Prediction of seizure recurrence risk following discontinuation of antiepileptic drugs.

OBJECTIVE: Discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is an important goal because of possible long-term side effects and the social stigma burden of epilepsy. The purpose of this work was to assess seizure recurrence risk after suspension of AEDs, to evaluate predictors for recurrence, and to investigate the recovery of seizure control after relapse. In addition, the accuracy of a previously published prediction model of seizure recurrence risk was estimated. METHODS: Seizure-free patients with epilepsy who had discontinued AEDs were retrospectively enrolled. The frequency of seizure relapses after AED withdrawal as well as prognosis after recurrence were assessed and the predictive role of baseline clinical-demographic variables was evaluated. The aforementioned prediction model was also validated and its accuracy assessed at different seizure-relapse probability levels. RESULTS: The enrolled patients (n = 133) had been followed for a median of 3 years (range 0.8-33 years) after AED discontinuation; 60 (45%) of them relapsed. Previous febrile seizures in childhood (hazard ratio [HR] 3.927; 95% confidence interval [CI] 1.403-10.988), a seizure-free period on therapy of less than 2 years (HR 2.313; 95% CI 1.193-4.486), and persistent motor deficits (HR 4.568; 95% CI 1.412-14.772) were the clinical features associated with relapse risk in univariate analysis. Among these variables, only a seizure-free period on therapy of less than 2 years was associated with seizure recurrence in multivariate analysis (HR 2.365; 95% CI 1.178-4.7444). Pharmacological control of epilepsy was restored in 82.4% of the patients who relapsed. In this population, the aforementioned prediction model showed an unsatisfactory accuracy. SIGNIFICANCE: A period of freedom from seizure on therapy of less than 2 years was the main predictor of seizure recurrence. The accuracy of the previously described prediction tool was low in this cohort, thus suggesting its cautious use in real-world clinical practice.

Time perception impairment in early-to-moderate stages of Huntington's disease is related to memory deficits.

Huntington's disease (HD) primarily affects striatum and prefrontal dopaminergic circuits which are fundamental neural correlates of the timekeeping mechanism. The few studies on HD mainly investigated motor timing performance in second durations. The present work explored time perception in early-to-moderate symptomatic HD patients for seconds and milliseconds with the aim to clarify which component of the scalar expectancy theory (SET) is mainly responsible for HD timing defect. Eleven HD patients were compared to 11 controls employing two separate temporal bisection tasks in second and millisecond ranges. Our results revealed the same time perception deficits for seconds and milliseconds in HD patients. Time perception impairment in early-to-moderate stages of Huntington's disease is related to memory deficits. Furthermore, both the non-systematical defect of temporal sensitivity and the main impairment of timing performance in the extreme value of the psychophysical curves suggested an HD deficit in the memory component of the SET. This result was further confirmed by the significant correlations between time perception performance and long-term memory test scores. Our findings added important preliminary data for both a deeper comprehension of HD time-keeping deficits and possible implications on neuro-rehabilitation practices.

Donor-Specific Anti-HLA Antibodies in Huntington's Disease Recipients of Human Fetal Striatal Grafts.

Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0-49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.

Human striatum remodelling after neurotransplantation in Huntington's disease.

BACKGROUND: Restoration of functions in Huntington's disease (HD) by neurotransplantation stems from the formation of a striatum-like structure capable of establishing host connections as a result of grafted striatal neuroblast maturation. For the first time, we demonstrated some developmental steps accomplished by progenitor cells in the brain of an HD patient and analysed the molecular asset of the human primordium. CASE REPORT: Surgery involved bilateral (two sessions) stereotactic, caudate-putaminal transplantation of whole ganglionic eminence fragments from single legally aborted fetuses. MRI showed that the tissue deposits of the left hemisphere grew and joined to constitute a single tissue mass that remodelled basal ganglia anatomy and remained stable in size over time. No evidence of graft growth was observed contralaterally. PET demonstrated increased striatal and stable cortical metabolism. Unified Huntington's Disease Rating Scale assessments demonstrated improvement of motor performances, which faded over the 36-month follow-up. Cognitive performance tended to decrease at a lower rate than before transplantation. CONCLUSION: The striatal primordium grew into the host brain and this process was associated with metabolic change and some clinical benefit. The study suggests the plasticity and reparative potential of un-manipulated primordium in an era where promising cell-based therapies are still in their infancy.

Multifaceted roles of BDNF and FGF2 in human striatal primordium development. An in vitro study.

Grafting fetal striatal cells into the brain of Huntington's disease (HD) patients has raised certain expectations in the past decade as an effective cell-based-therapy for this devastating condition. We argue that the first requirement for successful transplantation is defining the window of plasticity for the striatum during development when the progenitor cells, isolated from their environment, are able to maintain regional-specific-identity and to respond appropriately to cues. The primary cell culture from human fetal striatal primordium described here consists of a mixed population of neural stem cells, neuronal-restricted progenitors and striatal neurons. These cells express trophic factors, such as BDNF and FGF2. We show that these neurotrophins maintain cell plasticity, inducing the expression of neuronal precursor markers and cell adhesion molecules, as well as promoting neurogenesis, migration and survival. We propose that BDNF and FGF2 play an important autocrine-paracrine role during early striatum development in vivo and that their release by fetal striatal grafts may be relevant in the setting of HD cell therapy.

Large-sized Fetal Striatal Grafts in Huntington's Disease Do Stop Growing: Long-term Monitoring in the Florence Experience.

Development of six large nodules of solid tissue after bilateral human fetal striatal transplantation in four Huntington's disease patients has raised concern about the safety of this experimental therapy in our setting. We investigated by serial MRI-based volumetric analysis the growth behaviour of such grafts. After 33-73 months from transplantation the size of five grafts was stable and one graft showed a mild decrease in size. Signs neither of intracranial hypertension nor of adjuctive focal neurological deficit have ever been observed. This supports long-term safety of the grafting procedure at our Institution.

Fetal striatal grafting slows motor and cognitive decline of Huntington's disease.

OBJECTIVE: To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington's disease (HD). METHODS: We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. RESULTS: Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [(18)F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [(123)I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. CONCLUSIONS: Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.

Human fetal striatal transplantation in huntington's disease: a refinement of the stereotactic procedure.

BACKGROUND: Human fetal striatal transplantation (HFST) is an experimental stereotactic intervention in the treatment of Huntington's disease (HD). This procedure has proved feasible, safe, well tolerated and it offers a potential strategy for brain repair in HD patients. Target areas are the nucleus caudatus caput (NCc) and the precommissural and postcommissural putamen (Pu). A suboptimal spatial distribution of grafts was frequently reported, especially for the postcommissural Pu, because of striatal atrophy and the concurrent ventricular frontal horn enlargement. An improvement of the stereotactic procedure aimed to optimize the intrastriatal placement of grafts is therefore considered a timely issue. METHODS: Eight consecutive HD patients underwent bilateral HFST. For the first 6 procedures (first group) we performed both caudate and putaminal tracks through a single frontal entry point. For the following 10 procedures (second group), we adopted two completely distinct routes, with two separate entry points, for NCc and Pu tracks. The average number of stereotactic tracks and the average infused volume of tissue suspension were compared between the two groups. RESULTS: The average number of putaminal tracks and the average infused volume of suspension were significantly higher in the second group. CONCLUSION: Adopting two separate routes for caudate and putaminal trajectories allowed us to achieve a larger amount of fetal tissue deposits and a better spatial distribution of grafts.

Development of human striatal anlagen after transplantation in a patient with Huntington's disease.

Replacement of damaged neuronal population by fetal tissue transplantation represents a potential treatment for neurodegenerative diseases. Consistent success has been achieved with fetal striatal transplantation in Huntington's disease animal models and patients. We report the neo-generation of metabolically active tissue with striatum-like imaging features after transplantation of striatal primordia in a patient with Huntington's disease. This study represents the first "in vivo" demonstration that a human striatal anlagen, transplanted into the adult human brain, is able to progress in its development and to generate a new anatomical structure in the host, without evidence of neoplasia or teratoma.

Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies.

Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. Here we have characterized the clinical and laboratory features of two patients presenting with subacute onset, and chronic evolution, of anterograde amnesia and drug-resistant epilepsy associated with thyroid autoimmunity and in absence of tumoral pathology despite long follow-up. Antibodies against onconeural antigens, voltage gated potassium channel and glutamate receptors, which may accompany paraneoplastic as well as non-paraneoplastic LE, were negative. However, biochemical studies showed high titers, and sustained intrathecal synthesis, of antibodies directed against neuronal glutamic acid decarboxylase (GAD). In one patient, plasma exchange determined a dramatic improvement of the neurological deficits along with the decrease of autoantibodies.

Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.

BACKGROUND: Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, and more rarely in beta-amyloid precursor protein (betaAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). OBJECTIVE: To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the betaAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. DESIGN AND METHODS: Polymerase chain reaction-single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD. RESULTS: We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the betaAPP Val717Ile mutation. CONCLUSIONS: One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and betaAPP genes was beneficial in characterizing gene function in FAD.