reason, we were forced to plan a surgical approach able to maximize the disconnection for good seizure control while, at the same time, minimizing sequelae from disconnection syndromes and neurosurgical complications because in such cases of long-lasting epilepsy the gyri cinguli and the arteries can be tenaciously adherent and dislocated with all the normal anatomy altered. In this scenario, we opted for a microsurgical endoscopy-assisted anterior two-thirds corpus callosotomy. The endoscopic minimally invasive approach proved to be quite adequate in this technically demanding case and confirmed that CC may offer advantages, with good results, even in adult patients with drop attacks who have had inadequate response to VNS.

Vagus nerve stimulation during pregnancy: an instructive case.

BACKGROUND: Little is known about the safety of vagus nerve stimulation during pregnancy. CASE REPORT: Herein we report the case of a young woman affected by childhood-onset partial epilepsy, obesity, and depression in which a malfunctioning of VNS was detected during pregnancy. Although device functioning was not optimal during the critical period of organogenesis, no morphological abnormalities of the fetus were detected. CONCLUSION: A confirmation of VNS safety may increase its use during pregnancy, thus reducing possible systemic effects of antiepileptic drugs and antidepressants on the women and the baby.

A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: is there a common core deficit?

We report a three-generation, clinically heterogeneous family in which we identify a novel inherited splicing mutation of the SCN1A gene. Thirteen subjects were submitted to genetic analysis, clinical and instrumental examination, and neuropsychological assessment. In eight subjects, a heterozygous c.2946+5G>A donor splice site alteration in the SCN1A gene was found. Half of them had never had a seizure and showed normal EEG and cognitive profile, whereas the other half had a history of seizures and variable neuropsychological impairments ranging from moderate cognitive disabilities to mild visual-motor impairments. Different clinical phenotypes were identified, including generalized epilepsy with febrile seizure plus (GEFS+), Dravet syndrome, and partial epilepsy with febrile seizure plus (PEFS+). Remarkable clinical heterogeneity can be found among family members carrying the same SCN1A gene mutation. Variable involvement of visual-motor abilities might represent a neuropsychological feature which needs to be further explored in other familial cases.

Long-term seizure and behavioral outcomes after corpus callosotomy.

Outcomes of corpus callosotomy (CC) have been mainly focused on seizures. The present study aimed to evaluate the long-term effects of CC on adaptive behaviors and caregivers' satisfaction in addition to seizures and to identify clinical predictors of postsurgical outcomes. Medical records of 26 patients (mean age at study time: 40 years, mean follow-up: 14 years) with childhood-onset epilepsy who underwent anterior or 2-stage complete CC were reviewed. A structured questionnaire was submitted to caregivers asking about relative changes in different seizure types, behavioral functions, and satisfaction with the postoperative outcomes. Formal neuropsychological assessment was carried out in a subgroup of patients. Selected clinical variables including age at surgery, extent of callosal section, length of follow-up, epilepsy syndrome, and presurgical cognitive level were submitted to multiple regression analysis. At the last follow-up visit, a reduction greater than 50% was observed mainly for drop attacks (65% of patients), followed by generalized tonic-clonic seizures (53%), and complex partial seizures (50%). No presurgical variables were significantly associated with seizure outcome. After surgery, more than half of patients showed attention enhancement, which was related to drop seizure improvement. Early age at surgery was associated with better behavioral regulation; complete CC slightly worsened language abilities. Satisfaction with surgery outcomes was expressed by 73% of caregivers and was dependent on drop seizure reduction and improvements in activities of daily living. A long-term positive psychosocial outcome is likely after CC also in severely disabled patients, especially if surgery is performed early.

Vaccination and occurrence of seizures in SCN1A mutation-positive patients: a multicenter Italian study.

BACKGROUND: The relation between epileptic seizures and vaccinations is sometimes debated. In the present work, the impact of vaccination on seizure onset and clinical outcome of SCN1A mutation-positive patients is addressed. METHODS: Seventy-two patients diagnosed with Dravet syndrome or generalized epilepsy with febrile seizure plus, carrying SCN1A mutations or not, were included. Details on vaccination type, temporal relationship between vaccination and seizure occurrence, seizure type at onset and during development, cognitive functioning, and vaccination completion was obtained by reviewing clinical records. Patients were divided into two groups based on the temporal window between vaccination and seizure onset (proximate group: <48 hours; distant group: >48 hours). RESULTS: Vaccination-related seizures occurred in 25% of patients with SCN1A mutation and 18% of patients without the mutation (no significant difference). The proximate group showed an earlier age at seizure onset and a higher frequency of status epilepticus during development than did the distant group. No other significant differences were found. Subsequent vaccinations did not significantly alter the evolution of the disease. CONCLUSIONS: Results from this relatively small series provide evidence that vaccinations do not significantly affect clinical and cognitive evolution of Dravet syndrome and generalized epilepsy with febrile seizure plus patients even if they carry SCN1A mutations.

Early clinical features in Dravet syndrome patients with and without SCN1A mutations.

BACKGROUND: SCN1A is the most clinically relevant epilepsy gene, most mutations causing Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI). We evaluated clinical differences, if any, between young patients with and without a SCN1A mutations and a definite clinical diagnosis of Dravet syndrome. METHODS: Twenty-five patients with a diagnosis of Dravet Syndrome (7 males, 18 females; mean age at inclusion: 10.3; median: 9±7; range: 18 months-30 years) were retrospectively studied. A clinical and genetic study focusing on SCN1A was performed, using DHPLC, gene sequencing and MLPA to detect genomic deletions/duplications. A formal cognitive and behavioral assessment was available for all patients. RESULTS: Analysis revealed SCN1A mutations comprising missense, truncating mutations and genomic deletions/duplications in eighteen patients and no mutation in seven. The phenotype of mutation positive patients was characterized by a higher number of seizures/month in the first year of life, an earlier seizure onset and a higher frequency of episodes of status epilepticus. The cognitive and behavioral profile was slightly worst in mutation positive patients. CONCLUSIONS: These findings confirm that SCN1A gene mutations are strongly associated to a more severe phenotype in patients with Dravet syndrome.

New association between ring chromosome 20 syndrome and hypomelanosis of Ito.

Hypomelanosis of Ito is an uncommon neuroectodermal disease associated with a wide range of cytogenetic abnormalities. Ring chromosome 20 is a rare chromosomal disorder characterized by severe, refractory epilepsy, cognitive delay, and unspecific dysmorphic traits. An association between the hypomelanosis of Ito and ring chromosome 20 syndrome was never reported peviously. We describe a young girl who has ring chromosome 20 and who also has clinical symptoms of hypomelanosis of Ito. After her diagnosis of epilepsy, she was submitted to neurologic and genetic testing, a skin biopsy, and repeated neuropsychologic examinations. Karyotyping revealed a 46 XX, r(20) with mosaicism in 34% of peripheral blood lymphocytes and 8% of skin fibroblasts. A severe, progressive cognitive deterioration was evident. The epilepsy was refractory to antiepileptic drugs, in apparent contrast with the evidence that both telomeric regions were preserved. The percentage of mosaicism seems unrelated to the severity of the clinical phenotype.

Clinical course of young patients with Dravet syndrome after vagal nerve stimulation.

Medical treatment of Dravet syndrome is disappointing. Ketogenic Diet and neurostimulation procedures as Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation are in ongoing evaluation. In the present study, the long-term effectiveness of VNS on seizures, cognition and behavior was retrospectively evaluated in eight young patients with DS and medically refractory epilepsy (mean age at VNS implant: 10.28 years, range: 5-25). The average duration of treatment was 54 months (range: 12-120). Compared to baseline (mean: 55; standard deviation: 83, range: 4-200), the mean number of monthly seizures after VNS implantation was 39 ± 67 at 3 months, 42 ± 67 at 6 months and 38 ± 69 at twelve months (not significant comparisons). In particular, VNS produced a mean seizure rate reduction of 12% at three months, 6% at six months, and 31% at twelve months. All patients but three experienced some reduction in seizure burden (range: 33-61%) at twelve months. Seizure outcome after one year of stimulation was rated as Mc Hugh class II (50-79% reduction in seizure frequency) in four patients, class III (<50% reduction) in one patient and class V (no improvement) in three patients. In this small case series of patients with DS, VNS therapy had a clinically significant effect in reducing seizures at twelve months in four of the eight patients. Even in patients in whom seizure reduction was not dramatic, a slight improvement in alertness and communicative skills was seen. The long-term clinical course of two selected cases is discussed.

Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis.

The goal of the study was to assess the long-term seizure and neuropsychologic outcomes of patients with tuberous sclerosis and refractory epilepsy who received vagus nerve stimulator implantation. Eleven patients with a follow-up period of at least 12 months were studied retrospectively. The mean age at the time of implantation was 14 years (range, 2-35). Seizure outcome was rated as class I (>80% seizure frequency reduction) in 1 (9%), class II (50-79% reduction) in 7 (63%), and class III (<50% reduction) in 3 (27%). No patient experienced permanent adverse effects after the procedure. A significant increase of adaptive behaviors and quality of life was observed. Patients who had implantation during childhood exhibited a greater improvement in cognitive and neuropsychologic functioning. Vagus nerve stimulation can be considered an effective and safe therapeutic option in patients with tuberous sclerosis and refractory epilepsy who are not candidates for epilepsy surgery.

Visual recalibration of auditory spatial perception: two separate neural circuits for perceptual learning.

A remarkable example of rapid perceptual learning is the visual recalibration of auditory spatial perception, which can result in either a bias (ventriloquism after-effect) or an improvement (multisensory enhancement) in auditory localization. Here, we examine the possibility that these after-effects might depend on two distinct neural pathways (geniculostriate vs. collicular-extrastriate). To this end, patients with a lesion of the striate cortex (hemianopic patients) or temporoparietal cortex (neglect patients) were asked to localize weak sounds, before and after a brief exposure to repetitive auditory-visual stimulation which was given either in the normal or in the affected field. Adaptation comprised spatially disparate (Experiment 1) or spatially coincident (Experiment 2) auditory-visual stimuli. After exposure to spatially disparate stimuli in the normal field, all patients exhibited the usual shifts toward the visual attractor, at each sound location. In contrast, when the same kind of adaptation was given in the affected field, a consistent shift was still evident in neglect patients but not in patients with hemianopia. After adaptation to spatially coincident stimuli, and regardless of the adaptation hemifield, all patients exhibited a significant improvement in auditory localization, which was largest for sounds presented at the adapted location. The findings suggest the presence of two distinct recalibration mechanisms. Adapting to spatially conflicting stimuli invokes a corrective mechanism implemented within the geniculostriate circuit, which tries to reduce the registered discrepancy. Adapting to spatially aligned inputs invokes a mechanism implemented along a collicular-extrastriate circuit, which tries to reduce the localization error.

Audio-visual stimulation improves oculomotor patterns in patients with hemianopia.

Patients with visual field disorders often exhibit impairments in visual exploration and a typical defective oculomotor scanning behaviour. Recent evidence [Bolognini, N., Rasi, F., Coccia, M., & Làdavas, E. (2005b). Visual search improvement in hemianopic patients after audio-visual stimulation. Brain, 128, 2830-2842] suggests that systematic audio-visual stimulation of the blind hemifield can improve accuracy and search times in visual exploration, probably due to the stimulation of Superior Colliculus (SC), an important multisensory structure involved in both the initiation and execution of saccades. The aim of the present study is to verify this hypothesis by studying the effects of multisensory training on oculomotor scanning behaviour. Oculomotor responses during a visual search task and a reading task were studied before and after visual (control) or audio-visual (experimental) training, in a group of 12 patients with chronic visual field defects and 12 controls subjects. Eye movements were recorded using an infra-red technique which measured a range of spatial and temporal variables. Prior to treatment, patients' performance was significantly different from that of controls in relation to fixations and saccade parameters; after Audio-Visual Training, all patients reported an improvement in ocular exploration characterized by fewer fixations and refixations, quicker and larger saccades, and reduced scanpath length. Overall, these improvements led to a reduction of total exploration time. Similarly, reading parameters were significantly affected by the training, with respect to specific impairments observed in both left- and right-hemianopia readers. Our findings provide evidence that Audio-Visual Training, by stimulating the SC, may induce a more organized pattern of visual exploration due to an implementation of efficient oculomotor strategies. Interestingly, the improvement was found to be stable at a 1 year follow-up control session, indicating a long-term persistence of treatment effects on the oculomotor system.

Cross-modal localization in hemianopia: new insights on multisensory integration.

The superior colliculus (SC) has been implicated in the mediation of residual visual function in hemianopic patients, and has been shown to be capable of using multiple sensory cues to facilitate its localization functions. The aim of the present study was to examine the possibility that the SC could effect covert visual processes, via multisensory integration of auditory and visual stimuli in patients with visual field loss. To this aim hard-to-localize auditory targets were presented alone (unimodal condition) or with a visual stimulus (cross-modal condition) in either hemifield and at various spatial (0 degree, 16 degrees, 32 degrees) and temporal (0 ms, 500 ms) disparities. The results showed substantial field-specific differences. As expected, a visual stimulus in the intact hemifield induced a strong visual bias in auditory localization independent of the spatial disparities, and did so even when the two stimuli were temporally offset. In these spatially disparate conditions, the localization accuracy was markedly reduced. In the blind hemifield, however, the visual stimulus affected auditory localization only when it was coincident with that target in both space and time. In this circumstance auditory localization performance was markedly enhanced. This result strongly suggests that covert visual processes remain active in hemianopia, though they differ from those in the normal hemifield. A likely explanation of these differences is that enhancement and visual bias depend on different neural pathways: with the former dependent on circuits involving the superior colliculus, a structure involved in the integration of cues from multiple senses to facilitate orientation/localization; and the latter dependent on geniculo-striate circuits that facilitate more detailed analyses of the visual scene. Overall the present results not only enhance our understanding of the impact of covert visual processes in hemianopic patients, but also enhance our knowledge of how different brain regions areas contribute to processing cross-modal information.

Multisensory-mediated auditory localization.

Multisensory integration is a powerful mechanism for maximizing sensitivity to sensory events. We examined its effects on auditory localization in healthy human subjects. The specific objective was to test whether the relative intensity and location of a seemingly irrelevant visual stimulus would influence auditory localization in accordance with the inverse effectiveness and spatial rules of multisensory integration that have been developed from neurophysiological studies with animals [Stein and Meredith, 1993 The Merging of the Senses (Cambridge, MA: MIT Press)]. Subjects were asked to localize a sound in one condition in which a neutral visual stimulus was either above threshold (supra-threshold) or at threshold. In both cases the spatial disparity of the visual and auditory stimuli was systematically varied. The results reveal that stimulus salience is a critical factor in determining the effect of a neutral visual cue on auditory localization. Visual bias and, hence, perceptual translocation of the auditory stimulus appeared when the visual stimulus was supra-threshold, regardless of its location. However, this was not the case when the visual stimulus was at threshold. In this case, the influence of the visual cue was apparent only when the two cues were spatially coincident and resulted in an enhancement of stimulus localization. These data suggest that the brain uses multiple strategies to integrate multisensory information.