Highly purified cannabidiol in the treatment of drug-resistant epilepsies: A real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center.

Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months. At the last follow-up (Tn), nine patients (50%) were considered CBD responders with at least a 50% decrease in seizure frequency. No serious adverse effects were found. No statistically significant differences were found concerning sleep, including daytime sleepiness, and no statistically significant effect was found on parental stress at Tn. An improvement was found for social interaction in quality of life (p < 0.05) for all patients. Our results demonstrate that CBD is a safe and effective antiseizure medication (ASM). CBD doesn't seem to affect sleep measures in adults and children or worsen daytime sleepiness. However, CBD improves specific QoL measures, which could indicate a possible use of CBD for other childhood disabilities. No impact of CBD was seen on parental stress, which could possibly be due to the limited follow-up or could mean that parental stress is not dependent on seizure frequency.

Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study.

Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.

Olfactory disorders in coronavirus disease 2019 patients: a systematic literature review.

OBJECTIVE: Recent scientific literature has widely described a possible major role of smell dysfunction as a specific symptom of coronavirus disease 2019. This systematic review may provide a more holistic approach to current knowledge of the disease. METHODS: A systematic review was completed using Embase, PubMed and Web of Science databases that considered original articles focused on olfactory evaluation in coronavirus disease 2019 patients, published between March and May 2020, in English language. RESULTS: From the 483 research papers initially identified, 32 original studies were selected, comprising a total of 17 306 subjects with a laboratory confirmed diagnosis of coronavirus disease 2019. Individual study sample sizes ranged from 6 to 6452 patients. This comprehensive analysis confirmed that olfactory disorders represent an important clinical feature in coronavirus disease 2019, with a prevalence of 11-100 per cent in included patients, although there was heterogeneity in terms of assessment tools and population selection criteria. CONCLUSION: The results indicate that an accurate clinical evaluation should be carried out using structured questionnaires and tests with olfactory substances.

Electro-clinical and neurodevelopmental outcome in six children with early diagnosis of tuberous sclerosis complex and role of the genetic background.

BACKGROUND: Seizures in individuals affected by tuberous sclerosis complex (TSC) commonly develop in the first year of life, are often preceded by a progressive deterioration of the electroencephalogram (EEG), and likely influence developmental outcome. Although early diagnosis of TSC has offered a tremendous opportunity to monitor affected patients before seizure onset, reports of the neurological manifestations of TSC in infants before seizure onset are still scarce. Here we describe early EEG activity, clinical and genetic data and developmental assessment in a group of TSC infants, with the aim of identifying possible prognostic factors for neurodevelopmental outcome. METHODS: We report on six infants diagnosed with TSC pre- or perinatally, who underwent serial Video-EEG recordings during the first two years of life. EEGs were classified based on distribution and intensity of interictal epileptiform discharges, and Vigabatrin was introduced in case of ictal discharges. Psychomotor development, cognitive functioning and behavioral problems were assessed through standardized scales. Molecular testing included analysis for point mutations and deletions/duplications in TSC1 and TSC2. RESULTS: EEG abnormalities appeared at a mean age of 4 months. Four of the six patients developed seizures. EEG abnormalities preceded the onset of clinical seizures in all of them. The two individuals with good seizure control showed normal development, while the other two exhibited psychomotor delays. The patients who did not develop seizures had normal development. A pathogenic variant in the TSC2 gene was detected in all patients but one. The one without a mutation identified did not develop seizures and showed normal neurodevelopment. Of note, the two patients presenting with the worst outcome (that is, poor seizure control and intellectual/behavioral disability) both carried pathogenic variants in the GAP domain of TSC2. CONCLUSION: Our report supports the importance of EEG monitoring before seizure onset in patients with TSC, and the correlation between prompt seizure control and positive neurodevelopmental outcome, regardless of seizure type. Our results also indicate a possible role of the genetic background in influencing the outcome.

Movement cognition and narration of the emotions treatment versus standard speech therapy in the treatment of children with borderline intellectual functioning: a randomized controlled trial.

BACKGROUND: Borderline intellectual functioning (BIF) is defined as a "health meta-condition… characterized by various cognitive dysfunctions associated with an intellectual quotient (IQ) between 71 and 85 which determines a deficit in the individual's functioning both in the restriction of activities and in the limitation of social participation". It can be caused by many factors, including a disadvantaged background and prematurity. BIF affects 7-12% of primary school children that show academic difficulties due to poor executive functioning. In many children with BIF, language, movement and social abilities are also affected, making it difficult to take part in daily activities. Dropping out of school and psychological afflictions such as anxiety and depression are common in children with BIF. This study investigates whether an intensive rehabilitation program that involves all of the areas affected in children with BIF (Movement, Cognition and Narration of emotions, MCNT) is more effective than Standard Speech Therapy (SST). METHODS: This is a multicenter interventional single blind randomized controlled study. Children aged between 6 to 11 years who attend a mainstream primary school and have multiple learning difficulties, behavioral problems and an IQ ranging between 85 to 70 have been enrolled. Participants are randomly allocated to one of three groups. The first group receives individual treatment with SST for 45 min, twice a week for 9 months. The second group receives the experimental treatment MCNT for 3 h per day, 5 days/ week for 9 months and children work in small groups. The third group consists of children on a waiting list for the SST for nine months. DISCUSSION: BIF is a very frequent condition with no ad hoc treatment. Over the long term, there is a high risk to develop psychiatric disorders in adulthood. Due to its high social impact, we consider it very important to intervene during childhood so as to intercept the remarkable plasticity of the developing brain. TRIAL REGISTRATION: "Study Let them grow: A new intensive and multimodal Treatment for children with borderline intellectual functioning based on Movement, Cognition and Narration of emotions", retrospectively registered in ISRCTN Register with ISRCTN81710297 at 2017-01-09.

Dreaming experience as a useful diagnostic clue for syncopal episodes.

BACKGROUND: The differential diagnosis between epileptic seizures and syncopes is a common occurrence in clinical practice. The manifestations of seizure and syncope sometimes overlap, and available diagnostic testing often not provides a conclusive answer. Syncope is often preceded by a symptom complex characterized by lightheadedness, generalized muscle weakness, giddiness, visual blurring, tinnitus, and gastrointestinal symptoms. These subjective symptoms are very important in guiding the diagnosis. In our experience, the impression of coming out of a dream after the syncopal episode is a subjective symptom commonly reported by patients, if questioned. METHODS: To verify the occurrence of dreaming experience after syncope and after generalized tonic-clonic seizures (GTCS) and its diagnostic value in differential diagnosis, we asked 100 patients with GTCS and diagnosis of idiopathic generalized epilepsy (Group 1) and 100 patients with a certain diagnosis of syncope (Group 2) whether they have never felt the impression of coming out of a dream after the loss of consciousness (GTCS or syncope, respectively). RESULTS: In Group 1, nobody referred the dreaming experience, whereas in the syncope group, 19% of patients referred this subjective symptom. CONCLUSIONS: Dreaming experience seems to be an additional useful diagnostic clue for syncopal episodes, helping the clinician to differentiate them from seizures.

Exploring dopaminergic activity in ring chromosome 20 syndrome: a SPECT study.

AIM: Several lines of evidence indicate that the dopaminergic system may play a role in the propagation of epileptic seizures and, indeed, DOPA metabolism impairment has recently been demonstrated in PET studies of ring chromosome 20 [r(20)] patients. We conducted a study looking for correlations between r(20) mosaicism, other clinical variables and both pre-synaptic dopamine transporter (DAT) expression and post-synaptic D2 receptor density. METHODS: Five patients with r(20) and epilepsy were enrolled in the study. DAT expression and D2 density were measured by single photon emission tomography (SPECT) imaging with 185 MBq of [¹²³I]ioflupane and [¹²³I]IBZM, respectively, on different days. Linear correlations between r(20) mosaicism, clinical variables and binding of [¹²³I]ioflupane or [¹²³I]IBZM were examined. RESULTS: A significant correlation between seizure frequency and r(20) mosaicism was detected (r=0.903, P<0.05), along with a negative correlation between r(20) mosaicism and binding of [¹²³I]ioflupane in the putamen and in the caudate nucleus (r=-0.692 and r=-807; P<0.05). Seizure frequency was positively correlated with post-synaptic D2 density (r=0.925, P<0.05). CONCLUSION: Striatal neurons are involved in r(20) epilepsy; the relationship found between r(20) mosaicism and DAT expression suggests that drugs acting on the dopaminergic system could have a place in the treatment of this rare form of epilepsy.

Exploring dopaminergic activity in ring chromosome 20 syndrome: a SPECT study.

AIM: Several lines of evidence indicate that the dopaminergic system may play a role in the propagation of epileptic seizures and, indeed, DOPA metabolism impairment has recently been demonstrated in PET studies of ring chromosome 20 [r(20)] patients. We conducted a study looking for correlations between r(20) mosaicism, other clinical variables and both pre-synaptic dopamine transporter (DAT) expression and post-synaptic D2 receptor density. METHODS: Five patients with r(20) and epilepsy were enrolled in the study. DAT expression and D2 density were measured by single photon emission tomography (SPECT) imaging with 185 MBq of [123I]ioflupane and [123I]IBZM, respectively, on different days. Linear correlations between r(20) mosaicism, clinical variables and binding of [123I]ioflupane or [123I]IBZM were examined. RESULTS: A significant correlation between seizure frequency and r(20) mosaicism was detected (r=0.903, P<0.05), along with a negative correlation between r(20) mosaicism and binding of [123I]ioflupane in the putamen and in the caudate nucleus (r=-0.692 and r=-807; P<0.05). Seizure frequency was positively correlated with post-synaptic D2 density (r=0.925, P<0.05). CONCLUSION: Striatal neurons are involved in r(20) epilepsy; the relationship found between r(20) mosaicism and DAT expression suggests that drugs acting on the dopaminergic system could have a place in the treatment of this rare form of epilepsy.

The role of formative courses in the professional integration of patients with epilepsy. An Italian experience.

The aim of the present paper was to describe some formative projects on work integration of patients with epilepsy and mild cognitive deficits, so that similar initiatives may be promoted. The different phases of the formative projects were described: the inclusion criteria, the selection of participants, the assessment instruments, the courses themselves and the final results in terms of working experience. Thirteen participants were selected for each course. Patients were treated in different Lombardy Epilepsy departments, which addressed them to the Epilepsy Center, S. Paolo Hospital, Milan, where the selection took place. Seventy percent of the participants in the formative courses found a job in 1 year, even though most of the positions were temporary. The work integration seemed to be mainly related to the level of intelligence and to verbal memory. We stress the importance of organising similar courses in the future, in the context of wider networks. This will help more patients in acquiring both economic and psychological autonomy from their families.

Italian neuropsychological instruments to assess memory, attention and frontal functions for developmental age.

In this study, a series of tests exploring long-term verbal memory (the Short Story Test), attention (a modified version of Attentional Matrices and the Trail Making Test) and frontal functions (a modified version of the Frontal Assessment Battery) have been standardised on an Italian population of 283 children aged 5-14. Raw scores for each test have been adjusted for a series of variables (child's age, years of parents' education, handedness, gender) and transformed in equivalent scores enabling direct comparison across measures. This study was promoted by LICE (the Italian League Against Epilepsy) in order to provide Italian instruments standardised on the developmental age population and to study some of the most frequently impaired cognitive functions in epilepsy.

Reflex writing seizures in two siblings with juvenile myoclonic epilepsy.

We report on two siblings who presented with juvenile myoclonic epilepsy, and in whom myoclonic jerks of the right arm and hand were also triggered by writing tasks. Both patients underwent intensive video-electroencephalography monitoring, with simultaneous neuropsychological tests. In both patients, reflex epileptic myoclonus was more easily triggered by writing that required a higher degree of concentration. Conversely, other cognitive tasks, such as reading, typing, thinking, or calculation never elicited any seizures or myoclonus. Valproate was effective in controlling both spontaneous and reflex epileptic seizures. The results of this study further support the notion that 'praxis-induced' reflex epilepsy precipitated by specific stimuli occurs in the context of idiopathic generalized epilepsy. Our results also illustrate that writing tasks are more effective in eliciting seizures when they require higher levels of concentration and mental elaboration.

Symptomatic epilepsy with facial myoclonus triggered by language.

We report on a patient with a left frontal lesion who, many years after an injury, developed non-fluent aphasia and facial myoclonic jerks triggered by speaking and listening to spoken language. At age 57, the patient first noted that he would begin to stutter when delivering lectures at conferences. The stuttering would worsen if he continued talking. The video-polygraphic EEG recording shows brief paroxysms of spikes and polyspikes, followed by a slow wave, more evident in the left fronto-temporal region. The myoclonic jerks originating from the submental area correlate with EEG abnormalities. Clinically, these jerks determined a form of stuttering. The triggering factors were reading, speaking and listening to spoken language. This case had several characteristic features: facial myoclonus was the only seizure type experienced by the patient; the seizures and language impairment had a very late onset--about 50 years after the traumatic event that produced a dramatic lesion in the left fronto-polar region. (Published with videosequences.)

The perception of memory failures in patients with epilepsy.

The aim of the study is to evaluate the correlation between subjective memory complaints and neuropsychological tests in the epilepsy population. We administered a Self Report Memory Questionnaire, based on possible everyday memory failures, two questionnaires on anxiety and depression and a battery of cognitive tests to 150 patients with epilepsy (n=100 with partial epilepsy, n=50 with idiopathic generalized epilepsy) and a control group (n=50). A discrepancy between the results of the memory questionnaire and the cognitive tests was found in the epilepsy patients: the Self Report Memory Questionnaire did not show any correlation with the psychological tests. The same discrepancy was not seen in the controls, where the memory questionnaire was related to two verbal memory tests. Furthermore, patients with epilepsy reported greater difficulties on the Self Report Memory Questionnaire than the controls (P < 0.05). It appeared that the tendency to overstate memory problems was mainly related to anxiety and depression, but was not connected with the type of epilepsy, nor with its duration (in years). Seizure frequency, on the other hand, seemed to greatly influence mood, which in turn is probably affect subjective memory perception.

Malformations in offspring of women with epilepsy: a prospective study.

PURPOSE: The incidence of malformations among infants of mothers with epilepsy treated with antiepileptic drugs (AEDs) during pregnancy is higher than that found in the general population. The aim of this study was to contribute to providing a definition of the rate of congenital anomalies in the offspring of mothers with epilepsy and to detect possible risk factors. METHODS: Since 1977, 517 pregnancies were followed up at the San Paolo Hospital in Milan by a team of epileptologists and obstetricians. The patients received monthly obstetric and neurologic examinations, and the blood levels of AEDs were tested monthly. During pregnancy the patients underwent ultrasound investigations to evaluate fetal morphology and development. At the time of delivery, the infants were submitted to a standardized examination by a pediatrician, and a more detailed clinical examination was performed on day 5. Malformations were classified as (a) genetic and chromosomic, (b) severe and mild malformations, and (c) deformities. RESULTS: The overall rate of malformations was 9.7%: of these, 5.3% were structurally severe, 2.2% were mild, 0.4% were chromosomic-genetic, and 1.8% were deformities. No malformation was detected in the 25 untreated patients. CONCLUSIONS: The risks of teratogenicity have been regarded as multifactorial, involving such factors as genetic predisposition, although most prospective studies show that AED-related factors are the primary risk factors for an increased incidence of congenital malformations.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Chromosome 20 ring: a chromosomal disorder associated with a particular electroclinical pattern.

PURPOSE: The chromosome 20 ring [r(20)] is a rare chromosomal disorder without clear phenotypical markers. We describe the electroclinical pattern in a group of patients with r(20). METHODS: We observed 3 patients (a boy, patient 1; his mother, patient 2; and an unrelated man, patient 3), performing prolonged video-EEG and cytogenetic studies and fluorescent in situ hybridization (FISH) with chromosome-specific telomeric probes. RESULTS: All 3 patients had a very similar abnormal electroclinical pattern characterized by long bursts or trains of rhythmic theta waves, which were sharply contoured or had a notched appearance (with no detectable clinical correlate), and generalized spike waves (SW) associated with seizures of probable frontotemporal origin (SFT). In all 3 patients, the cytogenetic analysis of T lymphocytes showed mosaicism with a normal cell line and a second cell line with a chromosome 20, although the latter was little represented in patients 2 and 3. A few cells with a single chromosome 20 were also found. The same cytogenetic findings were confirmed in the lymphoblastoid cell line of patient 1 and in the fibroblasts of patient 3. FISH with chromosome-specific telomeric probes and TTAGGG sequences demonstrated the integrity of the ring chromosomes. CONCLUSIONS: The clinical picture of these patients appears to be related to the instability of the r(20)-generating cells monosomic for chromosome 20 and is thus haploinsufficient for a gene. In these patients, the electroclinical pattern of theta waves (probably unrelated to epilepsy) and the SW and SFT, even with mild mental retardation (MR) or no MR and without dysmorphic features, suggest that the r(20) syndrome may be present.

Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy.

BACKGROUND: Mood disorders have been described as the commonest psychiatric disorders in patients with temporal lobe epilepsy. Secondary depression in temporal lobe epilepsy could be interpreted either as an adjustment reaction to a chronic disease or as a limbic dysfunction. To clarify this issue, a controlled study of psychiatric disorders was conducted in different forms of epileptic and non-epileptic chronic conditions. METHODS: Twenty outpatients with temporal lobe epilepsy, 18 outpatients with juvenile myoclonic epilepsy--a primary generalised seizure disorder--20 matched type I diabetic patients, and 20 matched normal controls were assessed by a structured interview (SADS) and by self rating scales (Beck depression inventory (BDI) and the state and trait anxiety scales STAIX1 and STAIX2). RESULTS: Sixteen (80%) patients with temporal lobe epilepsy fulfilled the criteria for a psychiatric diagnosis at the SADS interview with a significantly higher frequency than patients with juvenile myoclonic epilepsy (22%) and diabetic patients (10%) (P < 0.0001). The most frequent disorder in temporal lobe epilepsy was a mood disorder: 11 (55%) patients with temporal lobe epilepsy had depression compared with three patients with juvenile myoclonic epilepsy and two diabetic patients (P < 0.001). Eight patients with temporal lobe epilepsy with an affective disorder also had a comorbid personality or anxiety disorder. Patients with temporal lobe epilepsy scored significantly higher on BDI, STAIX1, and STAIX2 than the three control groups (P < 0.001, P < 0.01, P < 0.001). CONCLUSIONS: Patients with temporal lobe epilepsy have a higher incidence of affective and personality disorders, often in comorbidity, than patients with juvenile myoclonic epilepsy and diabetic patients suggesting that these psychiatric disorders are not an adjustment reaction to a chronic disease but rather reflect a limbic dysfunction.

4p(-) syndrome: a chromosomal disorder associated with a particular EEG pattern.

We report an electroclinical and cytogenetic study of 4 patients with Wolf-Hirschhorn syndrome (WHS). In all cases, we observed a stereotyped EEG and clinical picture characterized by generalized or unilateral myoclonic seizures followed later by brief atypical absences. Electrographically, these were accompanied by a sequence of centroparietal or parietotemporal sharp waves; high-voltage wave with a superimposed spike becoming unusual spike-wave complexes, often elicited by eye closure; burst of diffuse spikes and waves; and frequent jerks. This electroclinical pattern is very similar to the one described in Angelman syndrome (AS) in which a defect in GABAA receptor function has been suggested. Moreover, the genes encoding the GABAA receptor subunit have been mapped to the p12-p13 bands of chromosome 4. Even though the deletion in these cases does not encompass the 4p12-p13 region, we suggest that the electroclinical picture common to WHS and AS might represent a characteristic type of epilepsy linked to a common genetic abnormality.

Increased interictal cerebral glucose metabolism in a cortical-subcortical network in drug naive patients with cryptogenic temporal lobe epilepsy.

Positron emission tomography with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) has been used to assess the pattern of cerebral metabolism in different types of epilepsies. However, PET with [18F]FDG has never been used to evaluate drug naive patients with cryptogenic temporal lobe epilepsy, in whom the mechanism of origin and diffusion of the epileptic discharge may differ from that underlying other epilepsies. In a group of patients with cryptogenic temporal lobe epilepsy, never treated with antiepileptic drugs, evidence has been found of significant interictal glucose hypermetabolism in a bilateral neural network including the temporal lobes, thalami, basal ganglia, and cingular cortices. The metabolism in these areas and frontal lateral cortex enables the correct classification of all patients with temporal lobe epilepsy and controls by discriminant function analysis. Other cortical areas--namely, frontal basal and lateral, temporal mesial, and cerebellar cortices--had bilateral increases of glucose metabolism ranging from 10 to 15% of normal controls, although lacking stringent statistical significance. This metabolic pattern could represent a pathophysiological state of hyperactivity predisposing to epileptic discharge generation or diffusion, or else a network of inhibitory circuits activated to prevent the diffusion of the epileptic discharge.

Intrauterine growth in the offspring of epileptic mothers.

The present paper concerns the fetal growth of 315 newborns of epileptic mothers prospectively followed from the beginning of pregnancy. In comparison with Italian standards, neonatal weight, length and head circumference at birth were below the 10th percentile in respectively 15.7%, 1.1% and 19.2% of the newborns. Weight at birth was above the 90th percentile in 8 cases. Observed frequencies were significantly higher than expected frequencies for both weight and head circumference. The percentage of newborns with a small head circumference increased significantly according to the number of drugs taken by the mother during the first three months of pregnancy: 7.1% with no drug, 16.8% with one drug, 23.6% with two drugs and 50% with three drugs. A statistically significant correlation was found between gestational age-adjusted head circumference and drug-level scores during the first trimester. Head circumferences below the 10th percentile were fewer among newborns treated with CBZ than among newborns treated with either PB or VPA.