Claudia Vinciguerra

Music intervention efficacy in elderly: a promising non-pharmacological approach to cognitive dysfunctions

Aging, due to the gradual elongation of average life expectancy, represents the strongest known risk factor for cognitive decline and behavior disorders. A slow weakening of some cognitive functions such as memory, processing information speed, language, visual learning, problems solving ability, and executive functioning, with sparing of crystallized intelligence (i.e., the experience), is fairly common. These dysfunctions are often associated with changes in behavior, reduced environmental adaptation skills, depression and anxiety, which lead to a worsening of the quality of life, accounting a considerable burden due to the negative impact on various functions, including social and daily living activities [1, 2]. Currently, music intervention (MI) plays an important role among the drug-free treatment and rehabilitation of patients with acute and chronic neurological and somatic diseases. Also, previous studies showed its effectiveness in cognitive, mood, and behavior disorders [3]. Moreover, being non-invasive, free of adverse events and not requiring an expensive training, it can be delivered easily and successfully. The power of sound and music has been recognized in all cultures and their therapeutic use has gone through the centuries, social and political travails, cultural movements, and scientific discovery without ever being questioned, representing a part of our heritage, genetic and experience, worldwide shared since the prenatal age. Generally, MI is focused on the relationship between body language and sound, such as interaction between perception and action, but above all it represents a form of a communication alternative to the verbal one. It also excites emotions by taking into account some sound parameters (height, intensity, duration, and timbre) and others of dynamic type (mode, genre, executive style). Awide spectrum of MI programs (interactive or passive) are known: singing songs of the repertoire of light and popular music, music/movement association (from physical relaxation to free gestures or structured in rhythmic sequences dancing and dancing popular), instrumental improvisation, and listening music tracks [3, 4]. The goal is not to acquire musical skills, but to use the language of sound to open alternative communication channels. In the elderly, MI could be very important to protect brain and potentiate the normal cognitive reserve also after different pathological processes. As Claude Levi Strauss said: BMusic is a machine to suppress time.^ Research in this field can count on some decades of experience and has considerably developed in relation to the demands of the medical and psychological backgrounds to have greater control and reliability in regards of the methods and the evaluation of results. Music can induce, at the same time, different emotions and this is probably linked to the activation of different brain areas based on the perceived sound stimulus. A recent functional magnetic resonance imaging (fMRI) study showed that popular music can arouse pleasure experience and strong emotional response, probably related to characteristic patterns of brain activity [5]. Another group of researchers using binaural beats phenomenon (that occurs within the cortex when two different frequencies are presented separately to each ear) during a visuospatial working memory task demonstrated an increased response accuracy, but also modified strengths of the cortical networks during the task [6]. Moreover, many others fMRI studies conducted during music interventions, especially listening, in stroke patients reported connectivity changes in different brain networks [7, 8]. In a recent article, Bing Xu et al. * Claudia Vinciguerra claudiavinci@hotmail.it

Eye movement abnormalities in a patient with Zellweger spectrum disorder

Dear Sir, Zellweger spectrum disorders (ZSDs) are included in peroxisomal biogenesis disorders, a wide spectrum of diseases due to mutations in genes (PEX), leading to loss of peroxisomal metabolic functions. ZSDs have an autosomal recessive transmission and encompass a continuum of three different phenotypes, i.e. Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The onset is in the newborn period or later in childhood. Though the prognosis is usually poor, milder phenotypes with clinical heterogeneity have been reported [1]. Visual system abnormalities, including retinal degeneration, optic nerve atrophy, cataracts, corneal changes and glaucoma are commonly described in ZSDs [2]. Moreover, pendular nystagmus (PN) is almost always present [3]. However, given the precocious appearance of hypovision and the usually young age of the patients, little is known about quantitative eye movements features in the various phenotypes of ZSDs. We examined the eye movements features of a 56-yearold man, already diagnosed as having a peculiar mild phenotype of ZSD caused by two heterozigous mutations of the PXMP3 (PEX2) gene (c.355 C[T (p.Arg119X) and c.865_866insA (p.Ser289-LysfsX36), with onset at age 3 years and slow progression. Neurological examination showed predominant cerebellar signs as gait ataxia, dysartria, dysmetria, and gaze-evoked nystagmus, mild retinopathy and bilateral neurorim pallor with preserved good visual acuity, hypoacusia, generalized areflexia, and bilateral pes cavus; brain MRI revealed marked atrophy of cerebellum, cerebellar peduncles and brainstem, particularly of pons, and moderate atrophy of the supratentorial regions, with no signal abnormalities in the white matter. Patient’s detailed clinical and biochemical aspects have already been described [1]. Eye movements were recorded by means of an eye tracker device (ASL 504, Applied Science Laboratories, Bedford, MA, USA). An interactive procedure based on nine static points of calibration was performed to ensure a minimization of spatial error. The subject’s head movements were minimized by a chinrest. We recorded horizontal (target of 10 and 18 of amplitude) and vertical (8 ) visually guided saccades, elicited, after the disappearance of the central fixation target (1500 ms) and a period of Gap (200 ms), by a peripheral target appearing randomly at left–right or up–down position for 1500 ms. The antisaccade task was analogous to the horizontal visually-guided task, but the subject had to make a saccade opposite to the target. In the fixation task, the patient was required to hold his eye still in response to target in central (90 s) and eccentric (10 –18 , 15 s each) position. Standard saccadic parameters of horizontal and & A. Rufa rufa@unisi.it

Hydroxychloroquine neuromyotoxicity: a case with rapid course and complete recovery

Hydroxychloroquine (HCQ), a 4-aminoquinoline, with addition of a hydroxyl group initially used as antimalarial agent, is now mainly utilized for the long-term management of rheumatological disorders such as rheumatoid arthritis (RA) and lupus erythematosus (SLE). Its toxicity against retina, heart, skin, nervous system and muscle is documented [1]. HCQ myopathy may onset from months (at least six) to years after drug intake with symptoms characterized by aspecific mild to moderate proximal muscle weakness with normal or slightly increased creatine kinase (CK) levels [2– 5]. We report a case of severe neuromyopathy with a very early diagnosis, rapid and complete recovery followed 2 weeks after HCQ discontinuation. A 63-year-old Italian woman was referred to us for severe and generalized weakness, with more evident involvement of lower limbs, progressing from 3 weeks, associated with gait disturbance and falls. The patient, with a history of rheumatoid arthritis, has been treated with HCQ for the last 2 months (from September to November 2013, 200 mg twice a day). In the previous 4 years, she assumed Salazopyrin with poor improvement. She received also ramipril and bisoprolol for hypertension from many years. Family history was negative for neuromuscular disorders. On admission to our Department, the patient complained tingling of distal districts of all limbs and diffuse wasting. Neurological examination presented waddling gait, possible with unilateral support. Muscle strength evaluated in proximal and distal muscles of the upper and lower limbs (graded according to the Medical Research Council scaleMRC), showed severe muscle weakness mainly at the girdles (2/5 vs 1/5 at upper limbs and 4/5 vs 2/5 at lower limbs, in distal and proximal district, respectively). Deep tendon reflexes were normal in the upper limbs, decreased in the lower. Serum CK, lactate dehydrogenase (LDH) and aldolase levels were normal. Nerve conduction velocity study (NCS) showed mild multiple mononeuropathies of the sensory median and sural nerves and motor tibial nerve. Standard needle electromyography (EMG) of trapezius, deltoid, brachial biceps, rectus femoris and tibialis anterior muscles showed myopathic pattern (polyphasic motor unit action potentials of short duration and low amplitude, and early recruitment at full effort). Deltoid muscle biopsy showed variation in fiber sizes with rare regeneration. Ultrastructural analysis detected diffuse agglomerates of lipofuscin-like membrane-bound electron-dense material (Fig. 1). Suspecting an iatrogenic myopathy, HCQ was discontinued and replaced with Salazopyrin. Two months (February 2014) later the patient referred a rapid improvement of all symptoms; neurological examination showed recovery of muscle strength in all districts, with evidence only of mild weakness to the upper right limb that completely disappeared in June 2014 (MRC in proximal and distal & A. Federico federico@unisi.it

Eye movement changes in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease due to ECGF1 gene mutations (chromosome 22) causingmultiple deletions and depletion of mitochondrial DNA in skeletal muscle. The determination of the activity of the geneproduct tymidine phosphorylase (TP) in leukocytes and genetic analysis are diagnostic. External ophthalmoplegia, severe gastrointestinal dysmotility, cachexia, peripheral sensory-motor neuropathy, diffuse myopathy and leukoencephalopathy are typical findings. The severe disease progression leads to death in a few years [1]. Allogeneic hematopoietic stem cell transplantation (HSCT)may restore enzymatic levels improving the clinical outcome [2]. Extraocular muscles (EOMs), fast and fatigue resistant, are affected early in MNGIE, as in other mitochondrial diseases, and their dysfunction parallels the disease evolution. This vulnerability is due to their higher mitochondrial content and metabolic rate than limb skeletal muscles, implying a particular dependence on oxidative phosphorylation and a selective vulnerability to respiratory chain dysfunctions. Moreover, EOMs are functionally divided in the orbital and global layers, containing muscle fibers with unique structural and functional properties that may make them differently susceptible to the mitochondrial failure [3].Their recruitment appear to reflect their fatigability, being the fast but low fatigue resistant fibers of the orbital layer activated mainly during saccades [4]. These changes may be quantified by the analysis of the dynamic properties of saccades, which therefore could provide a reliable and reproducible clinical assessment and follow-up in MNGIE and other mitochondrial disorders.

Spatial ranking strategy and enhanced peripheral vision discrimination optimize performance and efficiency of visual sequential search

Visual sequential search might use a peripheral spatial ranking of the scene to put the next target of the sequence in the correct order. This strategy, indeed, might enhance the discriminative capacity of the human peripheral vision and spare neural resources associated with foveation. However, it is not known how exactly the peripheral vision sustains sequential search and whether the sparing of neural resources has a cost in terms of performance. To elucidate these issues, we compared strategy and performance during an alpha‐numeric sequential task where peripheral vision was modulated in three different conditions: normal, blurred, or obscured. If spatial ranking is applied to increase the peripheral discrimination, its use as a strategy in visual sequencing should differ according to the degree of discriminative information that can be obtained from the periphery. Moreover, if this strategy spares neural resources without impairing the performance, its use should be associated with better performance. We found that spatial ranking was applied when peripheral vision was fully available, reducing the number and time of explorative fixations. When the periphery was obscured, explorative fixations were numerous and sparse; when the periphery was blurred, explorative fixations were longer and often located close to the items. Performance was significantly improved by this strategy. Our results demonstrated that spatial ranking is an efficient strategy adopted by the brain in visual sequencing to highlight peripheral detection and discrimination; it reduces the neural cost by avoiding unnecessary foveations, and promotes sequential search by facilitating the onset of a new saccade.

GABAAergic dysfunction in the olivary-cerebellar-brainstem network may cause eye oscillations and body tremor

http://dx.doi.org/10.1016/j.clinph.2016.12.014 1388-2457/Published by Elsevier Ireland Ltd on behalf of International Fe Opsoclonus and flutter are ocular oscillations consisting of continuous, involuntary, conjugate saccades without intersaccadic intervals. If these saccadic oscillations are purely horizontal, they are called ocular flutter; if they have horizontal, vertical and torsional components, they are called opsoclonus. Behavioral disturbances, cerebellar ataxia, and limb tremor may co-occur. Several infectious, paraneoplastic, metabolic, and toxic etiologies cause these disturbances, but how neural circuits generate the oscillations is not clear. Two main hypotheses for the pathomechanism of opsoclonus/flutter have been proposed on the basis of different clinical and experimental observations. In the first, reduction of glycinergic inhibition generates oscillations in the positive feedback loop between saccadic brainstem burst neurons (Shaikh et al., 2007). In the second, disinhibition of cerebellar fastigial nuclei induces unwanted saccades through excitatory projections to the burst neurons (Wong et al., 2001). However, both theories remain controversial because they were not confirmed by lesion studies in animals, clinical findings, or model simulations (Lemos and Eggenberger, 2013). Analysis of high-resolution eye movement recordings from patients with opsoclonus/flutter might clarify the underlying mechanisms, but these are extremely rare. Here, novel observations from two patients with opsoclonus and body tremor subsequent to performance-enhancing substance abuse suggest that eye and body oscillations may be generated by a GABAergic dysfunction of the olivary-cerebellar-brainstem network. The study was approved by the local ethics committee and informed consent was obtained from the patients. Two tennis-players developed opsoclonus/flutter after a few months of self-administration of performance-enhancing substances. Patient 1, a 32-year-old male, presented with rapid onset of behavioral disturbances, vertigo, ataxia, head tremor, and opsoclonus causing visual blur and oscillopsia (Supplementary Video 1). Patient 2, a 34-year-old male, showed rapid progression of limb and axial tremor, vertigo, mood changes, ataxia, and ocular flutter (Supplementary Video 2). Common infectious, toxic, paraneoplastic, and metabolic causes of opsoclonus/flutter were excluded by negative brain MRI, blood, and CSF exams. Both patients reported an analogous typology, supply, and use of the enhancing chemicals, but only patient 1 provided a sample of the compound for testing, which led to the identification of anabolic androgenic steroids (AAS): nandrolone, stanozolol, and testosterone propionate. Treatment with intravenous IgG and benzodiazepine led to recovery in three-to-four weeks in both patients. In patient 2, limb tremor characterized by tonic motor activity at 8 Hz was recorded by electromyography (EMG) from the

Persistent hiccup after chemo-radiotherapy in nasopharyngeal cancer: an atypical side effect?

Nasopharyngeal carcinoma (NPC) is a relatively uncommon cancer of the head and neck region, although it has a higher incidence in certain populations, including Southern Asian and Chinese [1]. The most common histological type of NPC is the undifferentiated nonkeratinizing histotype, strongly associated with the Epstein–Barr virus (EBV) in almost all of the cases, whereas the keratinizing and the basaloid histotypes are less common. The symptomatology includes nasal symptoms, otitis, local pain, headache and cranial nerve involvement, and this varied spectrum often results in delayed diagnosis. Chemotherapy plus radiotherapy in different associations is generally accepted as the first-line therapy, although acute and late toxicities remain highly detrimental [2]. Intensity-modulated radiation therapy can highly concentrate the radiation dose to target volumes while avoiding or reducing radiation doses to normal tissues and organs, thereby leading to gains in the therapeutic ratio in an anatomically complex site such as the nasopharynx. Our patient was a 45-year-old italian male with a nonkeratinizing NPC, clinical staging cT3N2M0, receiving two cycles of induction chemotherapy with cisplatin (75 mg/m), docetaxel (75 mg/m) and 5-fluorouracil (750 mg/m 9 5 days) every 4 weeks. The induction chemotherapy was well tolerated with a partial response (50 % reduction on CT scan) and the only side effects were alopecia (grade I), diarrhea (grade I) and weakness (grade I). The patient was then submitted to radiation therapy with concomitant chemotherapy (cisplatinum 40 mg/m/ weekly) and the total radiation therapy dose was 6600 cGy to planned target volume 1 (PTV1), including nasopharynx, positive-neck node levels II and III bilaterally, with a fractionation of 220 cGy per fraction, 6000 cGy to PTV2 (skull base, neck node levels Ib and V, both sides), with a fractionation of 200 cGy per fraction, and 5400 cGy to PTV3 (neck node levels IV, both sides), fractionation 180 cGy per fraction. Total dose, fractionation and contouring of target volumes and organs at risk were according to the recent literature [3]. Treatment side effects were characterized by thrombocytopenia (grade III), leukopenia (grade II), lingual edema (grade I), mucositis (grade III), epistaxis (grade I), rise in transaminases (grade II) and otitis (grade I), but, 3 weeks after the end of the chemoradiation treatment, our patient developed nausea, unresponsive to usual antiemetics, and, few days later pernicious hyperemesis and severe hiccup. Brain MRI and neurological examination were negative, thus suspecting an isolated irritation of the nucleus of the vagal nerve we started chlorpromazine endovenous (100 mg/die), with clinical improvement in 3 days. & Valerio Nardone v.nardone@hotmail.it

Paroxysmal supraventricular tachycardia in anti-musk Myasthenia gravis: A case report

• Autonomic system involvement expressed by paroxysmal supraventricular tachycardia in a MuSK-MG patient.