U. Del Carro

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4+CD69−CD25+Foxp3+) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

Recommendations for the management of urinary disorders in multiple sclerosis: a consensus of the Italian Multiple Sclerosis Study Group.

Urinary disorders are uncommon in the initial phases of multiple sclerosis, but increase in frequency as the disease progresses, with a negative impact on quality of life. The goal of this study was to propose a protocol for the diagnosis and treatment of urinary disorders in multiple sclerosis, based on data from the scientific literature and the experience of Italian clinical centres. In particular, the following clinical aspects were considered: what to do with patients with asymptomatic multiple sclerosis; what to do with symptomatic patients; how and when to perform a second-level diagnostic evaluation; and how to treat urinary disorders. A diagnostic–therapeutic algorithm is proposed, that can be applied in Italian clinical centres.

Atypical hereditary neuropathy with liability to pressure palsies (HNPP): the value of direct DNA diagnosis.

We report two patients with suspected hereditary liability to pressure palsies. Neurophysiological studies showed a mixed axonal-demyelinating sensory-motor polyneuropathy with focal slowing of conduction velocities at the common sites of entrapment. Morphological studies on sural nerve biopsy from the proband showed active axonal regeneration without typical tomacula. Molecular analysis confirmed the presence of a deletion of chromosome 17p11.2 in both patients. Our observation confirms the heterogeneity of hereditary liability to pressure palsies and the relevance of DNA testing for the diagnosis of this hereditary neuropathy.

Cortical activation to voluntary movement in amyotrophic lateral sclerosis is related to corticospinal damage: Electrophysiological evidence

OBJECTIVES The time course of mu and beta sensorimotor rhythms, with event-related desynchronisation (ERD) to preparation and execution of voluntary movement followed by synchronisation (ERS) after movement, is considered to indicate cortical activation and idling, respectively. We investigated ERD and ERS in amyotrophic lateral sclerosis (ALS) patients and the relationship with anatomical and neurophysiological measures of corticospinal tract damage. METHODS Pre-movement mu and beta ERD, and post-movement beta ERS were analysed in 16 ALS patients and 15 healthy controls performing self-paced brisk right thumb extensions. Apparent diffusion coefficient (ADC) of corticospinal tract was measured with magnetic resonance imaging (MRI). Motor-evoked potentials (MEPs) to the right abductor pollicis brevis were obtained using transcranial magnetic stimulation (TMS). RESULTS Movement-related electromyographic activity was similar in the two groups. Post-movement ERS was significantly reduced in ALS group and negatively correlated with the amount of corticospinal damage as from MRI and TMS measures. ERD did not significantly differ between groups. CONCLUSIONS Alterations of cortical activity in ALS patients were limited to the post-movement phase, as indicated by reduced ERS, and could be linked to reduced cortical inhibition rather than to generalised hyperexcitability. SIGNIFICANCE The correlation between ERS and corticospinal damage severity might be interpreted as a functional compensation or dysfunction of inhibitory systems paralleling corticospinal damage.

Acute myelopathy selectively involving lumbar anterior horns following intranasal insufflation of ecstasy and heroin

We report a patient who developed acute myelopathy after intranasal insufflation of amphetamines and heroin. The functional prognosis was very poor; after 4 months, she remained paraplegic. MRI imaging showed selective T2 hyperintensity and intense enhancement confined to the spinal anterior horns and lumbar nerve roots and plexus. This unique MRI pattern, together with neurophysiological data, suggests that the pathological process at the first primary affected spinal anterior horns (SAH), conditioning motoneuron cell death, and then nerve roots and lumbar plexus as a consequence of wallerian degeneration A 17-year-old girl was admitted to the emergency department in a drowsy state and unable to walk after an overdose of intranasal insufflated heroin and amphetamines. After a few hours, drowsiness progressed to stupor, and progressive weakness in all four limbs, mainly involving the lower limbs, developed. At that time, laboratory data showed massive rhabdomyolysis (creatine phosphokinase 36 880 mg/dl) with acute renal failure (ARF), and hepatic failure; medical therapy was promptly started. The patient’s past medical history was unremarkable except for habitual use of amphetamines (ecstasy) and cannabinoids since the age of 12 years. The previous week she had insufflated heroin about once a day; the previous night she reported a double dose of heroin consumption, and a high dose (approximately 1 g) of intranasal insufflation of amphetamines. The next day the …

P6.6 Effect of sensory tricks on brain excitability in cervical dystonia: TMS study

controls and remained so (except for CV) after DBS. The postoperative Low Frequency (LF) band was lower than the preoperative and the controls’ LF. A significant decrease in Total Power (TP) in the patients after the implantation as opposed to controls was also noted. Pre and post DBS values of High Frequency (HF) band and ratio LF/HF were not significant different. Conclusions: Unlike motor improvement, DBS does not offer a clear benefit to cardiovascular dysautonomia. The reduced postoperative LF, an index of sympathetic activity, might be explained by the LEDD reduction.

ID 214 – Optical coherence tomography and multifocal visual evoked potentials usefulness to detect visual pathway abnormalities in clinical practice

Objective Full-field visual evoked potentials (ff-VEP) are fundamental in neurological practice to define the nature of visual disturbances. We explored whether, in case of normal ff-VEP and suspected organic visual pathway involvement, multifocal visual evoked potentials (mf-VEP) and optical coherence tomography (OCT) can be useful in the diagnostic workup. Methods Observational case reports. Results Three patients arrived at our department for visual disturbances. Two had relapsing optic neuritis (ON) and visual acuity (VA) loss, with normal or non-significant ff-VEP outside acute clinical episodes. In both cases OCT showed a retinal nerve fiber layer (RNFL) thickness reduction, allowing visual pathway damage identification. The third, with meningioma involving left optic nerve, complained of blurred vision in the nasal field of the left eye as confirmed by computerized perimetry (CP). While ff-VEP showed normal latency and non-significant amplitude reduction in the left eye, mf-VEP showed important amplitude reduction in the whole lower left eye field. OCT scan confirmed axonal damage showing left RNFL thinning. Conclusions Sometimes ff-VEP fails in identifying abnormalities in patients with processes involving the visual pathway, particularly in cases with axonal or sectoral optic nerve involvement. We suggest the importance of a multimodal evaluation, including OCT and mf-VEP.

13. Optical coherence tomography and multifocal visual evoked potential clinical usefulness in identifying visual pathway involvement

Full-field visual evoked potentials (ff-VEP) are fundamental in neurological practice, for defining the nature of visual disturbances. We explored whether, in case of normal ff-VEP and suspected organic visual pathway involvement, multifocal visual evoked potentials (mf-VEP) and optical coherence tomography (OCT) can be useful in the diagnostic workup. Observational case reports on 3 patients presenting with visual disturbances. Two had relapsing optic neuritis (ON) and visual acuity (VA) loss, with normal or non-significant ff-VEP outside acute clinical episodes. In both cases OCT showed a retinal nerve fiber layer (RNFL) thickness reduction, allowing visual pathway damage identification. The third, with meningioma involving left optic nerve, complained of blurred vision in the nasal field of the left eye as confirmed by computerized perimetry (CP). While ff-VEP showed normal latency and non-significant amplitude reduction in the left eye, mf-VEP showed important amplitude reduction in the lower visual field of the left eye. OCT scan confirmed axonal damage showing left RNFL thinning. Sometimes ff-VEP fails in identifying abnormalities in patients with pathologic processes involving the visual pathway, particularly in cases with axonal or sectorial optic nerve involvement. We suggest the importance of a multimodal evaluation, including OCT and mf-VEP.

62. Sensory Tricks in cervical dystonia: A neurophysiological study with short latency afferent inhibition

A classic hallmark of cervical dystonia (CD) is the improvement of dystonic symptoms during a specific maneuver, defined ‘sensory trick’ (ST). Even if the mechanism by which ST improves dystonia is not well understood, it is likely that cortical sensorimotor integration processes are involved. In a previous preliminary study, we evaluated the short latency afferent inhibition (SAI) in a group of CD patients and the effects of ST on the SAI profile. To date, we have increased our sample including 28 patients with primary CD (18 with ST, CD+, and 10 without ST, CD-) and 11 controls. The analysis of variance showed no significant differences between CD- patients and controls. On the contrary, a remarkable trend toward a reduced SAI was observed in CD+ patients when they did not perform ST. Interestingly, SAI was further reduced in CD+ patients when they performed ST, reaching a strong statistical relevance. Our results show the presence of an abnormal sensorimotor integration in CD+ patients. Furthermore, they prove that ST acts by modulating the abnormal link between sensory input and motor output.

P573: Optical coherence tomography and visual evoked potentials in monitoring neural damage in multiple sclerosis

Background: In the assessment of visual pathway involvement in Multiple Sclerosis-MS, optical coherence tomography-OCT is used to measure retinal nerve fiber layer-RNFL thickness as a marker of axonal loss and visual evoked potentials-VEPs as an indicator of demyelination. However, no clear indications are available on their combined use in MS monitoring. We evaluated cross-sectional and longitudinal correlations and sensitivity of OCT and VEPs and their correlates with clinical and magnetic resonance imaging-MRI evidence of disease activity in a real-world clinical setting. Methods: 80 MS patients (13 clinically isolated syndrome-CIS, 55 relapsingremitting-RR, 9 secondary progressive-SP, 3 primary progressive-PP), age 36.7+9.7 years, disease duration 6.0+6.6 years, underwent neurological and neurophysiological evaluation with OCT and VEPs, with routine clinical and MRI monitoring for a mean period of 1 year. Additional OCT-VEPs follow-up was obtained in 50 patients. Results: While VEPs were more sensitive than OCT in eyes with recent (<3 months) optic neuritis-ON at baseline (80.0% Vs 6.7%, p=0.001), the two sensitivities were similar in chronic ON eyes (78.4%). Comparing eyes with and without previous ON, VEP latency and RNFL thickness were respectively significantly higher (131.2 ms Vs 118.8 ms, p=0.008) and lower (78.15 μm Vs 90.00 μm, p<0.001) in the first subgroup. No significant differences were found between the two subgroups when analyzing VEP latency and RNFL thickness evolution during the follow-up period. However, eyes with baseline recent ON had significant reduction in VEP latency (−15.3 ms) and RNFL thickness (−7,7 μm) at follow-up. No significant correlation was found between OCT-VEPs parameters and disease activity. Similar results were found when considering only RR and CIS patients. Conclusions: These results would exclude recommending OCT and VEPs as surrogate biomarkers in MS phase II clinical trials evaluating disease modifying drugs, even when focusing on relapsing form of MS. The main role for OCT and VEPs in short-to-medium term follow-up programs would consist in monitoring neural damage after acute ON. However, these findings cannot exclude the usefulness of these techniques for longer follow-ups and/or large phase III studies.