Michele Romoli

Triptans and CGRP blockade – impact on the cranial vasculature

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.

Magnetization transfer MRI in dementia disorders, Huntington's disease and parkinsonism.

Magnetic resonance imaging is the most used technique of neuroimaging. Using recent advances in magnetic resonance application it is possible to investigate several changes in neurodegenerative disease. Among different techniques, magnetization-transfer imaging (MTI), a magnetic resonance acquisition protocol assessing the magnetization exchange between protons bound to water and those bound to macromolecules, is able to identify microstructural brain tissue changes peculiar of neurodegenerative diseases. This review provides a report on the MTI technique and its use in the dementia disorders, Huntingtons disease and parkinsonisms, comprehensive of the predictive values of MTI in the identification of early-phase disease.

Stopping onabotulinum treatment after the first two cycles might not be justified: Results of a real-life monocentric prospective study in chronic migraine

Introduction Onabotulinum toxin A (OnabotA) cyclic treatment is approved for the prophylactic treatment of chronic migraine (CM), a highly disabling disorder. Although treatment response varies among patients, current guidelines suggest to stop treatment after cycle 2 if no response is achieved. This prospective study aimed to define, in real-life setting, the evolution of the response to OnabotA over five cycles of treatment among patients non-responding to cycle 1. The results of this study might help in decision-making, in particular whether prosecuting OnabotA further or not, when facing a patient not responding to cycle 1. Methods Patients failing to respond at cycle 1 were recruited to complete five cycles. Key outcomes were: (i) a ≥50% reduction in headache days, (ii) a ≥50% reduction in total cumulative hours of headache on headache days and (iii) a ≥5-point improvement in Headache Impact Test-6 (HIT-6) scores. Results Overall, 56 patients were included. Mean age was 45.7 years (female 83.9%). Severe (≥60) HIT-6 score was reported at baseline by 95.8% of patients. Responders (headache days reduction of more than 50%) progressively increased cycle after cycle, doubling from cycle 2 to cycle 5 (from 27 to 48%). In addition, patients regressed from CM to episodic migraine moving on with each cycle, with 78% of them reaching less than nine migraine days/month after cycle 5. The headache days per month decreased significantly from cycle 1 to cycle 5 (overall from 23.3 ± 5.7 to 9.2 ± 3.6; p < 0.001). During 12 months (5 cycles), migraine days per month progressively abated (from 18.5 to 8.7; p < 0.001), days with symptomatic medications intake/month consistently decreased (from 17.4 to 8.1; p < 0.001), and mean HIT-6 score lowered (from 72.4 ± 5.7 to 50.2 ± 4.3; p < 0.001). Conclusion The positive effect of OnabotA treatment spreads over the course of the treatment and might also manifest late in treatment course among patients with no benefit after the first two cycles. Thus, the results of this real-life study suggest to extend OnabotA treatment further, beyond cycle 2, to avoid premature withdrawal in patients who would have become responders at cycle 3, 4, or 5.

Antiepileptic drugs in migraine and epilepsy: Who is at increased risk of adverse events?

Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered.

Neuropsychiatric adverse events of antiepileptic drugs in brain tumour-related epilepsy: an Italian multicentre prospective observational study

We assessed the prevalence and magnitude of neuropsychiatric adverse events (NPAEs) associated with antiepileptic drugs (AEDs) among patients with brain tumour‐related epilepsy (BTRE).

Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

Objective: To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations. Methods: Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel. Results: The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism. Conclusions: KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

Genotype-phenotype correlation of F484L mutation in three Italian families with Thomsen myotonia

Myotonia congenita (MC; Mendelian Inheritance in Man [MIM] #118425) is a nondystrophic skeletal muscle disease characterized by muscle stiffness. The phenomenon of myotonia is the main clinical manifestation. It is due to diminished activity of the voltage-gated chloride channel ClC-1, which contributes up to 80% of the resting membrane conductance in normal skeletal muscle. The disease segregates as both autosomal dominant Thomsen myotonia (MIM #160800) and autosomal recessive Becker myotonia (Becker disease; MIM #255700). The age of onset is variable and may be as late as the third or fourth decades of life. Loss-offunction mutations in the CLCN1 gene (chloride channel voltage-sensitive 1 gene; OMIM*118425) located on 7q35, are the primary contributors to the pathogenesis of MC. Myotonia-causing mutations are scattered over the entire sequence of the channel protein. Clinical and electrophysiological data can be sufficient to establish the diagnosis; however, they cannot allow one to distinguish between the recessive and dominant forms. Thus inheritance and genotype-phenotype correlations are difficult to elucidate without the possibility to compare many patients and families who share the same mutation. Moreover, there are reports of evident phenotypic heterogeneity, even among relatives who carry the same mutation.

Selective basal ganglia vulnerability to energy deprivation: Experimental and clinical evidences

HighlightsIntrinsic and extrinsic factors participate in basal ganglia peculiar vulnerability to toxic and ischemic damage.Vascular network represents the main extrinsic factor, with lack of anastomoses between 2nd order branches leading to terminal microvascular supply.Glutamate receptor subunit expression, poor calcium homeostasis, and dopamine‐glutamate interplay are key intrinsic factors for vulnerability.Exposure to toxic and ischemia leads to specific damage of basal ganglia structures, with peculiar neuroimaging findings. ABSTRACT The basal ganglia (BG) include structures pivotal for motor and cognitive functions. Such structures are affected in neurodegenerative disorders and toxic or ischemic insults. The peculiar vulnerability of BG to toxic and ischemic damage has been the focus of preclinical research for all over the last century. This comprehensive review collects all evidences supporting a specific susceptibility of BG to energy deprivation, highlighting the pathways through which neuronal survival is jeopardized, and the consequent clinical correlates. In particular, we addressed intrinsic and extrinsic factors participating in BG neuronal vulnerability. The terminal blood supply, the main extrinsic factor, is crucial to the low threshold for hypoxic hazard. Specific, the lack of anastomoses between second and third order branches represents the frailty of an archaic terminal network, unable to guarantee collateral supply and resistance to oxygen deprivation. In addition, BG neurons survival is jeopardized by several intrinsic molecular factors. Among them, the subunit composition of ionotropic and metabotropic glutamate receptors, the impairment of mitochondria, the deficit in neurotransmitter clearance, the poor control of intracellular calcium homeostasis and the glutamatergic‐dopaminergic pro‐excitotoxic interplay, all play a significant role. Intrinsic and extrinsic factors represent two faces of the same coin, producing excitotoxic damage and poor ability to deal with energy deprivation. The clinical correlates of BG vulnerability are represented by ischemic lesions, such as striatocapsular infarcts and lacunar infarcts, and local toxic‐induced damage, mainly associated with energy production impairment, due to carbon monoxide, cyanide and manganese.

Intravenous thrombolysis in stroke after dabigatran reversal with idarucizumab: case series and systematic review

Idarucizumab can reverse the effect of the direct thrombin inhibitor dabigatran,1 a non-vitamin K oral anticoagulant (NOAC) available for primary and secondary prevention of cardioembolic stroke due to non-valvular atrial fibrillation. Ischaemic stroke may happen despite ongoing anticoagulation, a contraindication to intravenous thrombolysis (IVT).2 Thus, patients with ischaemic stroke while on dabigatran might be eligible for anticoagulation reversal with idarucizumab to allow IVT. Here, we report our case series and provide a systematic review to define outcomes of such treatment algorithm. Case series of patients undergoing IVT after dabigatran reversal was identified from our stroke registry (online supplementary file 1). Systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines3 and specified protocol (PROSPERO: http://www.crd.york.ac.uk/PROSPERO, registration no. CRD42017060274) (online supplementary file 2). Search strategy, performed on Cochrane Library, MEDLINE, EMBASE and PubMed, can be found in online supplementary file 1. ### Supplementary data [jnnp-2018-318658-supp1.pdf] ### Supplementary data [jnnp-2018-318658-supp2.pdf] ### Data extraction and outcome assessment All available data were collected (online supplementary file 1). According to National Institute of Health Stroke Scale (NIHSS) total score, stroke were divided into mild (1–4), moderate (5–15), moderate to severe (16–20) and severe (21–42 4). Unfavourable outcome was defined as an increase in NIHSS score or death. Additional outcomes included modified Rankin Scale (mRS) at follow-up, symptomatic intracerebral haemorrhage, systemic bleeding, allergic reactions to idarucizumab, recurrent stroke and venous thrombosis during post-acute phase. ### Statistical analysis Statistical analysis was performed with R software using …

Migraine and cluster headache – the common link

Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.