Dacia Dalla Libera

Myeloid microvesicles are a marker and therapeutic target for neuroinflammation.

Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive microglia/macrophages release MVs in vitro. The aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS).

Microglia convert aggregated amyloid- β into neurotoxic forms through the shedding of microvesicles

Alzheimer’s disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes

Background: Growing evidence suggests that vitamin D deficiency may be one of the most important environmental factors for the development of multiple sclerosis (MS). Objectives: The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients with clinically isolated syndromes (CIS) and to examine whether they are related to MS risk. Methods: This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital, Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. Results: A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17 years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91–4.96) and 1.61 (0.85–3.03), respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This association was even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)D levels < 10th and 25th percentiles: 3.34 (1.32–8.45) and 2.04 (0.96–4.36), respectively). Conclusion: Low serum vitamin D is associated with increased MS risk in patients with CIS.

T Regulatory Cells Are Markers of Disease Activity in Multiple Sclerosis Patients

FoxP3+ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.

Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease.

We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ability to produce toxic amyloid β1–42 (Aβ1–42) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI).

Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning

Natalizumab discontinuation is a frequent clinical practice, mainly as part of the progressive multifocal leukoencephalopathy (PML) risk management strategy, but this approach has raised concerns about the possible consequences related to subsequent multiple sclerosis (MS) reactivation. Preliminary results of a randomized prospective trial1 and observational studies yielded conflicting results (Table 1).2-9 We report the case of 16-year-old woman who in December 1996 developed relapsing–remitting MS with acute-onset lower limb paraesthesia followed by four relapses in the subsequent 10 months. Interferonbeta 1a therapy was initiated, but in the following years she had six new relapses and in July 2002 was enrolled in the SENTINEL study (natalizumab plus interferon beta 1a).2 At that time, she had mild disability (Expanded Disability Status Scale (EDSS) 2.0) and the pre-treatment brain MRI performed in June 2002 showed six gadolinium (Gd)-enhanced lesions. During natalizumab treatment, no clinical or radiological relapses occurred but in February 2005, after 31 Letter 492246 MSJ0010.1177/1352458513492246Multiple Sclerosis JournalMartinelli et al. 2013

Delayed Diagnosis in Pediatric Headache: An Outpatient Italian Survey

(Headache 2011;51:1267‐1273)

Parry Romberg Syndrome associated with chronic facial pain

Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.

Migralepsy: a new case confirming the existence of this migraine complication and proposing therapy

We describe the case of a 43-years-old, right handed woman, who suffered from migraine with aura and epilepsy. Co-morbidity of migraine and epilepsy is a well known condition since more than 100 years ago [1]. Although it is a rare phenomenon, migraine attack may trigger an epileptic seizure. ICHD II (International Classification of Headache Disorders) [2] classified migralepsy (migraine triggered seizures) as a complication of migraine (coded 1.5.5) if two diagnostic criteria are fulfilled: (1) migraine fulfilling diagnostic criteria for coded 1.2 migraine with aura and (2) a seizure fulfilling diagnostic criteria for one type of epileptic attack developing during or within 1 hour of a migraine aura. Despite the fact that the term migralepsy (attributed to Lennox and Lennox) [3] was coined in 1960 both to define an ‘‘ophtalmic migraine with perhaps nausea and vomiting followed by symptoms characteristics of epilepsy’’ and to describe three specific cases, the migraine-epilepsy sequence (migralepsy) seems to be less common than epilepsymigraine (hemicrania epileptica coded 7.6.1) and post-ictal headache (coded 7.6.2). A review of the literature suggested that migralepsy as coded by ICHD II is quite infrequent but not indeed inexistent [4]. A 43-years-old woman referred to the ER Department of San Raffaele Hospital, Milano, because of a generalized tonic seizure. She was born full term with a normal delivery and had normal developmental milestones. She has a family history positive for migraine with aura (mother) but no family member suffered from epilepsy. At age 9 years she developed migraine with visual and sensitive aura. Aura consisted of flickering flashing lights, developing gradually in 15 min with a global duration of 45 min, followed by sensitive symptoms (paresthesia of hand and face) and finally by headache with migraine features (frequency of 1 attack/month in the past; in the last months they rapidly increased to 8 attacks/month). In 21 September 2011, at 10:30 a.m. she experienced her typical visual aura (photopsia) for 15 minutes. After few minutes she noted the appearance of clonic palpebral movements in her right eye. She eventually lost consciousness, felt to the ground and had a generalized seizure (lasting 5 min). She was rapidly admitted at the Hospital, being unresponsive and confused during the transport. At Neurological examination (11:30 a.m.), patient was responsive to pain stimulus with no other signs. At general examination, blood pressure was 140/80, Heart rate 98 and O2 saturation 96 %. A slight metabolic acidosis was detected at blood gas analysis. Brain CT scan (12:00) was normal. She was treated with Diazepam i.v. (10 mg). A second neurological examination (1:30 p.m.) was normal, but patient reported the onset of a severe migraine attack (9/10 VAS) localized on the left parietal and temporal side with nausea, vomiting and photo-phonophobia. EEG (2:30 p.m.) revealed epileptiform discharges in right temporal hemisphere. Brain MRI was normal and when she performed EEG again, a normalization of the previously described epileptiform features was noted, with only residual theta slowing over the left hemisphere. A therapy with topiramate was started at the initial dose of 50 mg (after one week the dose was increased to 100 mg). At follow-up (3 and 6 months), she reported only three migraine attacks without aura in the first month of therapy (VAS 5/10) and no more migraine with aura attacks or epileptic seizures. EEG was normal. B. Colombo D. Dalla Libera (&) M. A. Volontè F. Spagnolo G. Dalla Costa V. Martinelli G. Comi Department of Neurology, San Raffaele Hospital, Vita-Salute University, Via Olgettina 48, Milan, Italy e-mail: dallalibera.dacia@hsr.it

Headache therapy with neuronal stabilising drugs

Migraine is a frequent episodic condition that often requires prophylaxis treatment to reduce the severity, frequency and duration of attacks and to ameliorate disability. Migraine can be interpreted as a disorder of pain modulation, which involves the trigeminovascular system and central nervous system modulation of paincontrolling structures. Antiepileptic drugs (neuronal stabilising drugs, NSD) have been increasingly recommended for migraine prophylaxis because of several well conducted studies confirming their efficacy. Valproate, Topiramate and Gabapentin are indicated as useful drugs for migraine preventive therapy according to the results of randomised double-blind, placebo-controlled trials. Due to these positive results, neuronal stabilisation may be considered as a pivotal approach for headache therapy.