Flavio Villani

Experience with immunomodulatory treatments in Rasmussen’s encephalitis

The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in the few cases of bilateral disease.

Epileptic phenotypes associated with mitochondrial disorders

Objective: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME). Methods: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect. Results: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or “overlapping” characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome. Conclusions: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.

Periventricular Nodular Heterotopia: Classification, Epileptic History, and Genesis of Epileptic Discharges

Summary:  Purpose. Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug‐resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges.

Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients

The present study included analysis of data from 243 patients surgically treated for Temporal Lobe Epilepsy (TLE). Resection was confined to the temporal lobe, with at least two years of follow-up, and specimens sufficiently preserved to allow a precise evaluation of both lateral neocortex and hippocampus. The frequency of different types of lesion and hippocampal sclerosis (HS), isolated or associated with neocortical lesions, risk factors and surgical outcomes in relation to neuropathological findings were evaluated. We found tumours in 33% of patients, malformations of cortical development (MCD) in 45%, isolated HS in 14%, no lesion in 5% and less common lesions in 3%. HS was present in 8% of tumour cases and 70% of MCD. Statistical analysis of antecedents was significantly associated only with febrile seizures (FS). In MCD patients with no history of FS, a strong association between HS and duration of epilepsy was revealed. A Class I outcome was identified in 87% of cases with tumours and 79% in cases with MCD. In 93 patients the antiepileptic drug therapy was withdrawn. Our findings show that MCD, which is significantly associated with HS, is the most common lesion in TLE and support the concept that an optimal outcome is obtained when mesial and neocortical structures are removed. FS are particularly relevant in patients with focal cortical dysplasia and HS.

Mutant Prion Protein Expression Causes Motor and Memory Deficits and Abnormal Sleep Patterns in a Transgenic Mouse Model

A familial form of Creutzfeldt-Jakob disease (CJD) is linked to the D178N/V129 prion protein (PrP) mutation. Tg(CJD) mice expressing the mouse homolog of this mutant PrP synthesize a misfolded form of the mutant protein, which is aggregated and protease resistant. These mice develop clinical and pathological features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral PrP deposition, and gliosis. Tg(CJD) mice also display electroencephalographic abnormalities and severe alterations of sleep-wake patterns strikingly similar to those seen in a human patient carrying the D178N/V129 mutation. Neurons in these mice show swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant PrP, suggesting that ER dysfunction could contribute to the pathology. These results establish a transgenic animal model of a genetic prion disease recapitulating cognitive, motor, and neurophysiological abnormalities of the human disorder. Tg(CJD) mice have the potential for giving greater insight into the spectrum of neuronal dysfunction in prion diseases.

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

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

Positive response to immunomodulatory therapy in an adult patient with Rasmussen’s encephalitis

Rasmussen’s encephalitis (RE) is a rare and progressive neurologic condition of uncertain etiology that typically has a childhood onset. The authors describe a 45-year-old woman with adult-onset progressive aphasia, right hemiparesis, severe drug refractory epilepsy, and left cerebral hemisphere atrophy. High-dose corticosteroids and plasmapheresis were not effective. She improved with high-dose therapy with human IV immunoglobulin.

Deep Brain Stimulation of Two Unconventional Targets in Refractory Non-Resectable Epilepsy

Introduction: Several deep brain targets have been assessed for the treatment of unresectable refractory epileptic conditions. Adrian Upton in 1985 proposed deep brain stimulation (DBS) of the anterior nucleus of the thalamus for the treatment of seizures and psychosis [Cooper I.S., Upton A.R.: Biol Psychiatry 1985;20:811–813]. Francisco Velasco, in 1987, introduced DBS of the thalamic centromedian nucleus, proposing its employment for Lennox-Gastaut syndrome and for multifocal epilepsy. Other proposed targets are the subthalamic nucleus, caudate nucleus, Forel fields and mammillothalamic tract. We employed DBS for stimulating 2 ‘unconventional targets’, the posterior hypothalamus (pHyp) and caudal zona incerta (CZi), for the treatment of 2 patients with multifocal epilepsy and behavioural comorbidity, and 2 patients with sensorimotor focal seizures, respectively. Such patients did not meet criteria for resective surgery. Material and Methods: In our institution, between January 2003 and May 2004, we started DBS in 2 epileptic patients The former patient was affected by multifocal epilepsy, and the second one by refractory partial motor and secondary generalized seizures. The chosen targets were the pHyp in the former case and the CZi in the latter. The encouraging results obtained led us to replicate such a favourable experience in 2 more patients, 1 with focal motor epilepsy once again (resulting in status epilepticus) and the other with behavioural comorbidity and multifocal epilepsy. Results: A significant reduction in seizure frequency was observed, and the 2 patients with behavioural comorbidity also showed a dramatic improvement in their disruptive behaviour. The patient with motor focal seizures showed a 70% reduction in seizure frequency, and in the last patient remission from status epilepticus was obtained. Conclusion: Our data confirm DBSof deep brain structures modulates the functional activity of the cerebral cortex as suggested by Adrian Upton in 1985. In the reported series, deep-brain stimulation of 2 unconventional targets belonging to the reticulo-cortical system (the brainstem-diencephalon functional system including structures that act as remote controls in modulating cortical excitability) was found to be effective in controlling otherwise refractory multifocal (pHyp) and focal sensorimotor (CZi) epilepsy when resective surgery was not feasible.

Theory of mind in frontal and temporal lobe epilepsy: Cognitive and neural aspects

Purpose:  Theory of mind (ToM) is an important prerequisite to social behavior. This study evaluated ToM in patients with temporal (TLE) or frontal lobe epilepsy (FLE) aiming to determine the cognitive aspects, severity, and pathophysiologic mechanisms of ToM impairment in focal epilepsy.

7T MRI features in control human hippocampus and hippocampal sclerosis: An ex vivo study with histologic correlations

Hippocampal sclerosis (HS) is the major structural brain lesion in patients with temporal lobe epilepsy (TLE). However, its internal anatomic structure remains difficult to recognize at 1.5 or 3 Tesla (T) magnetic resonance imaging (MRI), which allows neither identification of specific pathology patterns nor their proposed value to predict postsurgical outcome, cognitive impairment, or underlying etiologies. We aimed to identify specific HS subtypes in resected surgical TLE samples on 7T MRI by juxtaposition with corresponding histologic sections.