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The article 'Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures',written by J. A. Kanis, was originally published Online First without Open Access. After publication in volume [#], issue [#] and page [#-#], the author decided to opt for Open Choice and to make the article an Open Access publication.

Summary Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods Clinical perspective and updated literature search. Results The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions.

Several epidemiological studies have shown that Diabetes Mellitus (DM) or Insulin Resistance (IR) increases the risk of dementia. Besides, some authors suggested that poor glucose control to be associated with worse cognitive function. We aimed to assess cognitive functions and IR-degree over time in diabetic. We also evaluated whether a greater magnitude of cognitive decline could be related with their IR degree. We enrolled 335 diabetic patients and 142 non-diabetic subjects; participants were subdivided into three groups in accordance with their IRdegree assessed by Homa-Index (HI): Normal-HI (non-diabetic NHI < 2,6), Moderate-HI (MHI > 2,6 < 10) and High-HI (HHI > 10). Metabolic status and a comprehensive neuropsycological test battery (MMSE, ADAS-Cog, ACDS-ADL) were assessed at baseline and every 12-months during the follow-up (6,8 years). At the end of the study, the average MMSE decreased significantly in patients of HHI group (P = .001) compared to baseline. MMSE scores were also reduced both in MHI group and in controls, but the difference between two groups was not significant. In HHI group, similar effects were observed for the ADAS-Cog score compared to baseline (P = 0.001); instead, when ACDS-ADL was evaluated, no differences was observed among the three groups. These results remained unchanged also after adjustment for confounding variables (i.e. APO epsilon-status, sex, BMI, education level, heart diseases and HbA1c). We suggest that higher IR-degree is associated with greater cognitive decline in diabetic patients; so we hypothesize that IR degree, more than IR status itself, could be related to the severity of cognitive impairment.

The neurorehabilitation of cerebellar damage in neurological patients (i.e., stroke or multiple sclerosis) remains sparsely studied. This case report is aimed at providing evidence on the development of a new cognitive approach targeting cerebellar functions. We hope that our paper will stimulate an interesting scientific debate (http://neurosciencenews.com/chef-neurobiology-6196/), which comes from our previous study demonstrating the tight relationship between cooking activity and the cerebellar functioning: (https://doi.org/10.1371/journal.pone.0171457; https://doi.org/10.1016/j.jns.2018.01.037).

Background and importance The therapeutic approach for cerebellar damages heavily relies on neurorehabilitation since there are no medications that may improve clinical symptoms mainly those related to cognitive dysfunctions. Nevertheless, neurorehabilitation programs tailored to cerebellar damages have never been validated. Here we describe a new rehabilitation approach based on cooking training (CT). The idea that cooking may stimulate cerebellar activity relies on previous evidence demonstrating the beneficial effect on the executive functions as well as in promoting neural plasticity within the cerebellum. Indeed, CT requires motor/mental coordination, thinking flexibly, planning, implementing strategies, shifting and self-monitoring behaviors, all functions drastically affected in cerebellar disorders. Case description A 68-year-old male stroke patient with isolated right cerebellar ischemia in the posterior cerebellum characterized by mild executive dysfunctions. After intensive six weekly two-hour sessions, we found that CT was effective in improving some cognitive abilities in a context of mild motor impairment. In particular, deficits in the execution of the Symbol digit modality test and Wisconsin card-sorting test were recovered. Conclusion The comparison of our data with those reported in previous studies confirmed the Schmahmann’s hypothesis on the effectiveness of neurorehabilitation approaches in cerebellar patients acting as external timekeeping of conscious thoughts.

This paper details a report concerning a case of PG associated with Cerebral Autosomal Dominant Arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is an inherited small artery disease caused by mutations of the NOTCH-3 gene on chromosome 19 [1]. Usually, the first manifestations are attacks of migraine with aura, observed in 20–30 % of patients. Ischemic diseases, the most common clinical manifestations, are reported in 60–80 % of patients, generally during the fourth or fifth decade. Neuropsychiatric manifestations include mood disturbances and various degree of cognitive impairment, observed at all stages of the disorder. Psychiatric symptoms, mainly episodes of mood disturbances, are reported in 10–20 % of patients [2]. Pathological gambling (PG) is as a maladaptive and recurrent pattern of gambling behaviours that persists despite substantial negative consequences for the individual, his/her work and his/ her family. Gambling disorders (referred to as pathological gambling in the DSM-IV) have been recently reclassified in the 5th DSM edition under the category of ‘‘Addictions and Related Disorders’’ because of similarities to substance use disorder (SUD) (i.e. genetic predisposition, treatment response, clinical characteristics, cognitive deficits and underlying neurobiological mechanisms) [3]. A 39-yearold married male, unemployed and genetically diagnosed with CADASIL, carrying a heterogeneous mutation (R90C in the exon 3) of the NOTCH-3 on chromosome 19 p13.213.1 [1], was hospitalized to our neurological outpatient clinic for an episode of transient confusion. His family history revealed that his mother, suffering from CADASIL, died at age of 76 years after a stroke. Our patient had also a history of frequent attacks of migraine without aura since the age of 20 years. Furthermore, he and his relatives denied depressive episodes or previous diagnosis of mood disorder, and he did not display any sleep or eating disorders at the time of the visit. About 6 months before, he started to gamble every day, mainly football betting, slot machines and national lottery, cumulating about 40.000 euros in debts due to gambling. His wife reported that he had become excessively talkative, impulsive and verbally aggressive. During the hospitalization, his labile confusion completely resolved in a few days. Magnetic Resonance Imaging (MRI) of the brain revealed severe leukoencephalopathy with confluent and discrete, fairly symmetric T2 hyperintense foci in the deep and subcortical white matter of the cerebral hemispheres. Similar foci were present in the brainstem, thalami, basal ganglia and the subcortical white matter of anterior temporal lobes (Fig. 1). He had begun to impulse buy multiple items also make many unnecessary purchases for him or his family. When his mental condition was assessed, he showed no confirmation of delusions or hallucinations, but he did have labile moods, poor impulse control, and made grandiose plans. He demonstrated no insight into the changes in his personality and behaviour. Due to a suspected gambling disorder, neuropsychological testing was performed by a clinical psychologist. To evaluate his comprehensive & Domenico Bosco nico_bosco@libero.it

Imaging measurements, such as the ratio of the midsagittal areas of the midbrain and pons (midbrain/pons) and the Magnetic Resonance Parkinsonism Index (MRPI), have been proposed to differentiate progressive supranuclear palsy (PSP) from Parkinson's disease (PD). However, abnormal midbrain/pons values suggestive of PSP have also been reported in elderly individuals and in patients with PD. We investigated the effect of aging on single or combined imaging measurements of the brainstem. We calculated the midbrain/pons and the MRPI (the ratio of the midsagittal areas of the pons and the midbrain multiplied by the ratio of the middle cerebellar peduncle and superior cerebellar peduncle widths) in 152 patients affected by PD, 25 patients with PSP, and a group of 81 age-matched and sex-matched healthy controls using a 3-Tesla magnetic resonance imaging scanner. In healthy controls, aging was negatively correlated with midsagittal area of the midbrain and midbrain/pons values. In patients with PD, in addition to the effect of aging, the disease status further influenced the midbrain/pons values (R2 = 0.23; P

Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

Objective: Magnetic resonance parkinsonism index (MRPI) has been proposed as a powerful tool to discriminate patients with progressive supranuclear palsy (PSP) from those with Parkinson disease (PD) or other parkinsonisms, on an individual basis. We investigated the usefulness of MRPI in predicting the clinical evolution in PSP of patients with clinically unclassifiable parkinsonism (CUP), i.e., parkinsonism not fulfilling the established clinical diagnostic criteria for any parkinsonian disorders, using a cohort study. Methods: Forty-five patients with CUP underwent baseline clinical evaluation and MRI with calculation of MRPI. All patients were divided in 2 groups according to MRPI values. A group included 30 patients with CUP with normal MRPI values while the other group included 15 patients with CUP with MRPI values suggestive of PSP (higher than 13.55). A clinical follow-up was performed in all patients. Results: Duration of clinical follow-up in these 2 groups was 28.4 ± 11.7 months (mean ± SD). None of the patients with CUP with normal MRPI values fulfilled established clinical criteria for PSP (follow-up ranging from 24 to 60 months). By contrast, 11 of 15 patients with CUP with abnormal MRPI values (higher than 13.55) developed during the follow-up (range from 6 to 48 months) additional clinical features characteristic of probable (1 patient) or possible (10 patients) PSP. MRPI showed a higher accuracy in predicting PSP (92.9%) than clinical features, such as vertical ocular slowness or first-year falls (61.9% and 73.8%, respectively). Conclusions: Our findings suggest that MRPI is more powerful than clinical features in predicting the evolution of CUP toward PSP phenotypes.

Levodopa-induced dyskinesias represent disabling complications from long-term therapy with dopaminergic drugs for treating Parkinson's disease (PD). Although several neuroimaging studies have reported altered striatofrontal function that contributes to the emergence of these motor complications, the neuroanatomical correlates of this disorder are still unknown. Optimized voxel-based morphometry (VBM) was applied to the MRI brain images of 36 PD patients with levodopa-induced dyskinesias, 36 PD patients without levodopa-induced dyskinesias, and 32 age- and sex-matched controls. The VBM analysis comparing dyskinetic and nondyskinetic groups provided evidence of increased gray matter volume of the bilateral inferior frontal gyrus in dyskinetic patients, a finding that was more evident in patients with early-onset PD. No significant differences were detected in the dyskinetic and nondyskinetic groups when compared with the controls. Our findings suggest that the presence of dyskinesias in patients with PD is characterized by an aberrant neural plasticity that could play a role in the pathophysiology of these motor complications.

Background: Combined measurements on conventional magnetic resonance imaging (MRI), such as midbrain area/pons area or magnetic resonance parkinsonism index (MRPI) (pons area/midbrain area × middle cerebellar peduncle width/superior cerebellar peduncle width), have been proposed as powerful tools in the differential diagnosis between progressive supranuclear palsy (PSP) and Parkinson disease (PD). In this study, we evaluated the accuracy of MRPI, compared with midbrain/pons ratio, in distinguishing PSP from probable and possible PD. Methods: Forty-two PSP patients, 170 probable PD patients, 132 possible PD patients, and 38 control subjects underwent MRI and, for each patient, midbrain/pons ratio and MRPI were calculated. Results: Midbrain/pons ratio showed low accuracy in distinguishing PSP patients from those with probable PD (92.9% sensitivity; 85.3% specificity; 86.8% diagnostic accuracy) or those with possible PD (88.1% sensitivity, 88.3% specificity, and 88.2% diagnostic accuracy) and control subjects (97.6% sensitivity, 92.1% specificity, and 95% diagnostic accuracy). By contrast, MRPI showed higher accuracy to distinguish PSP from probable PD (100% sensitivity, 99.4% specificity, and 99.5% diagnostic accuracy), from possible PD (100% sensitivity, 99.2% specificity, and 99.4% diagnostic accuracy), and from control subjects (sensitivity, specificity, and diagnostic accuracy of 100%). Conclusions: Our study confirms that MRPI is a more accurate measure than midbrain/pons ratio for differentiation of patients with PSP from those with probable and possible PD. © 2011 Movement Disorder Society

At 1.5 T, T2*-weighted gradient echo (GE) sequences are more sensitive in revealing mineral deposition in the basal ganglia than standard T2 weighted sequences. T2*-weighted GE sequences, however, may detect putaminal hypointensities either in patients affected by parkinsonian syndromes or in healthy subjects. The aim of this study was to identify the magnetic resonance imaging (MRI) T2*- weighted sequence which more specifically detected putaminal hypointensities differentiating atypical parkinsonian syndromes from Parkinson's disease (PD) and control subjects. In a sam- ple of 38 healthy subjects, we performed three T2*-weighted GE sequences at increasing time echo (TE; TE 5 15 millisec- ond, TE 5 25 millisecond, and echoplanar at TE 5 40 milli- second; T2* sequences study). The sequence not showing any putaminal abnormality in the healthy subjects was then used to assess putaminal signal intensity in 189 patients with PD, 20 patients with multiple system atrophy (MSA), 41 patients with progressive supranuclear palsy (PSP), and in 150 age and sex-matched control subjects. In the T2* sequences study, the T2*-weighted TE 5 15 (T2*/15) did not show any putaminal abnormalities in the healthy subjects. This sequence detected putaminal hypointensities in a significantly higher proportion of patients with MSA (35%, P < 0.05) and PSP (24.4%, P < 0.05) than in patients with PD (5.3%), but in none of the con- trols. The sensitivity of putaminal hypointensity in T2*/15 sequence was 25.4% for PD, 43.9% for PSP, and 55% for MSA versus controls whereas the specificity was 93.2% for all groups. Despite the suboptimal sensitivity, the high specificity of the T2*/15 sequence performed on routine MRI suggests its usefulness in clinical practice for identifying putaminal hypo- intensities associated with parkinsonian disorders. 2010 Movement Disorder Society

The cooccurrence of rest and postural tremor (mixed tremor) as the predominant clinical manifestation in patients who do not fulfill diagnostic established criteria for essential tremor (ET) or Parkinson's disease (PD) poses a clinical diagnostic challenge. Twenty-two patients with mixed tremor and additional mild extrapyramidal features, such as bradykinesia and rigidity, 20 patients with probable PD, 10 patients with probable ET, and 18 controls were investigated through the combined use of dopamine transporter (123)I-FP-CIT-single-photon emission tomography (DAT-SPECT) and cardiac (123)metaiodobenzylguanidine (MIGB) scintigraphy. Six of the 22 mixed-tremor patients had normal DAT-SPECT, a condition usually found in patients with ET, whereas 16 patients showed damage to the nigrostriatal system. Cardiac MIBG allowed further differentiation between these 16 patients because eight of them had decreased tracer uptakes (heart/mediastinum [H/M] ratio in delayed image, H/M ratio delayed: 1.16 +/- 0.11, P < 0.001 vs controls), indicating a PD, whereas the remaining eight had normal cardiac tracer uptakes, a finding suggestive of a parkinsonian syndrome (H/M ratio delayed: 1.90 +/- 0.13). Both DAT-SPECT and cardiac MIBG scintigraphies were abnormal in the 20 patients with probable PD, whereas these were normal in both the patients with probable ET as well as in the controls. Our study suggests that the combined use of both DAT-SPECT and MIBG scintigraphy in mixed tremors with additional extrapyramidal features can help distinguish patients with ET from those with PD and parkinsonism.

Freezing of gait (FOG) generally occurs as a late manifestation of Parkinson's Disease (PD). FOG, however, can present in isolation, constituting the so-called "Primary Progressive Freezing Gait"(PPFG). Myocardial (123)Metaiodiobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac nerve terminals. MIBG uptake reflects sympathetic system integrity, and reduced myocardial uptake of the tracer has been observed in nearly all patients with PD. We investigated MIBG uptake in 7 patients with PPFG, 14 patients with mild PD, and 6 patients with advanced PD and FOG (PD-FOG), and 18 control subjects. Our study shows that myocardial MIBG uptake was normal in all patients with PPFG (H/M ratio: mean+/-SD, 1.85+/-0.11 early; 1.71+/-0.15 delayed) and in the controls (H/M ratio: mean+/-SD, 1.94+/-0.18 early; 2.02+/-0.19 delayed) whereas it was markedly decreased in the patients with mild and advanced PD (H/M ratio: mean+/-SD, PD: 1.17+/-0.02 early; 1.16+/-0.02 delayed; PD-FOG: 1.22+/-0.10 early; 1.08+/-0.06 delayed). Our findings demonstrate that cardiac sympathetic denervation did not occur in patients with PPFG, confirming that PPFG and PD are distinct diseases.

The early diagnosis of progressive supranuclear palsy (PSP) may be challenging, because of clinical overlapping features with Parkinson's disease (PD) and other parkinsonian syndromes such as the Parkinsonian variant of multiple system atrophy (MSA-P). Conventional MRI can help in differentiating parkinsonian disorders but its diagnostic accuracy is still unsatisfactory. On the basis of the pathological demonstration of superior cerebellar peduncle (SCP) atrophy in patients with PSP, we assessed the SCP apparent diffusion coefficient (ADC) values in patients with PSP, PD, and MSA-P in order to evaluate its differential diagnostic value in vivo. Twenty-eight patients with PSP (14 with possible-PSP and 14 with probable-PSP), 15 PD, 15 MSA-P, and 16 healthy subjects were studied by using diffusion weighted imaging (DWI). ADC was calculated in regions of interest defined in the left and right SCP by two clinically blinded operators. Intrarater (r = 0.98, P < 0.001) and interrater reliability (r = 0.97; P < 0.001) for SCP measurements were high. Patients with PSP had higher SCP rADC values (median 0.98 × 10−3mm2/s) than patients with PD (median 0.79 × 10−3 mm2/s, P < 0.001), MSA-P (median 0.79 × 10−3 mm2/s, P < 0.001), and healthy controls (median 0.80 × 10−3 mm2/s, P < 0.001). DWI discriminated patients with PSP from PD and healthy subjects on the basis of SCP rADC individual values (100% sensitivity and specificity) and from patients with MSA-P (96.4% sensitivity and 93.3% specificity). The higher values of rADC in SCP of patients with PSP correspond with the in vivo microstructural feature of atrophy detected postmortem and provide an additional support for early discrimination between PSP and other neurodegenerative parkinsonisms. © 2008 Movement Disorder Society

Previous MR studies have established that bilateral transverse sinus stenosis (BTSS) predicts idiopathic intracranial hypertension without papilledema (IIHWOP) in migraine. However, it is uncertain whether BTSS identifies IIHWOP in patients with chronic tension-type headache (CTTH): using cerebral MR venography this study aimed to address this question.In a prospective study from February 2002 to December 2006, 198 consecutive patients with CTTH underwent MR venography. Of these patients, 58 underwent lumbar puncture to measure cerebrospinal fluid (CSF) pressure. MR venography and lumbar puncture were also performed in 45 age-matched control subjects. BTSS was considered present when the signal flow was poor or lacking (flow gap) in the mid-lateral portion of both transverse sinuses. IIHWOP was diagnosed if the patient met the diagnostic criteria for idiopathic intracranial hypertension and did not have papilledema. Among the 198 patients with CTTH who underwent MR venography, 18 (9%) had BTSS. Thirteen of these 18 patients with BTSS underwent lumbar puncture, and nine (69.2%) had IIHWOP. CSF opening pressure was normal in all 45 patients as well as in all 45 controls with normal MR venography.These data suggest that BTSS on MR venography is associated with increased intracranial pressure in the absence of papilledema in patients with headache mimicking CTTH.

Recent studies have reported an association between the glucocerebrosidase (GBA) gene and Parkinson's disease (PD). To elucidate the role of this gene in our population, we screened 395 PD patients and 483 controls from southern Italy for the N370S and the L444P mutations. We found 11 patients (2.8 %) carrying a heterozygous mutant GBA allele, whereas only one control subject (0.2%) had a heterozygous substitution (P = 0.0018). These results strongly suggest that Italian carriers of a GBA mutation have an increased risk of developing PD. (c) 2007 Movement Disorder Society.

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

PURPOSE: To explore the usefulness of histogram analysis of mean diffusivity (MD) derived from diffusion-weighted imaging of large infratentorial structures to distinguish parkinsonian syndromes. MATERIALS AND METHODS: Local research ethics committee approval and informed consent were obtained. Ten patients with Parkinson disease (PD), nine with the parkinsonian variant of multiple system atrophy (MSA-P), seven with the cerebellar variant of MSA (MSA-C), 17 with progressive supranuclear palsy-Richardson syndrome (PSP-RS), and 10 healthy subjects were recruited. Histograms of MD values were generated for all pixels in the whole infratentorial compartment and separately for the whole brainstem, vermis, and cerebellar hemispheres. To assess the differences in MD values among groups, the Kruskal-Wallis test was used, followed by the Mann-Whitney U test for pairwise comparisons. All P values resulting from pairwise comparisons were corrected with the Bonferroni method. RESULTS: MSA-P and MSA-C groups had higher median MD values (P < .01) in the brainstem and cerebellum when compared with other groups; this finding was in line with the known consistent neurodegenerative damage in posterior cranial fossa structures in these diseases. Median MD values from cerebellar hemispheres were used to discriminate patients with MSA-C and those with MSA-P from patients with PD and those with PSP-RS (P < .01; sensitivity, specificity, and positive predictive value equaled 100%). Furthermore, patients with PSP-RS had significantly higher MD values in the vermis than did healthy subjects (P < .05) and patients with PD (P < .001). CONCLUSION: These findings support the clinical usefulness of diffusion imaging in the differential diagnosis of parkinsonism, suggesting that the minimally operator-dependent histogram analysis of the infratentorial structures and particularly of the whole cerebellar hemispheres can be used to distinguish patients with MSA-P and those with MSA-C from patients with PSP-RS and those with PD.

The interhemispheric difference of the motor-cortical threshold (IDMT) was studied with focal magnetic transcranial stimulation (TCS) in ten patients with idiopathic generalized epilepsy (IGE) who also displayed versive or circling seizures (IGEvc). The data were compared with those obtained from two control groups; 13 patients with IGE without asymmetrical motor seizures, and 25 normal volunteer subjects. The IDMT, referred to as the percentage of maximum stimulator output, was assessed by focal TCS applied to the hand areas. Seven patients with IGEvc and only one patient with IGE had an interhemispheric motor threshold beyond the normal range. The IDMT in IGEvc patients was significantly higher compared to that of IGE patients and normal individuals. An interhemispheric imbalance of cortical excitability may explain lateralized ictal motor manifestations in patients with IGEvc.

To further elucidate the inheritance pattern and range of phenotypic manifestations of benign familial temporal lobe epilepsy (FTLE), we report a large family recently identified in southern Italy. There were 8 patients (4 men), ranging in age from 31 to 68 years in three generations. One affected patient was deceased at the time of the study. Genealogical study strongly supported autosomal dominant inheritance with incomplete penetrance, as three unaffected individuals transmitted the disease. Clinical anticipation could not be assessed because of the ascertainment method. Male to male transmission occurred. Identifiable antecedents for seizures were present in only two patients, who had a simple febrile convulsion and a closed head trauma, respectively. Migraine was overrepresented in this family. Onset of seizures ranged from 17 to 52 years (mean: 27 years). All patients had weekly simple partial seizures suggestive of temporal origin with vegetative or experiential phenomena. Very rare partial complex seizures occurred in 6/7 patients. One had two generalized nocturnal seizures as well. Two had previously been misdiagnosed as having gastritis or panic attacks, and one had not been diagnosed. Interictal anteromesiotemporal spiking was seen in 5/7 patients, and occurred mostly during NREM sleep. Neurological examination, brain CT or MR scans were normal. Antiepileptic medication always controlled the seizures.

Imaging measurements, such as the ratio of the midsagittal areas of the midbrain and pons (midbrain/pons) and the Magnetic Resonance Parkinsonism Index (MRPI), have been proposed to differentiate progressive supranuclear palsy (PSP) from Parkinson's disease (PD). However, abnormal midbrain/pons values suggestive of PSP have also been reported in elderly individuals and in patients with PD. We investigated the effect of aging on single or combined imaging measurements of the brainstem. We calculated the midbrain/pons and the MRPI (the ratio of the midsagittal areas of the pons and the midbrain multiplied by the ratio of the middle cerebellar peduncle and superior cerebellar peduncle widths) in 152 patients affected by PD, 25 patients with PSP, and a group of 81 age-matched and sex-matched healthy controls using a 3-Tesla magnetic resonance imaging scanner. In healthy controls, aging was negatively correlated with midsagittal area of the midbrain and midbrain/pons values. In patients with PD, in addition to the effect of aging, the disease status further influenced the midbrain/pons values (R(2) = 0.23; P 0.001). In both groups, MRPI values were not influenced either by aging or by disease status. No effect of aging on either midbrain/pons or MRPI values was shown in the patients with PSP. Our findings indicated that the MRPI was not significantly influenced by aging or disease-related changes occurring in PD; whereas, in contrast, the midbrain/pons was influenced. Therefore, the MRPI appears to be a more reliable imaging measurement compared with midbrain/pons values for differentiating PSP from PD and controls in an elderly population.

Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

At 1.5 T, T2*-weighted gradient echo (GE) sequences are more sensitive in revealing mineral deposition in the basal ganglia than standard T2 weighted sequences. T2*-weighted GE sequences, however, may detect putaminal hypointensities either in patients affected by parkinsonian syndromes or in healthy subjects. The aim of this study was to identify the magnetic resonance imaging (MRI) T2*-weighted sequence which more specifically detected putaminal hypointensities differentiating atypical parkinsonian syndromes from Parkinson's disease (PD) and control subjects. In a sample of 38 healthy subjects, we performed three T2*-weighted GE sequences at increasing time echo (TE; TE = 15 millisecond, TE = 25 millisecond, and echoplanar at TE = 40 millisecond; T2* sequences study). The sequence not showing any putaminal abnormality in the healthy subjects was then used to assess putaminal signal intensity in 189 patients with PD, 20 patients with multiple system atrophy (MSA), 41 patients with progressive supranuclear palsy (PSP), and in 150 age and sex-matched control subjects. In the T2* sequences study, the T2*-weighted TE = 15 (T2*/15) did not show any putaminal abnormalities in the healthy subjects. This sequence detected putaminal hypointensities in a significantly higher proportion of patients with MSA (35%, P0.05) and PSP (24.4%, P0.05) than in patients with PD (5.3%), but in none of the controls. The sensitivity of putaminal hypointensity in T2*/15 sequence was 25.4% for PD, 43.9% for PSP, and 55% for MSA versus controls whereas the specificity was 93.2% for all groups. Despite the suboptimal sensitivity, the high specificity of the T2*/15 sequence performed on routine MRI suggests its usefulness in clinical practice for identifying putaminal hypointensities associated with parkinsonian disorders.

Background and purpose: Quantitative analysis of brain atrophy may be useful in differentiating Parkinson’s Disease (PD) from Progressive Supranuclear Palsy (PSP) and parkinsonian variant of Multiple System Atrophy (MSA-P); the aim of this study was to identify the volumetric differences of subcortical structures in patients with PD, PSP and MSA-P using a novel and validated fully-automated whole brain segmentation method. Methods: Volumetric MRIs were obtained in 72 patients with PD, 32 patients with PSP, 15 patients with MSA-P, and in 46 control subjects. Subcortical volume was measured automatically by FreeSurfer. Multivariate analysis of covariance, adjusted for intracranial volume (ICV), sex and age, was used to explore group differences. Results: No volumetric differences were found between PD and controls group; otherwise the volumes of the cerebellum, the thalamus, the putamen, the pallidum, the hippocampus, and the brainstem were significantly reduced in PSP and MSA-P compared to patients with PD and control subjects. PSP and MSAP patients only differed in thalamus volume which was smaller in PSP group (p < 0.001). Moreover, patients with PSP and MSA-P showed a ventricular system (including lateral, third and fourth ventricles) larger than that detected in PD and controls (p < 0.001). Conclusions: Volumetric data obtained with automated segmentation of cerebral regions show a significant atrophy of different brain structures in parkinsonisms rather than in PD. Our study also demonstrates that the atrophy of the thalamus only occurs in PSP while the enlargement of the whole ventricular system characterizes both PSP and MSA-P.

Combined measurements on conventional magnetic resonance imaging (MRI), such as midbrain area/pons area or magnetic resonance parkinsonism index (MRPI) (pons area/midbrain area × middle cerebellar peduncle width/superior cerebellar peduncle width), have been proposed as powerful tools in the differential diagnosis between progressive supranuclear palsy (PSP) and Parkinson disease (PD). In this study, we evaluated the accuracy of MRPI, compared with midbrain/pons ratio, in distinguishing PSP from probable and possible PD.Forty-two PSP patients, 170 probable PD patients, 132 possible PD patients, and 38 control subjects underwent MRI and, for each patient, midbrain/pons ratio and MRPI were calculated.Midbrain/pons ratio showed low accuracy in distinguishing PSP patients from those with probable PD (92.9% sensitivity; 85.3% specificity; 86.8% diagnostic accuracy) or those with possible PD (88.1% sensitivity, 88.3% specificity, and 88.2% diagnostic accuracy) and control subjects (97.6% sensitivity, 92.1% specificity, and 95% diagnostic accuracy). By contrast, MRPI showed higher accuracy to distinguish PSP from probable PD (100% sensitivity, 99.4% specificity, and 99.5% diagnostic accuracy), from possible PD (100% sensitivity, 99.2% specificity, and 99.4% diagnostic accuracy), and from control subjects (sensitivity, specificity, and diagnostic accuracy of 100%).Our study confirms that MRPI is a more accurate measure than midbrain/pons ratio for differentiation of patients with PSP from those with probable and possible PD.

Mutations in the gene DJ-1 have been shown to be a rare cause of early-onset Parkinson's disease (EOPD). Since DJ-1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ-1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single-nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36-3.08). When we considered a three-marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ-1 gene confer risk to sporadic PD in southern Italy.

The cooccurrence of rest and postural tremor (mixed tremor) as the predominant clinical manifestation in patients who do not fulfill diagnostic established criteria for essential tremor (ET) or Parkinson's disease (PD) poses a clinical diagnostic challenge. Twenty-two patients with mixed tremor and additional mild extrapyramidal features, such as bradykinesia and rigidity, 20 patients with probable PD, 10 patients with probable ET, and 18 controls were investigated through the combined use of dopamine transporter (123)I-FP-CIT-single-photon emission tomography (DAT-SPECT) and cardiac (123)metaiodobenzylguanidine (MIGB) scintigraphy. Six of the 22 mixed-tremor patients had normal DAT-SPECT, a condition usually found in patients with ET, whereas 16 patients showed damage to the nigrostriatal system. Cardiac MIBG allowed further differentiation between these 16 patients because eight of them had decreased tracer uptakes (heart/mediastinum [H/M] ratio in delayed image, H/M ratio delayed: 1.16 +/- 0.11, P0.001 vs controls), indicating a PD, whereas the remaining eight had normal cardiac tracer uptakes, a finding suggestive of a parkinsonian syndrome (H/M ratio delayed: 1.90 +/- 0.13). Both DAT-SPECT and cardiac MIBG scintigraphies were abnormal in the 20 patients with probable PD, whereas these were normal in both the patients with probable ET as well as in the controls. Our study suggests that the combined use of both DAT-SPECT and MIBG scintigraphy in mixed tremors with additional extrapyramidal features can help distinguish patients with ET from those with PD and parkinsonism.

BACKGROUND AND PURPOSE: Essential tremor (ET) is a slowly progressive disorder characterized by postural and kinetic tremors most commonly affecting the forearms and hands. Several lines of evidence from physiologic and neuroimaging studies point toward a major role of the cerebellum in this disease. Recently, voxel-based morphometry (VBM) has been proposed to quantify cerebellar atrophy in ET. However, VBM was not originally designed to study subcortical structures, and the complicated anatomy of the cerebellum may hamper the automatic processing of VBM. The aim of this study was to determine the efficacy and utility of using automated subcortical segmentation to identify atrophy of the cerebellum and other subcortical structures in patients with ET. MATERIALS AND METHODS: We used a recently developed automated volumetric method (FreeSurfer) to quantify subcortical atrophy in ET by comparing results obtained with this method with those provided by previous evidence. The study included T1-weighted MR images of 46 patients with ET grouped into those having arm ET (n = 27, a-ET) or head ET (n = 19, h-ET) and 28 healthy controls. RESULTS: Results revealed the expected reduction of cerebellar volume in patients with h-ET with respect to healthy controls after controlling for intracranial volume. No significant difference was detected in any other subcortical area. CONCLUSIONS: Volumetric data obtained with automated segmentation of subcortical and cerebellar structures approximate data from a previous study based on VBM. The current findings extend the literature by providing initial validation for using fully automated segmentation to derive cerebellar volumetric information from patients with ET.

BACKGROUND AND PURPOSE: Our aim was to investigate the presence of brain gray matter (GM) abnormalities in patients with different forms of essential tremor (ET). MATERIALS AND METHODS: We used optimized voxel-based morphometry (VBM) and manually traced single region-of-interest analysis in 50 patients with familial ET and in 32 healthy subjects. Thirty patients with ET had tremor of the arms (a-ET), whereas the remaining 20 patients had both arm and head tremor (h-ET). RESULTS: VBM showed marked atrophy of the cerebellar vermis in the patients with h-ET with respect to healthy subjects (P-corrected < 001) Patients with a-ET showed a trend toward a vermal GM volume loss that did not reach a significant difference with respect to healthy controls (P-uncorrected < .01). The region-of-interest analysis showed a reduction of the cerebellar volume (CV) in the h-ET group (98.2 +/- 13.6 mm(3)) compared with healthy controls (110.5 +/- 15.5 mm(3), P < .012) as well as in the entire vermal area (790.3 +/- 94.5 mm(2), 898.6 +/- 170.6 mm(2), P

PURPOSE: To prospectively assess sensitivity and specificity of magnetic resonance (MR) imaging measurements of midbrain, pons, middle cerebellar peduncles (MCPs), and superior cerebellar peduncles (SCPs) for differentiating progressive supranuclear palsy (PSP) from Parkinson disease (PD) and Parkinson variant of multiple system atrophy (MSA-P), with established consensus criteria as reference standard. MATERIALS AND METHODS: All study participants provided informed consent; study was approved by the institutional review board. Pons area, midbrain area, MCP width, and SCP width were measured in 33 consecutive patients with PSP (16 possible, 17 probable), 108 consecutive patients with PD, 19 consecutive patients with MSA-P, and 50 healthy control participants on T1-weighted MR images. The pons area-midbrain area ratio (P/M) and MCP width-SCP width ratio (MCP/SCP) were also used, and an index termed MR parkinsonism index was calculated [(P/M).(MCP/SCP)]. Differences in MR imaging measurements among groups were evaluated with Kruskal-Wallis test, Mann-Whitney U test, and Bonferroni correction. RESULTS: Midbrain area and SCP width in patients with PSP (23 men, 10 women; mean age, 69.3 years) were significantly (P < .001) smaller than in patients with PD (62 men, 46 women; mean age, 65.8 years), patients with MSA-P (five men, 14 women; mean age, 64.0 years), and control participants (25 men, 25 women; mean age, 66.6 years). P/M and MCP/SCP were significantly larger in patients with PSP than in patients in other groups and control participants. All measurements showed some overlap of values between patients with PSP and patients from other groups and control participants. MR parkinsonism index value was significantly larger in patients with PSP (median, 19.42) than in patients with PD (median, 9.40; P < .001), patients with MSA-P (median, 6.53; P < .001), and control participants (median, 9.21; P < .001), without overlap of values among groups. No patient with PSP received a misdiagnosis when the index was used (sensitivity and specificity, 100%). CONCLUSION: The MR parkinsonism index can help distinguish patients with PSP from those with PD and MSA-P on an individual basis.

Background: The headache profile of patients with idiopathic intracranial hypertension without papilledema (IIHWOP) may be indistinguishable from that of migraine. Bilateral transverse sinus stenosis (BTSS) has been found in the majority of patients with IIHWOP. The frequency of BTSS associated with IIHWOP in patients with migraine is unknown. Objective: To detect the frequency of BTSS in adult patients with migraine and to investigate whether the presence of BTSS identifies patients with IIHWOP. Methods: In a prospective study from December 2000 to November 2005, 724 consecutive patients with recurrent headaches who fulfilled International Headache Society diagnostic criteria for migraine underwent cerebral MR venography (MRV). A portion of these patients underwent a lumbar puncture (LP) to measure CSF pressure. MRV and LP were also performed in 70 age-matched control subjects. Results: Six hundred seventy-five of the 724 patients with migraines had normal MRV. Seventy of these 675 patients underwent LP, and all of them had normal CSF pressure. Forty-nine (6.7%) of the 724 patients with migraine had BTSS. Twenty-eight of these 49 patients with BTSS underwent LP, and 19 (67.8%) had IIHWOP. The headache profiles of patients with BTSS and IIHWOP did not differ from those of patients with normal MRVs and CSF pressures within normal limits. CSF pressure was normal in both patients and controls with normal MRV. Conclusions: Of patients with migraine, 6.7% had bilateral transverse sinus stenosis; 67.8% of these patients had idiopathic intracranial hypertension without papilledema (IIHWOP). These results suggest that patients with migraine who present bilateral transverse sinus stenosis on cerebral MR venography should undergo lumbar puncture to exclude IIHWOP.

Background Several factors, both clinical and genetic, may account for the risk of developing levodopa-induced peak-dose dyskinesias (PDD) in patients with Parkinson disease, but it is unclear how these factors interact for modulating the individual susceptibility for PDD. Objective To examine clinical and genetic risk factors for determining individual susceptibility of PDD in patients with Parkinson disease. Design Cohort study. Setting Referral center for Parkinson disease in Calabria, southern Italy. Patients Two hundred fifty patients with Parkinson disease were screened for the presence or absence of PDD following a short-term levodopa administration, and 215 subjects were available for further evaluations, including genotypic analysis of the CA dinucleotide short tandem repeat (CA n -STR) polymorphism located in the dopamine receptor D2 gene ( DRD2 ). Results One hundred five patients (48.8%) exhibited PDD following short-term levodopa administration, and 110 patients (51.2%) did not. Multivariate logistic regression analysis showed that independent predictors for the occurrence of PDD were female sex, earlier age at onset of Parkinson disease, longer duration of treatment, and higher dose of levodopa. Genetic factors related to the DRD2 CA n -STR polymorphism were not independent predictors for PDD in the total population, but they had a strong protective effect on the appearance of PDD when the multivariate analysis was performed in men (odds ratio, 0.34 [95% confidence interval, 0.14-0.84]). In women, a genetic protective effect on PDD was not evident. Conclusions Risk factors for PDD, both clinical and genetic, act in different ways for men and women. Genetic factors related to the DRD2 polymorphic status have a protective effect on PDD development in men but not in women. A female sex–related effect for the risk of PDD may be so strong that it overcomes any protective effect due to genetic factors.

Cerebral venous outflow abnormalities, as transverse sinuses (TSs) stenosis,may underlie a picture of idiopathic intracranial hypertension (IIH). To identify the best non–invasive MR venography (MRV) technique for exploring the disturbance of flow of TSs in IIH patients, we compared threedimensional phase contrast (3–DPC) MRV images, acquired with different velocity encodings (15 and 40 cm/s) with two–dimensional time–of–flight (2D–TOF) MR images in 6 subjects with IIH and 12 age–matched normal controls. In both groups, we also measured flow velocity in TSs by using single slice 2D–CINE PC acquisitions. In all subjects with IIH, 3D-PC showed marked flow disturbance in the mid–lateral portion of both TSs when velocity encoding (VENC) was set to 15 cm/s while only a slightly irregular flow in TSs was detected when VENC was set to 40 cm/s or when 2D–TOF was used. By contrast, 3D–PC (VENC 15 and 40) and 2D–TOF techniques were comparable in detecting TS signal flow in normal controls. Measures of flow velocity, by using 2D-CINE PC, revealed a three–fold increase of velocity at the level of the flow disturbance in IIH patients compared to normal controls (p < 0.0001), suggesting a marked stenosis of mid–lateral portion of TSs in these patients. Setting the VENC to 15 cm/s on 3D–PC MRV may represent the best technical approach for visualizing disturbances of flow in TSs in subjects with symptoms suggestive of IIH.

Background: The genes encoding myeloperoxiclase (MPO) and alpha(2),-macroglobulin (A2M) are involved in molecular pathways leading to beta-amyloid deposition. Two polymorphic sites in these genes (MPO-G/A and A2M-Ile/Val) have been associated with Alzheimer disease (AD), but conflicting findings have been reported in populations with different ethnic backgrounds. Objectives: To study the association of MPO-G/A and A2M-Ile/Val polymorphisms, with sporadic AD and to investigate the interactions among the MPO, A2M, and apolipoprotein E (APOE) gene polymorphisms in determining the risk of the development of AD. Design: Case-control study. Setting: Referral center for AD in Calabria, southern Italy Participants: One hundred forty-eight patients with sporadic AD and 158 healthy control subjects. Results: The MPO-G and A2M-Val alleles were found more frequently in cases than in controls, as were the MPO-G/G and A2M-Val/Val genotypes. The odds ratio (OR) for the MPO-G/G genotype was 1.78 (95% confidence interval [CI], 1.13-2.80); for the A2M-Val/Val genotype, 3.81 (95% Cl, 1.66-8.75). The presence of MPO-G/G and A2M-Val/Val genotypes synergistically increased the risk of AD (OR, 25.5; 95% Cl, 4.65-139.75). Stratification of cases by sex, age at onset of AD, and APOE-epsilon4 status did not show significant differences in the distribution of MPO or A2M polymorphisms. Conclusions: The MPO and A2M polymorphisms are associated with sporadic AD in southern Italy. Moreover, a genomic interaction between these polymorphisms increases the risk of the development of AD.

BACKGROUND: Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-epsilon4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer's Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. OBJECTIVE: To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. METHODS: Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms. RESULTS: Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the epsilon4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. CONCLUSION: The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.

Although multiple sclerosis (MS) is considered to be an inflammatory demyelinating disease, increasing evidence indicates that it is also an axonal pathology; indeed, studies of experimental allergic encephalitis showed that several neuronal proteins such as synapsins take part in the pathogenesis of the axonal dysfunction. Synapsins are a family of abundant neuron-specific phosphoproteins with crucial roles in synaptogenesis and neuronal plasticity. Distinct genes encode the three different isolated proteins (I, II and III); of interest, the gene of synapsin III (SYN3) is located in the chromosome 22q12-q13, a locus close to one of the candidate susceptibility regions (22q13.1) for MS. In the present study we selected two polymorphisms (g.-631C > G and g.-196A > G) within the SYN3 5?-promoter region because of the protein's role and genetic location; we analysed the allele and genotype distributions of these polymorphisms in a selected MS population of southern Italy. An inverse association between MS and the g-631C > G polymorphism was found; indeed, the two polymorphisms were in almost complete linkage disequilibrium and the haplotype analysis showed that the C631/A196 haplotype seemed to confer a significant protection against MS.

The effects of serotonin (5-HT) in the CNS are mediated through receptor subtypes distinguished by seven major families. The 5-HT6 receptor gene maps to the human chromosome region 1p35-p36 and a polymorphism (C267T) of the 5-HT6 gene has been associated with the risk of developing schizophrenia.1 Unlike most 5-HT receptors, the 5-HT6 receptor is highly expressed in the striatum,2 suggesting a possible involvement of this receptor in the extrapyramidal function. In this study, we investigated whether the allelic variant C267T of the 5-HT6 gene could contribute to the risk for developing PD. Patients diagnosed with sporadic PD (n = 243) and control subjects (n = 234) were included in our study. Patients with PD were consecutively selected starting in March 1999 until December 2000 from the outpatients attending the Institute of Neurology of the University of Catanzaro, Italy. PD was defined by the presence of at least two of four cardinal signs (bradykinesia, rigidity, rest tremor, and postural instability). Only cases with idiopathic PD responsive to levodopa were included. No patient had …

Alpha-2 macroglobulin (A2M) is a component of Lewy bodies, a hallmark of Parkinson's disease (PD). In 159 PD patients and 190 normal controls, we studied two A2M polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism method: a five-nucleotide deletion at the 5' splice site of exon 18; and a valine to isoleucine exchange in amino acid position 1000 near the thiolester active site. No significant differences in allelic and genotypic distribution were found between cases and controls or between early and late-onset PD patients. The present data suggest that these polymorphisms do not represent a risk factor for PD and do not modulate the age at onset of PD.

We used spike-triggered functional MRI in a patient with localization-related epilepsy to determine whether individual (as opposed to averaged) focal interictal epileptiform discharges (spikes) were associated with hemodynamic changes detectable with blood oxygen level-dependent functional MRI (fMRI). It was found that 15 of 43 spikes (34.9%) were associated with significant focal fMRI activation. Single event-related fMRI of interictal spikes is feasible in selected patients, giving complementary information to that provided by averaged fMRI data.

Summary: Purpose: To evaluate how many patients with a clinical picture of idiopathic childhood localization-related epilepsies may also have silent celiac disease (CD). This will help determine whether investigation for CD should be restricted to those patients with childhood partial epilepsy with occipital paroxysms (CPEO) or should be extended to all patients with childhood partial epilepsy (CPE) regardless of seizure type and electroencephalographic (EEG) paroxysms. Methods: The study group consisted of 72 patients (31 girls and 41 boys; mean age, 12.6 ± 4.28 years; age at onset, 6.4 ± 3.7 years) who were observed consecutively over a 5-year period and who received an initial diagnosis of idiopathic CPE. A diagnosis of CD was confirmed by using enzyme-linked immunosorbent assay (ELISA) to assess the presence of antigliadin antibodies and the immunofluorescent undirected test to assess the presence of antiendomysium antibodies. Results: Twenty-five patients had CPEO, whereas the remaining 47 had CPE with centrotemporal spikes (CPEC). None of the patients with CPEC had positive antibody tests. Of the 25 patients with CPEO, two (8%) had antiendomysium immunoglobulin (Ig) A antibodies. In both of these patients, the jejunal biopsy showed atrophy of the villi and hyperplasia of the crypts, consistent with a diagnosis of CD. Brain computed tomography (CT) was normal in one of these patients and revealed occipital corticosubcortical calcifications in the other. Conclusions: Our study indicates that CD screening should be performed routinely only in patients with CPEO.

Objectives – To describe the electroclinical features of the idiopathic generalized epilepsies (IGEs) with versive or circling seizures. Methods – Sixteen patients with versive or circling seizures and interictal electroclinical features of IGE were studied. Patients with insufficient clinical or imaging data, with a follow-up period less than 1 year or with partial seizures in addition to the versive or circling ones were excluded from the study. All patients underwent full interictal clinical and neurophysiological studies. The EEG patterns of 13 versive or circling seizures from 4 patients were also analyzed. Results – A specific IGE syndrome was recognized in 9 out of the 16 patients (56%). More specific, 1 patient had childhood absence epilepsy (CAE), 4 had juvenile absence epilepsy (JAE), and 4 had juvenile myoclonic epilepsy (JME). No specific IGE syndrome was recognizable in the remaining 7 patients (44%). These 7 patients had a juvenile epileptic syndrome (mean age at onset of seizures was 15.7 years) characterized by versive or circling seizures followed or not by generalized tonic-clonic fits. Three main EEG patterns were identified during versive or circling seizures: 1) generalized spike-and-wave discharges at 3–4 cps; 2) generalized polyspike-and-wave discharges at 1 to 2.5 cps beginning with generalized fast activity at 12–14 cps, and 3) generalized spike-and-wave discharges at 3–4 cps intermingled with fast activity at 12–14 cps. Most patients had good response to treatment on a single drug regimen (mainly valproic acid). Conclusions – Versive or circling seizures may occur in the context of an IGE. Although many individuals share the features of different IGE syndromes including CAE, JAE and JME, a consistent number of patients, who show circling or versive seizures solely, remain without a specific syndromic diagnosis. When occurring in the context of IGE, circling or versive seizures do not worsen the prognosis.

Summary: We have described a clinical EEG and molecular genetic study of a 9-year-old boy with inv-dup(15) syndrome in whom seizures were induced by emotionally gratifying stimuli. The reflex seizures began 5–20 s after the onset of repeated cheek-kissing from his mother or after viewing of pleasant or funny events. They were characterized by bilateral discharges involving mainly the temporal regions and evolving into myoclonic absence-like seizures. Nonemotional stimuli, such as a pinch, sucking or rubbing his cheeks, or the sound of the kiss alone, failed to provoke seizures. The seizures were resistant to antiepileptic (AED) treatments. Molecular genetic investigations revealed a correct methylation pattern of the chromosomes 15, and three copies (two maternal and one paternal) of the segment 15q11-q13, including the GABRb3 gene. We hypothesize that an overexpression of cerebral γ-aminobutyric acid (GABA)-mediated inhibition accounts for the severe epilepsy that we observed in this patient.

Periodic sharp wave complexes (PSWC) are sensitive and specific of Creutzfeldt-Jakob disease (CJD). Once they have emerged, PSWC may exceptionally disappear in the terminal stage of the disease, as a consequence of the flattening of scalp electroencephalogram (EEG). We document the disappearance of PSWC in serial EEG during the clinical course in two women (57 and 70 years of age) with pathologically proven CJD. Despite PSWC disappearance, diffuse theta-delta activity was still well recognizable. Moreover, external stimuli failed to trigger PSWC. The absence of PSWC in CJD might be due to the timing and frequency of EEG recordings. PSWC disappearance should not be interpretated as evidence against the diagnosis of CJD.

A large three-generation family with autosomal dominant type 1 porencephaly from southern Italy was studied. A high rate of miscarriages was observed. Of the nine affected individuals, four displayed a severe phenotype, and five had slight pyramidal signs or mild cognitive abnormalities. The MRI study disclosed unilateral porencephalic cyst, or colpocephaly. A genome-wide screen resulted in suggestive evidence for linkage to chromosome 13qter with a maximum logarithm-of-the-odds score of 3.16, from multipoint analysis, with marker D13S285.