VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab.

Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.

Electrophysiological Investigations of Shape and Reproducibility of Oropharyngeal Swallowing: Interaction with Bolus Volume and Age.

Electrophysiological assessment provides valuable information on physiological and pathophysiological characteristics of human swallowing. Here, new electrophysiological measures for the evaluation of oropharyngeal swallowing were assessed: (1) the activation pattern of the submental/suprahyoid EMG activity (SHEMG); (2) the reproducibility of the oral and pharyngeal phases of swallowing, by calculating the similarity index (SI) of the SHEMG (SI-SHEMG) and of the laryngeal-pharyngeal mechanogram (SI-LPM) during repeated swallows; and (3) kinesiological measures related to the LPM. An electrophysiological-mechanical method for measuring the activation pattern of the SHEMG, the SI-SHEMG, and the SI-LPM, and maximal LPM velocity and acceleration during swallowing was applied in 65 healthy subjects divided into three age groups (18-39, 40-59, 60 years or over). All the measures were assessed during three trials of eight consecutive swallows of different liquid bolus volumes (3, 12, and 20 ml). A high overall reproducibility of oropharyngeal swallowing in healthy humans was recorded. However, while values of SI-SHEMG were similar in all the age groups, the SI-LPM was found to fall significantly in the older age group. Both the SI-SHEMG and the SI-LPM were found to fall with increasing bolus volumes. The activation pattern of the SHEMG and the LPM kinesiological measures were differently modified by bolus volume and age in the older subjects with respect to the others. We describe a new approach to the electrophysiological study of swallowing based on computed semi-automatic analyses. Our findings provide insight into some previously uninvestigated aspects of oropharyngeal swallowing physiology, considered in relation to bolus volume and age. The new electrophysiological measures here described could prove useful in the clinical setting, as it is likely that they could be differently affected in patients with different kinds of dysphagia.

θ-burst stimulation of the cerebellum interferes with internal representations of sensory-motor information related to eye movements in humans.

Continuous theta-burst stimulation (cTBS) applied over the cerebellum exerts long-lasting effects by modulating long-term synaptic plasticity, which is thought to be the basis of learning and behavioral adaptation. To investigate the impact of cTBS over the cerebellum on short-term sensory-motor memory, we recorded in two groups of eight healthy subject each the visually guided saccades (VGSs), the memory-guided saccades (MGSs), and the multiple memory-guided saccades (MMGSs), before and after cTBS (cTBS group) or simulated cTBS (control group). In the cTBS group, cTBS determined hypometria of contralateral centrifugal VGSs and worsened the accuracy of MMGS bilaterally. In the control group, no significant differences were found between the two recording sessions. These results indicate that cTBS over the cerebellum causes eye movement effects that last longer than the stimulus duration. The VGS contralateral hypometria suggested that we eventually inhibited the fastigial nucleus on the stimulated side. MMGSs in normal subjects have a better final accuracy with respect to MGSs. Such improvement is due to the availability in MMGSs of the efference copy of the initial reflexive saccade directed toward the same peripheral target, which provides a sensory-motor information that is memorized and then used to improve the accuracy of the subsequent volitional memory-guided saccade. Thus, we hypothesize that cTBS disrupted the capability of the cerebellum to make an internal representation of the memorized sensory-motor information to be used after a short interval for forward control of saccades.

The angiotensin-converting enzyme insertion/deletion polymorphism modifies the clinical outcome in patients with Pompe disease.

PURPOSE: The insertion/deletion polymorphism of angiotensin-converting enzyme may influence muscle properties. We examined whether Pompe disease clinical manifestations, which are known to be highly variable among late-onset patients, may be modulated by angiotensin-converting enzyme polymorphism. METHODS: We included 38 patients with late-onset Pompe disease, aged 44.6 +/- 19.8 years. We compared the distribution of angiotensin-converting enzyme polymorphism according to demographic and disease parameters. RESULTS: The distribution of angiotensin-converting enzyme polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The three groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction). DISCUSSION: These findings suggest a potential role of angiotensin-converting enzyme polymorphism in modulating Pompe disease phenotype and prognosis.

Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II.

OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII. METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months. RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8%) showed transient secondary events during ERT. CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment.

Changes in skeletal muscle qualities during enzyme replacement therapy in late-onset type II glycogenosis: temporal and spatial pattern of mass vs. strength response.

Muscle quality is defined as muscle strength generated per unit muscle mass. If enzyme replacement therapy (ERT) has some effects on type II glycogenosis (GSDII) skeletal muscle pathology, we should be able to measure a change in strength and mass. We conducted a prospective study including 11 patients aged 54.2 ± 11.2 years, referring to a single institution and receiving ERT for ≥2 years. Median Walton score was 3 (2.5-6). Lower limb skeletal muscles were assessed by dynamometry and quantitative muscle MRI. Three segments (anterior thigh, posterior thigh, leg) were analysed separately. Clinical-MRI correlations were searched for at T0, T6/T8, and T18/24. Changes in lean and fat body composition were assessed by bioelectrical impedance analysis. We found that the anterior thigh showed the best therapeutic response, with an improvement in muscle quality (muscle mass: +7.5%, p = 0.035; strength: +45%, p = 0.002). BMI and lean body mass increased (p = 0.007). Patients with low BMI showed a better outcome. Intramuscular fat accumulation significantly progressed in spite of ERT (+3.7%, p = 0.001), especially in the poorly responsive posterior thigh muscles. Both clinical assessment and MRI revealed a definite improvement in the anterior thigh muscles. However, progression of intramuscular fat accumulation during ERT, as well as the limited responsiveness of posterior thigh muscles, suggests the necessity for early treatment intervention. The better outcome of patients with low BMI, if confirmed, may indicate that dietary protocols could be adopted as adjuvant measures to ERT in adult GSDII.

Immune-mediated neuropathies in myeloma patients treated with bortezomib.

OBJECTIVE: Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. METHODS: Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. RESULTS: Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS: In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE: This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

Septo-optic dysplasia and psychiatric disorders: a case report.

BACKGROUND: Septo-optic dysplasia, a variable combination of abnormalities of cerebral midline structures, is a clinically heterogeneous syndrome in which the midline defects may be implicated in psychiatric disturbances. OBJECTIVE: To describe a case of septo-optic dysplasia associated with depression and psychosis and to discuss the role of these developmental abnormalities in psychiatric disturbances. METHODS: The patient's clinico-anamnestic, neuroradiologic, neuropsychiatric, endocrinologic, ophthalmologic, and genetic profile was evaluated. CONCLUSIONS: Developmental abnormalities due to disruption of the complex neural network linking the septum pellucidum with other limbic structures may have been involved in the affective and psychotic disturbances observed in our patient.

Enzyme replacement therapy in severe adult-onset glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is an autosomal recessive myopathy caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Enzyme replacement therapy (ERT) with recombinant GAA (rh-GAA) has become available for GSDII, although its effectiveness in adults remains unknown. We present a case of ERT with rhGAA in a 49-year-old male with GSDII in a severe stage of the disease. Quantitative magnetic resonance imaging showed an increase in muscle mass of the inferior limb, especially evident on the quadriceps femoris and the patient's body weight increased up to 30%, although his reported dietary habits were the same as before ERT. Beyond improvement in muscle strength and respiratory function, we observed a dramatic increase in body mass index from 12.7 to 16.6 kg/m(2). This may reflect a change from a catabolic state to a more balanced metabolic state during ERT.

Pathogenetic role of myelitis for syringomyelia.

BACKGROUND: CSF-flow obstruction is regarded as a mandatory factor for the development of syringomyelia. However, there are conditions in which syringomyelia is not associated with evident persistent CSF-flow obstruction, as in the case of inflammatory spinal cord lesions. In these instances we hypothesize that the accumulation of vasogenic edema may play a role in the development of the syrinx. Recently proposed theories underline, even in the event of CSF-flow obstructions, a major role for the accumulation and final coalescence of interstitial spinal fluid, rather than CSF penetration through the spinal cord. AIM: To clarify the relationship between syrinx development and spinal cord inflammation, through the analysis of the role of intrinsic medullary factors versus CSF-flow block. METHODS: A prospective case series including patients with transient syringomyelia associated with different examples of non-infectious myelitis: sarcoidosis, post-infectious transverse myelitis, Devic's disease and multiple sclerosis. Cavitations resulting from cystic myelomalacia were excluded. CSF-flow block was assessed by structural MRI. RESULTS: Syringes associated with myelitis shared some common features: they developed during the acute phase of myelitis and disappeared after steroids, were all non-communicating cavitations involving the central canal, and occurred in the same spinal segment affected by myelitis. CSF-flow obstruction was detected in one patient (Chiari I malformation), while in the other three patients we could not detect anatomical predispositions. CONCLUSION: Only one patient had structural abnormalities, though without evidence of a pathogenetic role in itself: however, CSF space obstruction and reduced CSF compliance could have accelerated the development of syringomyelia triggered by intramedullary inflammation. The clinical and radiological features in this patient are consistent with the label "presyringomyelia". The absence of any anatomical predisposition in the other patients suggests a major pathophysiological role for intrinsic medullary mechanisms, including blood-spinal cord barrier breakdown, impairment of extracellular fluid drainage, and leakage of subarachnoidal CSF into the nervous tissue.

Botulinum Toxin Is Effective in the Management of Neurogenic Dysphagia. Clinical-Electrophysiological Findings and Tips on Safety in Different Neurological Disorders.

Background and Aims: Neurogenic dysphagia linked to failed relaxation of the upper esophageal sphincter (UES) can be treated by injecting botulinum toxin (BTX) into the cricopharyngeal (CP) muscle. We compared the effects of this treatment in different neurological disorders with dysphagia, to evaluate its efficacy over time including the response to a second injection. Materials and Methods: Sixty-seven patients with neurogenic dysphagia associated with incomplete or absent opening of the UES (24 with brainstem or hemispheric stroke, 21 with parkinsonian syndromes, 12 with multiple sclerosis, and 10 with spastic-dystonic syndromes secondary to post-traumatic encephalopathy) were treated with the injection of IncobotulinumtoxinA (dose 15-20 U) into the CP muscle under electromyographic guidance. The patients were assessed at baseline and after the first and second treatment through clinical evaluation and fiberoptic endoscopy of swallowing, while their dysphagia was quantified using the Dysphagia Outcome and Severity Scale (DOSS). An electrokinesiographic/electromyographic study of swallowing was performed at baseline. Results: Most patients responded to the first BTX treatment: 35 patients (52.2%) were classified as high responders (DOSS score increase >2 levels), while other 19 patients (28.4%) were low responders (DOSS score increase of ≤2 levels). The effect of the first treatment usually lasted longer than 4 months (67%), and in some cases up to a year. The treatment efficacy remained high also after the second injection: 31 patients (46.3%) qualified as high responders and other 22 patients (32.8%) showed a low response. Only in the parkinsonian syndromes group we observed a reduction in the percentage of high responders as compared with the first treatment. Side effects were mostly mild and reported in non-responders following the first injection. A severe side effect, consisting of ingestion pneumonia, was observed following the second BTX injection in two patients who had both been non-responders to the first. Non-responders were characterized electromyographically by higher values of the oropharyngeal interval. Conclusion: These findings confirm the effectiveness of IncobotulinumtoxinA injection in the treatment of neurogenic dysphagia due to hyperactivity and relaxation failure of the UES. Caution should be used as regards, the re-injection in non-responders to the first treatment.

Dietary treatment in adult-onset type II glycogenosis.

Eight patients with adult-onset type II glycogenosis (GSD II), all carrying the IVS1-13T

The prognostic value of sleep patterns in disorders of consciousness in the sub-acute phase.

OBJECTIVE: This study aimed to evaluate, through polysomnographic analysis, the prognostic value of sleep patterns, compared to other prognostic factors, in patients with disorders of consciousness (DOCs) in the sub-acute phase. METHODS: Twenty-seven patients underwent 24-h polysomnography and clinical evaluation 3.5 ± 2 months after brain injury. Their clinical outcome was assessed 18.5 ± 9.9 months later. Polysomnographic recordings were evaluated using visual and quantitative indexes. A general linear model was applied to identify features able to predict clinical outcome. Clinical status at follow-up was analysed as a function of the baseline clinical status, the interval between brain injury and follow-up evaluation, patient age and gender, the aetiology of the injury, the lesion site, and visual and quantitative sleep indexes. RESULTS: A better clinical outcome was predicted by a visual index indicating the presence of sleep integrity (p=0.0006), a better baseline clinical status (p=0.014), and younger age (p=0.031). Addition of the quantitative sleep index strengthened the prediction. CONCLUSIONS: More structured sleep emerged as a valuable predictor of a positive clinical outcome in sub-acute DOC patients, even stronger than established predictors (e.g. age and baseline clinical condition). SIGNIFICANCE: Both visual and quantitative sleep evaluation could be helpful in predicting clinical outcome in sub-acute DOCs.

Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes.

Nasu-Hakola disease is a rare, recessively inherited disease characterized by presenile dementia and bone cysts. Until now, no evidence of subclincal pathological changes in individuals heterozygous for the mutations underlying Nasu-Hakola disease has been reported. We performed a functional neuroimaging (99mTc-ECD SPECT) and neuropsychological study of healthy members of an Italian family carrying a mutation in the TREM2 gene. Two healthy subjects heterozygous for one mutated TREM2 allele showed a deficit of visuospatial memory associated with hypoperfusion in the basal ganglia, whereas the homozygotes for the wild-type allele of TREM2 did not show any abnormalities.

Ocular vestibular evoked myogenic potentials in response to air-conducted 500 Hz short tones: Effect of stimulation procedure (monaural or binaural), age and gender.

BACKGROUND: The ocular vestibular myogenic potentials (oVEMP) can be elicited by monaural air-conducted sound stimulation, and are usually recorded from the contralateral eye. In clinical setting a binaural stimulation would save time and require less effort from the subjects. OBJECTIVE: We evaluated the differences between monaural and binaural stimulation, and the possible effect of age and gender on oVEMP parameters. METHODS: Air-conducted oVEMP were recorded by binaural and by monaural stimulation in a group of 54 normal subjects, aged from 12 to 83 years, and in 50 vestibular patients. From each side, we measured the latency of the N1 component, and the peak-to-peak N1-P1 amplitude. For both parameters we also computed the asymmetry ratio. RESULTS: In normal subjects binaural stimulation produced slightly larger responses than monaural stimulation; detectability, latency and amplitude ratio were the same for the two techniques. We found no differences related to gender, and the age-induced amplitude decline was likely to be negligible.oVEMP recorded not in an acute phase of their disorder, proved to be abnormal in about 20% of the patients, and the normal or abnormal findings obtained either with monaural or with binaural stimulation were always concordant. CONCLUSIONS: The oVEMP obtained after binaural and monaural stimulation are very similar, and they are largely independent from age and gender.

Acute effects of high-frequency microfocal vibratory stimulation on the H reflex of the soleus muscle. A double-blind study in healthy subjects.

This study in healthy subjects examined the effects of a system delivering focal microvibrations at high frequency (Equistasi®) on tonic vibration stimulus (TVS)-induced inhibition of the soleus muscle H reflex. Highfrequency microvibrations significantly increased the inhibitory effect of TVS on the H reflex for up to three minutes. Moreover, Equistasi® also significantly reduced alpha-motoneuron excitability, as indicated by the changes in the ratio between the maximumamplitude H reflex (Hmax reflex) and the maximumamplitude muscle response (Mmax response); this effect was due to reduction of the amplitude of the H reflex because the amplitude of muscle response remained unchanged. The present findings indicate that Equistasi® has a modulatory effect on proprioceptive reflex circuits. Therefore, Equistasi® might interfere with some mechanisms involved in both physiological and pathophysiological control of movement and of posture.

Interictal spiking in adult newly-diagnosed focal epilepsy of unknown cause: The effect of age.

OBJECTIVE: To assess the yield of interictal EEG spiking in standard and whole-night sleep EEGs in elderly subjects with recent-onset focal seizures compared to younger patients. METHODS: Detection of interictal epileptiform abnormalities (IEAs) and rating of mean spike index (number of interictal discharges/minute) values for different sleep stages (NREM stages 1-2 and 3-4 and REM sleep) in standard EEG (S-EEG) and 24-h ambulatory EEG (A-EEG) at first referral in three groups of thirty consecutive outpatients [aged 20-39 (young), 40-59 (adults) and ⩾60years (elderly)], retrospectively selected according to a subsequent diagnosis of focal epilepsy of unknown cause, no sleep disorders or drugs or comorbidities affecting sleep and EEG. RESULTS: Elderly subjects showed a lower rate of IEAs on S-EEG (p<0.01) but a higher propensity for spiking during deep NREM sleep, 11/30 showing IEAs exclusively during stages 3-4. Mean spike index showed a significant increase in IEAs between sleep stages 1-2 and 3-4 in the elderly subjects (p<0.001). CONCLUSIONS: A significant association emerged between IEAs during deep sleep and age (p<0.001). SIGNIFICANCE: EEG recordings covering deep NREM sleep should be recommended when IEAs detection is needed to support a diagnosis of epilepsy in elderly subjects.

Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease.

OBJECTIVES: Mental disorders (MDs) are disabling complications of Parkinson disease (PD). We set out to demonstrate the short- and long-term efficacy of quetiapine, an antipsychotic drug, in controlling hallucinations and delusions in parkinsonian patients without worsening their motor function. Since current guidelines recommend that dopaminergic drugs be decreased or even withdrawn altogether upon the appearance of MDs, we also sought to establish whether quetiapine enables a modification of this common course of action, and hence improve the management of pre-existing motor complications in affected subjects. METHOD: Thirty-five PD patients with disabling MDs were enrolled in this open-label study. Motor function, MDs and cognitive state were evaluated before starting quetiapine therapy and after 1, 3, and 12 months of treatment. RESULTS: MDs significantly improved after 1, 3, and 12 months of quetiapine treatment. At the end of the study the mean daily dose of quetiapine (185 mg) did not produce significant changes in motor or cognitive function. Isolated hallucinations responded to low doses of quetiapine (110 mg daily), while delusions needed 265 mg daily. After 12 months, global dopaminergic therapy was reduced in 3 patients, modified (purely in terms of its components) in 17 patients, and increased in 15 patients. CONCLUSIONS: Quetiapine was effective in the treatment of hallucinations and delusions in PD. It did not worsen motor functions and allowed the dopaminergic treatment in PD patients affected by MDs to be managed safely.