Cinzia Lucchesi

A clinical and laboratory study evaluating the profile of cytokine levels in relapsing remitting and secondary progressive multiple sclerosis.

The main aim of the study was to evaluate levels of cytokines IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-alfa, TGB-beta1 and IFN-gamma in 30 patients with relapsing remitting (RRMS) compared to 30 secondary progressive multiple sclerosis (SPMS) in a peripheral blood sample. Statistical analysis showed significant higher levels of IL-17 and INF-gamma, which are cytokines with pro-inflammatory properties, and lower levels of TGF-beta1, a molecule with immunosuppressant activity, in RRMS compared to SPMS. These results underline the existence of a different cytokines dysregulation in RRMS compared to SPMS phases with higher pro-inflammatory activity in RRMS.

Occipital neuralgia: a symptomatic case caused by an abnormal left vertebral artery

Occipital neuralgia is a condition defined by the International Headache Society [1] as a paroxysmal jabbing pain in the distribution of the greater or lesser occipital nerves or of the third occipital nerve; it is sometimes accompanied by diminished sensation or dysaesthesia in the affected area and it is commonly associated with tenderness over the nerve concerned. Diagnostic criteria include the following: paroxysmal stabbing pain, with or without persistent aching between paroxysms, in the distribution of the greater, lesser and/or third occipital nerves, tenderness over the affected nerve and pain temporarily eased by local anesthetic block of the nerve [1]. The greater occipital nerve is more frequently involved (90%) as compared to the nervus occipitalis minor (10%); in 8.7% both occipital nerves are responsible for the neuralgia [2]. Occipital neuralgia is typically referred as an idiopathic condition, although secondary etiologies must be ruled out; occipital nerves can be irritated by different conditions, in particular vascular, neurogenic, muscolar-tendinous, osteogenic and tumoral etiologies must be ruled out [3]. As far as vascular etiology concerns, fenestrated arteria vertebralis pressing on C1-C2 nerve roots and aberrant course of the vertebral artery have been reported as rare causes of occipital neuralgia [4, 5]. We report a symptomatic case of occipital neuralgia, caused by a left vertebral artery, appearing hypertrophic and shifted back at the level of the first and second cervical vertebrae. A 78-year-old woman presented with episodes of stabbing paroxysmal headache in the left occipital region, over the previous 4 months; pain was intermittent and sharp, described as jabbing, starting in the left suboccipital region at the base of the skull near the midline, involving the entire posterior and lateral scalp and occasionally radiating toward the vertex. Episodes progressively increased in frequency, reaching multiple attacks per day, so she referred to the Headache Centre of the Institute of Neurology, at Pisa University. Neurological examination was normal, no hypo or dysesthesia in the area of the greater or lesser occipital nerves was reported; pressure over the course of the greater occipital nerve evoked tenderness. Suspecting an occipital neuralgia, a non-enhanced brain MRI with particular attention to the craniocervical junction was performed. MRI examination showed a hypertrophic aspect of the left vertebral artery, that appeared shifted back at the level of the first and second cervical vertebrae (Fig. 1a, b). In the meanwhile a pharmacological treatment was started, in particular, because of the age and general conditions of the patient, before administering carbamazepine or oxcarbazepine, i.e. the first-line drugs for cranial neuralgias [6], the more tolerable pregabalin was tried. Pregabalin was tapered to a dose of 300 mg/daily, with consistent improvement in pain control, in particular attacks progressively decreased in frequency and pain remission was achieved after 1 month of treatment; the follow-up is still at 8 months and the patient is in treatment with pregabalin at the maintenance dose of 150 mg/daily, with good efficay and tollerability. A neurosurgical evaluation was performed and the hypertrophic and shifted back aspect of the left vertebral artery was considered as an anatomic variant, without pathological significance and, mainly the age of the patient and the good response to pregabalin, discouraged a surgical approach. C. Lucchesi (&) S. Gori Department of Neurosciences, Institute of Neurology, University of Pisa, Via Roma, 67, 56126 Pisa, Italy e-mail: cinzia.lucchesi@gmail.com

Evidences of Reduced Antioxidant Activity in Patients With Chronic Migraine and Medication-Overuse Headache

Migraine is a complex multifactorial, neurobiological disorder, whose pathogenesis is not fully understood, nor are the mechanisms associated with migraine transformation from episodic to chronic pattern. A possible role of impaired oxidative mitochondrial metabolism in migraine pathogenesis has been hypothesized, and increased levels of peripheral markers of oxidative stress have been reported in migraine patients, although the literature data are limited and heterogeneous.

Inferior rectus myositis: a rare cause of painful ophthalmoplegia and a therapeutic challenge

Idiopathic orbital myositis is a rare non-specific inflammatory disease primarily involving the extraocular eye muscles. It is included in the wide group of the idiopathic orbital inflammatory syndrome that after thyroid-associated orbitopathy and lymphoproliferative disease, is the third most common cause of orbital inflammation [1]. Clinical characteristics of orbital myositis include orbital and periorbital pain, exacerbated by eye movements, ocular movement impairment, diplopia, proptosis, swollen eyelids and conjunctival hyperemia [2]. The mean age at onset is around 40 years, with a slight predominance in females. Superior, lateral and medial rectus muscle are more often affected than inferior rectus muscle [3]. Unilateral single muscle involvement is the most common presentation, although multiple or bilateral involvement can also be seen. The most common presentation is acute and unilateral; however, chronic and recurrent cases may involve both orbits [4]. The differential diagnosis of orbital myositis is wide and many inflammatory, vascular, neoplastic and infectious conditions that affect the extraocular muscles and other orbital tissues must be ruled out. The most important differential diagnoses include thyroid-related eye disease, primary or metastatic orbital tumors, in particular lymphoproliferative disorders, systemic immune-mediated diseases (such as vasculitis, sarcoidosis, systemic lupus erythematosus, Chron’s disease, etc.), systemic infectious disease (Lyme disease, aspergillosis, herpes zoster, etc.) and orbital cellulitis. Orbital myositis usually shows prompt response to systemic corticosteroid therapy; in refractory, chronic or recurrent cases, steroid-sparing agents, immunosuppressants or radiation therapy may be indicated [5–7]. We report the case of a patient with isolated, acute, monolateral and monomuscular inferior rectus myositis. A 47-year-old woman presented with a painful left eye, associated with double vision; left ocular movements were restricted upgaze. Conjunctival hyperemia and a slight proptosis of the left eye were evident. A cranial and orbital CT scan without contrast was performed, showing an enlargement of the left inferior rectus muscle. A subsequent contrast-enhanced orbital MRI confirmed a marked left inferior rectus enlargement; in particular, it was hyperintense in T2 sequences and contrast-enhanced (Figs. 1, 2); the remaining orbital anatomical structures showed normal signal characteristics. Contrast-enhanced brain MRI was normal. Suspecting an orbital myositis, an electromyographic study was performed and documented a marked increase of polyphasic motor unit potentials limited to the left rectus inferior muscle; this electrophysiological finding was completely in agreement with clinical and neuroimaging diagnosis of myositis. The remaining extensive useful diagnostic procedures which included several systemic and laboratory investigations failed. On the contrary, it showed no further abnormal findings or any systemic disease. In particular, complete blood count, muscle enzymes, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, anti-dsDNA S. Gori (&) C. Lucchesi R. Calabrese G. Siciliano Department of Neurosciences, Institute of Neurology, University of Pisa, Via Roma, 67, 56126 Pisa, Italy e-mail: s.gori@med.unipi.it

Fatigue is increased in episodic migraine without aura patients.

irritant molecule, acrolein, or umbellulone (a volatile compound of Umbellularia californica, which is also known as “headache tree” because of the ability of its scent to cause migraine attacks in humans) evokes the release of CGRP, thus inducing meningeal vasodilation via TRPA1 stimulation. To explain these phenomena, activation of reflex pathways originated in the nasal cavity and resulting in CGRP-dependent meningeal vasodilatation has been proposed. Intranasal capsaicin, because of its peculiar desensitizing action, may inhibit these same reflex pathways. A similar mechanism may occur if chili (capsaicin) is applied into the oral cavities, as in the case of the present patient. In line with this hypothesis, the other medications mentioned by Borgdorff and Tangelder as both migraine abortives and platelet aggregation inhibitors, including Cayenne pepper, garlic, onion, ginger, and turmeric, have also recently been identified as containing TRP channel agonists that may potentially desensitize the channel and nociceptive neuron.

Amyotrophic lateral sclerosis with long lasting disease course and SOD1 and TARDBP mutations: Report of two cases and overview of the literature.

Despite its canonical nosographic definition as a progressive neurodegenerative disorder typically involving both lower and upper motor neurons, leading to progressive muscle paralysis and death approximately 2–4 years after symptom onset, amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, including clinical presentation and disease course. Forms with exclusive/predominant upper or lower motor neuron involvement are known, as well as subgroups of patients with a long disease course. ALS is sporadic in approximately 90% of cases, whereas about 10% of cases are familial (1). Mutations in the copper/zinc superoxide dismutase (SOD1) gene were first reported in familial ALS patients and account for approximately 20% of these patients (2); subsequently, a growing number of ALS-causing genes have been identified, among which is the TARDBP gene, coding for the TAR DNA-binding protein 43 (TDP-43) (3). In addition, several known familiar ALS mutations have also been reported in apparently sporadic ALS cases, underlying the complex genetic heterogeneity of ALS pathology. We describe here two cases of apparently sporadic ALS associated with mutations, respectively, in SOD1 and TARDP genes, characterized by predominant lower motor neuron limb involvement and long disease course. Cases description

Chronic Migraine With Medication Overuse and OnabotulinumtoxinA: Two Positive Case Reports of a Modified Injection Protocol

This correspondence proposes a modified injection protocol for OnabotulinumtoxinA (BoNT-A) in chronic migraine, whenever first time treated patients experience local adverse events but good clinical response. BoNT-A is approved as a prophylactic treatment for chronic migraine with/without medication overuse; its safety and efficacy were evaluated in the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) study, which established the optimal total dose to maximize efficacy and tolerability between 150 UI and 200 UI. Treatment is usually safe and well tolerated; the most frequent adverse event is muscular weakness. Ptosis, local pain, paresthesia/hypoesthesia, erythema, ecchymosis are common; tearing and photophobia are less common. The exact mechanism of BoNT-A in pain control is still debated; according to the leading hypothesis, it inhibits the release of neurotransmitters from peripheral nociceptors blocking sensitization of painconducting nerve fibers and reducing peripheral pain signals to the central nervous system (CNS); moreover, a recent preclinical study suggested the role of BoNT-A in the processing of mechanical pain by selective inhibition of trigeminal meningeal nociceptors (C-fibers). However, the pre-clinical observation that BoNT-A can reduce secondary mechanical hyperalgesia not only on the injection side but also on the contralateral side, supports a possible additional central mechanism that could contribute to BoNT-A efficacy. We report two cases of patients, treated for the first time with BoNT-A for chronic migraine following the standard procedure, who experienced tearing and bilateral photophobia. Both patients were female (51and 54-year-old, respectively), with a diagnosis of chronic migraine according to International Classification of Headache Disorders (ICHD-III); they reported medication overuse and met clinical criteria for refractory migraine, since more than two classes of first-line prophylactic drugs (beta-blockers, From the Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Chronic inflammatory demyelinating polyradiculoneuropathy with cranial nerves hypertrophy, thyroid-related orbitopathy and IgG monoclonal gammopathy: a case report.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) clinical presentation can be highly heterogeneous and different clinical variants are known; moreover, CIDP clinical spectrum is expanded by the association with different concomitant conditions, including metabolic, genetic, autoimmune, infectious and hematologic disorders, the possible role of which in CIDP pathogenesis remains controversial [1]. We report the case of a 62-year-old woman affected by CIDP with hypertrophic cranial nerves involvement and sensitive ataxia, associated with thyroid-related orbitopathy and IgG monoclonal gammopathy. Familiar history was apparently negative for neuromuscular disorders; medical anamnesis was unremarkable until the age of 48 years old, when, after the appearance of transient diplopia, dysimmune thyroiditis with thyroidrelated orbitopathy was diagnosed. Subsequently, the patient progressively developed motor impairment with paresthesias/dysesthesias distally at both upper and lower limbs and, at the age of 52 years old, performed a first neurological evaluation, evidencing motor weakness distally at all extremities and diffuse osteo-tendon hyporeflexia. An electrophysiological evaluation showed a demyelinating mixed, prevalently motor, polyneuropathic pattern with evidence of nerve conduction blocks. Given the stable course, no specific therapy was started at that time. The patient came at our attention at the age of 62 years old, for worsening of sensory motor symptoms, additionally complaining fluctuating diplopia, dysphagia and trigeminal paresthesias, mainly affecting the mandibular region bilaterally. Neurological examination showed ataxic gait, positive Romberg sign, distal muscle weakness, deep and superficial sensory dysfunction of all extremities and osteo-tendon areflexia. Electrophysiology confirmed previous findings, including severe diffuse reduction of sensory motor nerve conduction velocities, in some instances at a value lower than 10 m/s, with presence of partial, mainly motor, nerve conduction blocks and neurogenic electromyographic pattern with positive sharp waves and fasciculations. Cerebrospinal fluid (CSF) analysis showed albumin-cytologic dissociation, with elevated protein levels and normal leukocyte count. Laboratory examinations on serum revealed a monoclonal IgG gammopathy, without evidence of lymphoproliferative disorders; conversely, paraneoplastic markers, anti-muscle specific kinase and acetylcholine receptor antibodies, as well as anti-ganglioside (GM1, GM2, GD1a, GD1b, GQ1b) IgM, anti-ganglioside (GM1, GM2, GD1a, GD1b) IgG and anti-sulfatide IgM antibodies proved negative. No mutations were found in genes for Charcot-Marie-Tooth HMSN type 1 disease and hereditary neuropathy with liability to pressure palsies, in particular for peripheral myelin protein22, myelin protein zero, gap junction B1 genes. Clinical, electrophysiological and CSF analysis were, therefore, in agreement with a CIDP diagnosis, according to EFNS/PNS criteria [1]. Due to the presence of cranial C. Lucchesi E. Schirinzi G. Siciliano (&) Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Via Roma, 67, 56126 Pisa, Italy e-mail: g.siciliano@med.unipi.it

P058. Refractory chronic migraine, fatigue and OnabotulinumtoxinA: a clinic setting experience.

Methods From March 2014 to May 2015 patients meeting the clinical diagnostic criteria for chronic refractory migraine were enrolled. Patients were treated with OnabotulinumtoxinA every three months according to the standard procedure (155-195 units) [2]. At baseline (T0) and after 6 months, at the third treatment (T1), a structured questionnaire was administered, including: a) migraine features [frequency (headache days/month), pain severity (Verbal Numeric Scale, VNS), acute medicines consumption/month, disability (Headache Impact Test, HIT-6), ictal cutaneous allodynia (Allodynia Symptoms Check-list 12, ASC-12)]; b) associated symptoms [fatigue (Fatigue Severity Scale, FSS), anxiety symptoms (Generalized Anxiety Disorder, GAD7), depressive symptoms (Patient Health Questionnaire, PHQ-9)]. Wilcoxon test was performed for the T0-T1 comparisons.

P041. Analysis of body mass index, psychiatric comorbidity, sleep-wake pattern and occurrence of fatigue in episodic and chronic migraine patients

Background Migraine clinical picture and life-time disease course can be highly heterogeneous, with a subgroup of patients developing chronic migraine, a highly disabling condition, associated with high socio-economic burden. Moreover, migraine clinical spectrum is expanded by the association with different comorbid/coexisting conditions and interictal dysfunctions, contributing to modulate migraine clinical profile. Taking this scenario into consideration, the aim of this study was to systematically evaluate migraine clinical features, body mass index (BMI), depressive and anxiety symptoms, sleep-wake pattern and occurrence of fatigue in a sample of episodic and chronic migraine patients, as well as their reciprocal interaction.