Urinary JCV-DNA testing during natalizumab treatment may increase accuracy of PML risk stratification.

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

Retinal nerve fibre layer measurements and optic nerve head analysis in multiple sclerosis patients.

PURPOSE: To verify whether scanning laser polarimeter with the new variable corneal compensation algorithm (GDx VCC) and scanning laser ophthalmoscopy (Heidelberg Retina Tomograph (HRT)) allow measuring retinal ganglion cell loss in patients with multiple sclerosis (MS). PATIENTS AND METHODS: We enrolled 23 MS patients with a history of previous demyelinating monocular optic neuritis. Examination included visual evoked potentials (VEPs), scanning laser ophthalmoscopy, and scanning laser polarimeter. HRT was performed to assess optic nerve head (ONH) shape, while GDx VCC was used to evaluate the retinal nerve fibre layer thickness (RNFLt) around the ONH. Statistical analysis was performed comparing results obtained for each eye with the available normative database and with the unaffected fellow eye. RESULTS: When the affected eye group was compared to the fellow-eye group, a significant (P<0.05) difference was found for few GDx VCC parameters. In contrast, no significant correlation was observed between clinical assessment and imaging techniques when the normal database of HRT and GDx VCC was used. A significant association was observed between VEP latency and some GDx VCC parameters. CONCLUSIONS: Our results suggested that scanning laser polarimetry could detect loss of ganglion cells following demyelinating optic neuritis, but further studies are needed.

Conventional perimetry, short-wavelength automated perimetry, frequency-doubling technology, and visual evoked potentials in the assessment of patients with multiple sclerosis.

PURPOSE: To evaluate the diagnostic power of conventional, achromatic, automated perimetry (CAP), short-wavelength automated perimetry (SWAP), frequency-doubling technology (FDT) perimetry, and visual evoked potentials (VEP) in a group of patients with multiple sclerosis (MS) with or without a history of optic neuritis. METHODS: Thirty eyes of 15 patients (5 male, 10 female, average age 38+/-7 years) with confirmed diagnosis of MS underwent CAP, SWAP (Humphrey 750-II VFA, program central 30-2, full-threshold strategy), FDT perimetry (program N-30), and pattern VEPs. Sixteen eyes (53.3%) had no history of ocular involvement and a negative ophthalmologic examination. They were matched with a control group of 10 healthy volunteers (4 male, 6 female, average age 31+/-10 years). The mean deviation (MD) and the pattern standard deviation (PSD) of the two groups were compared (t-test). Fourteen eyes (46.7%) had, on the contrary, a history of optic neuritis. Inside this group, the MD and the PSD of the three techniques were correlated (Spearman's rank test), in order to investigate whether any significant differences might be revealed by these techniques in pointing out the total amount of visual field damage. RESULTS: When comparing MS patients without signs or symptoms of ocular involvement and a control group, no significant differences were found for CAP MD, CAP PSD, and FDT PSD. Significant differences were found, on the contrary, for SWAP MD (p=0.0014), SWAP PSD (p=0.0001), and FDT MD (p=0.0001). When considering the MD and the PSD of the three techniques in the group of MS patients who had a history of optic neuritis, a significant correlation was found only between CAP MD and SWAP MD (r=0.0057), with a tendency by SWAP to reveal a higher rate of visual field loss. The other correlations were not significant. According to predefined criteria, the group of asymptomatic subjects had abnormal CAP in 1 eye (6.25%), abnormal SWAP in 9 (56.2%), abnormal FDT in 11 (68.7%), and abnormal VEPs in 7 (43.7%). The combined use of all techniques allowed us to identify silent optic nerve impairment in 15 (93.7%) eyes. CONCLUSIONS: Short-wavelength automated perimetry and FDT perimetry are two non-conventional perimetric techniques that were mainly developed for the early detection of glaucomatous damage. The results of this study demonstrate their efficacy also in detecting early visual field deficits in MS patients without clinical signs of optic neuropathy. Frequency doubling perimetry, in particular, proved to be an easy, fast, and sensitive technique in the assessment of patients with MS. Our results also suggest that subclinical visual involvement in MS can be better diagnosed using multiple (neurophysiologic and psychophysical) tests.

Are dyspepsia management guidelines coherent with primary care practice?

BACKGROUND: Spontaneous physician behaviour can affect guideline applicability, implementation strategies and application costs, particularly in relation to widespread pathologies chiefly managed by general practitioners (GPs). Of the array of dyspepsia management guidelines, the closest to general practice, partly owing to proposing committee composition, are the European Society for Primary Care Gastroenterology (ESPCG) guidelines. METHODS: To evaluate variability in dyspepsia management among GPs in Padua and divergence in spontaneous prescriptive behaviour from the ESPCG dyspepsia guideline, we prospectively studied the behaviour of 39 GPs over a 3-month period of outpatient activity, through questionnaires on each consultation. Test-group representativeness was preliminarily defined in terms of antisecretory drug expenditure. RESULTS: 1790 forms on dyspepsia-related consultations were studied in a population of 51,193 registered patients; 1264 patients with a history of dyspeptic pathology consulted their GP (19% duodenal ulcer (DU), 9% gastric ulcer (GU), 54% gastro-oesophageal reflux disease (GERD), 32% non-ulcer dyspepsia (NUD), 1% cholelithiasis), while 526 patients presented with symptoms of dyspepsia with no previous gastroscopy (EGDS) (42% were aged <45 years), of whom 42% had twice consulted their GP. Empirical management by prescription of symptomatic drugs was the most common procedure in DU (33%), GU (73%) and NUD (74%) relapses. Helicobacter pylori eradication therapy was prescribed in only 2% of patients with a history of organic or functional dyspepsia. 145 patients with uninvestigated dyspepsia were referred for second-level endoscopy and 43 for H. pylori testing. Forty-four percent of endoscopies prescribed for uninvestigated patients did not comply with the ESPCG guideline; full compliance would have determined a 105% rise in endoscopies. Prescriptive variability between GPs was high (based on the Goodman-Kruskal (0.41, P < 0.001) and Cramer tests (V = 0.51, P < 0.005)) and agreement between observed and expected prescriptions according to ESPCG criteria was as low as V = 0.11. On the basis of the most frequently observed behaviours, we developed three options of the ESPCG guideline and compared them to spontaneous prescriptions. CONCLUSIONS: Highest compliance emerged where the clinical approach for all patients with uninvestigated dyspepsia was symptomatic therapy at first presentation followed by a different attitude at second presentation, setting a higher cut-off age than in the guideline (which in our case proved, on mathematical calculation, to be 55 years).

The visuo-cognitive and motor effect of amantadine in non-Caucasian patients with Parkinson's disease. A clinical and electrophysiological study.

It has been reported that non-Caucasian populations often suffer from an atypical type of Parkinson's disease (PD) characterized by poor levodopa response, early cognitive impairment and autonomic dysfunction. We tested the effect of a well known antiparkinsonian compound, amantadine, in 23 Afro-American patients with PD in a time-limited (six months), open-label, clinical and electrophysiological (simultaneously recorded primary and cognitive visual evoked potentials) trial. Patients were given amantadine either as monotherapy (first group) or added to levodopa treatment (second group). Amantadine produced a significant (p < 0.05) shortening of the latency of the event related potential (P300) obtained in a visual discrimination paradigm, while the timing of primary visual evoked potentials was little or not at all affected. Amantadine also showed significant beneficial effects (p < 0.01) on the motor score of both groups as assessed by the Rated Parkinson's Disease Neurological Exam, including items related to autonomic dysfunction. These findings suggest that amantadine alone and as adjuvant to levodopa can significantly improve both the speed of visual cognitive processing and the clinical score in non caucasian patients with PD. For these populations amantadine can be thus considered a helpful therapeutical option.

Time dynamics of stimulus- and event-related gamma band activity: contrast-VEPs and the visual P300 in man.

OBJECTIVES: To investigate the time dynamics and phase relationship with the stimulus of the onset/offset visual evoked potentials (VEPs), P300 and gamma band oscillatory responses to visual (contrast) stimulation. Gamma band oscillatory activity mediates in sensory and cognitive operations, with a role in stimulus-related cortical synchronization, but is reportedly reduced in the time window of the P300 response. METHODS: Ten healthy volunteers were studied. VEPs and P300 were obtained in a stimulus condition combining standard contrast stimulation and a visual odd-ball paradigm. Visual stimuli were gratings with a sinusoidal luminance profile (9.0 degrees central retina; 1.3 cycles/degree; 70% contrast) that were presented monocularly in onset/offset mode, with vertical orientation (frequent stimulus; 80%) or with a 15 degrees rotation to the right (infrequent, target stimulus). The total signal activity (temporal spectral evolution), the activity phase-locked to the stimulus onset (rectified integrated average), and the 'locking index' (ratio of the activity phase-locked to the stimulus to the total signal activity) were computed over time and across frequencies on the signals recorded at occipital (visual responses) and central locations (P300). RESULTS: Oscillatory activity centered around approximately 20.0-35.0 Hz and phase-locked to the stimulus was recorded at occipital locations with time dynamics anticipating the conventional VEPs. Phase-locking was higher after frequent than in response to target stimuli and after the stimulus offset compared to onset, while the phase-locking of the VEP frequency components was higher after the stimulus onset. The low frequency components of the P300 recorded at Cz (below approximately 8.0-10.0 Hz) were almost totally phase-locked to the stimulus, while the gamma band activity at the P300 location did not vary over time in amplitude or phase-locking and was mostly non-locked to the target stimulus. CONCLUSIONS: These observations add to the evidence of a role of the gamma band oscillatory responses (centered at approximately 20.0-35.0 Hz) in visual information processing and suggest that the increment in gamma band activity during cognitive operations also depends on task characteristics, vigilance or selective attention, and brain functional state. The visual P300 appears to reflect low frequency synchronization mechanisms.

Leber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases.

The previously unrecognised association of myoclonus in two patients with LHON with the 11778/ND4 pathogenic mutation is described. EEG failed to disclose epileptic figures, and a back averaging study suggested that myoclonus was cortical in origin in both patients.

Ocular myasthenia mimicking a one-and-a-half syndrome.

A 52-year-old patient developed an eye movement disorder first resembling a left internuclear ophthalmoplegia and subsequently a "one-and-a-half syndrome" as the presenting symptoms of ocular myasthenia gravis. No accompanying myasthenic features were present except for the fluctuation in the amplitude of dissociated nystagmus. This patient shows that an oculomotor disorder considered a typical pontine lesion may instead be caused by myasthenia gravis, even in the absence of other clinical and electrophysiologic features of neuromuscular deficit.

Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: How valid is the GABAergic hypothesis?

Acquired nystagmus occurs frequently in patients with multiple sclerosis and is often the cause of illusory motion of the environment (oscillopsia), and blurring of vision. Based primarily on the beneficial effect of gabapentin on acquired pendular nystagmus (APN), a GABAergic mechanism in controlling nystagmus has been hypothesised. If increasing GABA concentrations in the CNS are critical for the treatment of nystagmus, then a selective GABAergic drug should be highly successful. However, as gabapentin is not a selective GABAergic agent, vigabatrin, a "pure" GABAergic medication, and gabapentin, were compared in a single blind cross over trial in eight patients with definite multiple sclerosis. Patients were randomly assigned to begin with gabapentin (1200 mg daily) or vigabatrin (2000 mg daily). Neuro-ophthalmological and electro-oculographic (EOG) evaluations were performed four and three times, respectively. Treatment efficacy was based on improving visual acuity and EOG indices (amplitude or frequency of nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects. In the remaining five patients gabapentin improved symptomatic pendular or gaze evoked jerk nystagmus in four. Three patients decided to continue gabapentin therapy. Importantly, vigabatrin proved useful in only one out of five patients, suggesting that gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action. Interaction with cerebral glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of gabapentin.

Parkinson's disease changes the balance of onset and offset visual responses: an evoked potential study.

OBJECTIVES: We investigated whether the transient pattern onset and offset visual evoked potential (VEP) can distinguish between patients with Parkinson's disease (PD) and normal subjects. METHODS: Two horizontal sinusoidal gratings differing in spatial frequency, i.e. 1 and 4 cycles per degree, were presented to 17 patients with PD and 16 age-matched control subjects. We analyzed the responses in the time-domain and measured the latencies and amplitudes of N1 and P1 to the onset and the offset of the stimulus; we also derived the measures of offset N1 and P1 amplitude responses 'normalized' to onset N1 and P1 amplitude values, respectively (amplitude ratios). RESULTS: Absolute and normalized offset P1 amplitude is a distinguishing feature of PD patients from controls. Offset P1 amplitude was significantly larger in PD patients than in controls, particularly to the lower spatial frequency stimulus (P<0.01 for absolute and P<0.001 for normalized values, respectively). CONCLUSIONS: We conclude that the pattern onset/offset VEP amplitude provides a simple measure to evaluate visual processing deficits in PD and could contribute to an understanding of the pathophysiology of these changes.

Transferring patients for direct coronary angioplasty: a retrospective analysis of 135 unselected patients with acute myocardial infarction.

BACKGROUND: Direct coronary angioplasty (PTCA) represents the most effective treatment for acute myocardial infarction. However, only a minority of patients are initially admitted to hospitals with direct PTCA facilities available 24 hours daily. The safety and benefits of transfer direct PTCA are debated, and we have no data about the early return of patients to the admission hospital. METHODS: We report our experience with transfer direct PTCA in unselected patients with acute myocardial infarction, and the early post-procedural return to the referring hospitals. RESULTS: One hundred and thirty-five unselected patients with acute myocardial infarction were referred to our center for direct PTCA during 1998. The majority of patients (n = 93, 69%, group T) were initially admitted to a primary hospital whereas the rest (n = 42, 31%, group NT) were directly admitted to our hospital. One hundred and thirty-four patients underwent coronary angiography, and direct PTCA was attempted in 126 patients. The median time interval between admission and direct PTCA was higher in group T (60 vs 40 min, p < 0.001). Only 3 patients (3.2%) had severe complications during transfer to our center: 1 patient with cardiogenic shock died, and 2 patients had ventricular fibrillation. The procedural and in-hospital outcomes of both groups were similar. The early post-procedural transfer to the referring hospital was possible in 88% of patients; no complications occurred during the transfer. The incidences of cardiac mortality at 6 months and at long-term follow-up were 3.4 and 5.1% respectively. CONCLUSIONS: In our experience, interhospital transfer for direct PTCA in unselected patients with acute myocardial infarction is feasible and safe. The early return to the admission hospital is safe and does not negatively influence the in-hospital outcome.

Gabapentin as treatment for hemifacial spasm.

Hemifacial spasm, a life-long condition characterized by involuntary unilateral contractions of the facial muscles, is a disabling disorder often resulting in patient irritation and social embarassment. Its probable etiology is neurovascular compression of the facial nerve at its root exit zone. The current medical treatment consists of either baclofen or anticonvulsant drugs, with limitation due to side effects or low efficacy. In recent years botulinum toxin injection and microvascular decompression of the facial nerve have been shown to be highly successful. However, both procedures share some complications and require special techniques. We present 5 patients affected by hemifacial spasm who responded well to the novel anticonvulsant drug gabapentin. Gabapentin was administered at a dose ranging from 900 to 1,600 mg daily, with rapid and clear improvement of spasms and absence of any remarkable adverse effects. Our findings suggest that gabapentin may be an effective treatment for patients with hemifacial spasm with a very good ratio of therapeutic effects to side effects when compared with other drugs currently used.

Chlamydia pneumoniae antibody response in patients with acute myocardial infarction and their follow-up.

STUDY POPULATIONS: This study concerned the possible relations between seroreactivity to Chlamydia pneumoniae and myocardial infarction. A group of 29 patients with acute myocardial infarction (AMI), 74 members of a healthy control group, and a subgroup of 24 members of a healthy control group matched for age, sex, and coronary risk factors (HCM) were included in the study. In addition, we evaluated the AMI group in a 1-year patients' follow-up study. We used two different tests to detect anti-C. pneumoniae antibodies: recombinant enzyme immunoassay antilipopolysaccharide antibodies and a reference microimmunofluorescence test. RESULTS: High titers of C. pneumoniae microimmunofluorescence antibodies were found in 89.65% of the AMI group and in 25% of the HCM group (p = 0.0000065). Immunoglobulin A-microimmunofluorescence was 51.72% in the AMI group and 20.83% in the HCM group (p = 0.0042). Immunoglobulin G and immunoglobulin A antilipopolysoccharide titers were 65.51% and 62.60% in the AMI group and 20.83% in the HCM group, respectively (p = 0.006). High concentrations of interleukin-6 were found in 86.20% of our AMI group (p value = 54.38 pg/ml) when compared with the control group. A good correlation between interleukin-6 levels and immunoglobulin A-lipopolysaccharide titers (r = 0.658) was found. CONCLUSION: The presence of a high prevalence rate and high titers of immunoglobulin G and immunoglobulin A-specific anti-C. pneumoniae antibodies in AMI at admission demonstrated the presence of a specific anti-C. pneumoniae immunization in the AMI population.

Visuo-cognitive dysfunctions in Parkinson's disease.

Loss of will, decreased activity, and poverty of behavior are among the common symptoms observed in Parkinson's disease (PD). In line with these clinical observations, PD patients display prominent deficit in neuropsychological tests, requiring self-generated and effort-demanding operations. However, recent evidence suggests that this impairment is not generalized: visuo-spatial working memory and attentional set-shifting seem to be selectively impaired in the early stages of the disease. Electrophysiological studies also demonstrate the dysfunction of higher-level visual information processing. In this article, we discuss some current results to show the connection between clinical symptoms and neuropsychological deficits. We also consider dysfunction in underlying neural mechanisms, with particular emphasis on the dysregulation of fronto-striatal circuits. However, it is conceivable that visuo-cognitive impairment in PD reflects dysfunction of neural assemblies, involving basal ganglia, dorsal visual stream, and frontal-prefrontal circuits.

[Anti-Chlamydia pneumoniae antibodies and production of interleukin 6 in acute myocardial infarct]. / Anticorpi anti Chlamydia pneumoniae e produzione di interleuchina 6 nell'infarto miocardico acuto.

UNLABELLED: Chlamydia pneumoniae (C.p.) has been correlated with acute myocardial infarction (AMI). High levels of anti-C.p. antibodies and circulating immune complexes containing C.p. lypopolyaaccharide (LPS) antigens have been demonstrated in AMI. LPS antigen and especially Chlamydial LPS is one of the best antigen and it is also a very good Interleukin inductor. Moreover, interleukin 6 (IL-6) has been observed in AMI patients. The aim of our study was to assess the possible relationships between anti-C.p. immune response and IL-6 production in AMI patients. We studied 17 consecutive patients with myocardial infarction (12 males and 5 females; mean age 62; range 46-72). Blood samples were obtained immediately after hospital admission. There were 17 control subjects (HCM) (mean age 62; range 45-72) who were matched for the main coronary risk factors (gender, age, diabetes, hypertension, hypercolesterolemia, smoking, family history of ischemic heart disease). In addition, we evaluated the AMI patients in a one-year follow-up study (FU). RESULTS: High levels of C.p. IgG MIF were found in 82.3% of our AMI patients and in 29.4% of HCM subjects (p = 0.0000065). IgA-MIF were 70.5% in AMI patients and 29.4% in HCM (p = 0.0042). High levels of C.p. IgG and IgA anti-LPS were found, with a very high prevalence rate of 76.4% and 64.7% in AMI patients, and both rates were 47.0% (p = 0.158; p = 0.489) in HCM. Very high levels of IL-6 were found (m = 54.38 pg/ml) in 100% of the AMI patients (normal values in our population: 0-10.86 pg/ml) and only detectable levels in 5.8% of HCM. A good linear correlation was demonstrated between IL-6 and IgA levels in the first sample (r = 0.655). The high levels of anti-C.p. IgG, IgA and IL-6, with a good correlation between IL-6 and IgA levels, may confirm the presence of an active infection and probably of a reinfection.

Electrophysiological evidence for visuocognitive dysfunction in younger non Caucasian patients with Parkinson's disease.

A study of "primary" (VEPs) and "cognitive" (ERPs) visual evoked potentials was carried out in a group of non-demented Afro-American Parkinson's disease (PD) patients. Current studies suggest that differences exist in the clinical manifestations of PD in Caucasian and non-Caucasian populations. Two horizontal sinusoidal gratings differing in spatial frequency, i.e., 1 and 4 cycles per degree (cpd), were presented in an "odd-ball" paradigm to 17 patients with PD and 17 age-matched control subjects. While the 1 cpd stimulus, is not expected to reveal retinal dopaminergic deficency, but only visuocognitive deficits, the 4cpd may give direct information of both "retinal" and "cognitive" visual deficits. We measured the latencies and amplitudes of N70, P100 and P300 components, and derived the "normalized" measures of P300-N70 latency difference (Central Processing Time-CPT70), the P300-P100 latency difference (CPT100) and the P300 amplitude responses normalized to either N70 and P100 amplitude (Amplitude Ratios AR70 and AR100). Our results do show that cognitive electrophysiological deficits in younger PD patients exist in non-Caucasians, perhaps to an even greater degree than in Caucasians, and confirm that absolute and normalized ERP amplitude and latency abnormalities are a distinguishing feature of younger PD patients from controls. In particular P300 measures are abnormal for 1 cpd pattern. A negative correlation exists between P300 amplitude and the motor score. By comparing the results for 1 and 4cpd stimuli it can be concluded that "primary" and "cognitive" visual abnormalities are independently affected in PD, implying that visuo-cognitive abnormalities are not passively determined by retinal dopaminergic deficiency.