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A case of strio-pallido-dentate calcinosis associated with micromolecular myeloma

Fahr’s disease (FD) is a neurodegenerative disease whose aetiology is unknown, characterized by neuropsychiatric and motor problems associated with symmetrical, bilateral calcification of the basal ganglia. A drop in the metabolism and cerebral flow is deemed to be responsible for the onset of psychiatric and motor problems, cognitive deficit, painful symptoms and altered state of consciousness. The term Fahr’s syndrome (FS) is used when an etiological cause responsible for calcification can be identified. Fahr’s syndrome is associated with extremely diverse clinical conditions: calcium/phosphate metabolism disorders (hypo-hyperparathyroidism, pseudo-hypoparathyroidism), systemic lupus erythematosus, encephalitis and neoplasms [1]. Here, we describe clinical and radiological findings of a case of FS associated with micromolecular myeloma and hypothesize that bone remodelling could encourage the depositing of calcium at an intracerebral level as a result of an increase in the levels of alkaline phosphatase (ALP) and alteration of calcium levels. In January 2013, an 82-year-old woman was admitted to our hospital. The patient’s medical records showed a condition of severe osteoporosis with multiple collapsed vertebrae, dysphagia and rapidly ingravescent cognitive impairment over the last 18 months. No motor problems or psychiatric disturbances were reported. An acute onset of drowsiness made it necessary to hospitalize the patient, who appeared to be in generally serious conditions (Glasgow coma score (GCS) 10/15), and prompted us to perform a brain CT. The brain CT scan was negative regarding focal densitometric alterations and localized accumulation of blood, but showed dystrophic calcification of the dentate nuclei with bilateral occipital cortical calcification at the level of the calcarine cortex, as seen in FD (Fig. 1). Blood chemistry analysis also showed: kidney failure (GFR 13 ml/min); anaemia (Hb 9.5 g/dl; n.v. 12–16 g/dl); hypercalcaemia (13.3 mg/dl; n.v. 8.40–10 mg/dl) and hyperphosphatemia (5.9 mg/dl; n.v. 2.8–4.6 mg/dl); increase of ALP (123 U/l; n.v. 35–104 U/l) and inflammatory markers (VES 69 mm/h; n.v. 0–35 mm/h; PCR 18,600 lg/l; n.v. \5,000 lg/l). Protein electrophoresis test showed hypoalbuminemia (33.8 g/l; n.v. 40.2–47.6 g/l), increase of acute phase proteins and hypogammaglobulinemia (8 % n.v. 11.1–18.8 %). Alterations of the calcium and phosphate metabolism are the most common cause of FS. In our patient, the concomitance of calcification of the basal ganglia and hypercalcaemia led us to suspect a condition of secondary FS and hyperparathyroidism, but subsequent serum assays for parathormone (PTH) (40.7 pg/ml; n.v.15–65 pg/ml) and vitamin D (31 ng/ml; n.v. [30 ng/ml) were normal in both cases. During the clinical course, the patient was less drowsy and suffered extremely painful symptoms, visual analogue scale (VAS) 10/10; worsening renal function was also noted. Even though drowsiness and painful symptoms could be attributed to cerebral calcification, was ingravescent kidney failure simply a concomitant pathological condition or was there a link among the clinical picture, calcification of basal ganglia and renal dysfunction? A 24-h urine collection showed significant proteinuria (2,777 mg/ 24 h; n.v. 40–150 mg/24). The finding of proteinuria in the N. Gueli W. Verrusio (&) V. M. Magro M. Zaccone M. Cacciafesta Department of Anesthesiological, Cardiovascular, Respiratory, Nephrological, and Geriatric Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy e-mail: walter.verrusio@uniroma1.it

Pericarditis with troponin elevation

Cardiology Department, Maria Vittoria Hospital, Torino, Italy Correspondence to Massimo Imazio, MD, FESC, Cardiology Department, Maria Vittoria Hospital, Via Cibrario 72, 10141 Torino, Italy E-mail: [email protected] Received 13 May, 2013 Revised 20 July, 2013 Accepted 1 August, 2013

Evolving pervasive health research into clinical practice.

Correspondence to: Dr. Oscar Mayora CREATE-NET Via alla Cascata 56D Trento, 38123 Italy E-mail: oscar.mayora@create-net.org During the past years there has been a growing research trend on investigating the use of pervasive computing technologies for their use in the healthcare domain. The research activity on this topic known as “Pervasive Health”, has been defined as a scientific discipline integrating the technological advances on pervasive computing, the research on human-computer interaction and their application in the medical and wellbeing domains [1]. From its origin around a decade ago, Pervasive Health research has been evolv ing from the development of experimental proof-of-concept prototypes tested under limited pilot tests, into more robust systems able to satisfactorily perform in reallife conditions including a considerable amount of users for validation [2]. From a technology and users-acceptance point of view, previous Pervasive Health research has assessed various ways to maximize usefulness in treatment and care management and on users adoption. The question arising then is that if these technologies have proven to provide a real potential benefit, why don’t we see them yet as part of today’s mainstream healthcare provisioning practice? Which barriers still need to be overcome in order to implement Pervasive Health? Today, Pervasive Health research has achieved a maturity level that allows encouraging current developers and researchers to perform a quality step ahead by identifying the ways to integrate the lessons learnt in this discipline into the actual paths of healthcare provisioning. The implementation of Pervasive Health into clinical practice opens a new series of challenges that imply the need of conducting more intensive multidisciplinary research involving fields that in the past were considered less relevant to this topic. The new trends of Pervasive Health incorporate the traditional joint approach between pervasive computing and interactive technologies, the need of intensifying the relationship with clinical practitioners in a more structured and rigorous way than in previous years. It is not sufficient anymore to create novel ways of applying technology to prevention and treatment confined to labsettings, but the use of technology needs today to show a clear, measurable evidence of the advantages of Pervasive Health into actual clinical environments while contributing to medical science in a formal way. The future of Pervasive Health developments will need to incorporate from early design phases how solutions will cope with non-functional implementation constraints [3]. The clinical validity of new technology-based treatments will be a necessary condition to enable operation in real-life medical domain including all the relevant implications of conducting clinical research. Such implications include incorporation of legal aspects, ethical considerations, regulatory issues and all necessary conditions to permit inclusion of new technologies into healthcare with the assurance to patients and clinicians of secure and high quality level of treatment. Moreover, the amount of data useful for clinical prac-

Spinal hemorrhage in eosinophilic granulomatosis with polyangiitis (Churg–Strauss)

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as a Churg–Strauss syndrome [1], is a rare systemic small vessel vasculitis mainly affecting people aged 40–60 years without gender predominance [2, 3]. Asthma, eosinophilia, chronic paranasal sinusitis, nasal polyposis, non-fixed pulmonary infiltrates, and myocarditis are typical findings of EGPA [4]. Neurologic involvement is frequently observed and peripheral nervous system (PNS) is affected in 59–86 % of patients, mainly in the form of peripheral neuropathy [5]. On the contrary, central nervous system (CNS) involvement is described in less than 10 % of cases [5]. The most common CNS manifestations are cerebral infarction and diffuse encephalopathy, while cerebral hemorrhages have been seldom associated with EGPA [6] and only one case of spinal subarachnoid hemorrhage has been previously reported in the early 1980s [7]. In June of 2012, a 31-year-old pregnant Caucasian woman with a long-term history of asthma and rhinitis on the day of the delivery presented with high spiking fever (up to 39.5 C) and arthralgias, disappearing in a few hours. Further similar episodes were then observed in the subsequent months without other additional findings. In August 2012, painful paresthesias in left hand, right arm, and dorsal surface of right foot appeared, together with bilateral distal upper limbs weakness. Electromyography/ electroneurography (EMG/ENG) confirmed a severe sensory-motor axonal neuropathy, predominant in upper limbs, characterized by patchy pattern as in vasculitic mononeuritis multiplex. Laboratory investigations showed an increase of inflammatory markers (ESR 58 mm/h, CPR 6.9 mg/dl) and leukocytosis (21,000/ll) with eosinophilia (63 %). Antineutrophil cytoplasmic antibodies (ANCA) were positive both in IIF (p-ANCA pattern) and in ELISA (anti-MPO specificity). Because of headache and neck stiffness appearance, brain MRI was performed, displaying maxillary and sphenoid sinusitis without CNS pathological findings. After the exclusion of underlying infections, the patient was diagnosed with EGPA and methylprednisolone 1 mg/kg/ day i.v. was started. Despite corticosteroid treatment, headache and neck stiffness persisted, global left upper limb weakness worsened in particular arm and wrist extension, and brisk left supinator tendon reflex appeared. Lumbar puncture revealed hemorrhagic cerebrospinal fluid, with a protein value of 755 mg/dl, glucose value of 23 mg/ dl, and 205 cells (neutrophils and red blood cells). HumanCMV and HSV infections were excluded by real-time PCR on cerebrospinal fluid, as well as other infectious processes. Spinal MRI was performed showing cervical and dorsal subarachnoid bleeding with spinal cord compression and C6–C7 intramedullary hyperintensity on the left side (Figs. 1a, 2a). Intravenous steroid (methylprednisolone 1 mg/kg/day i.v. for 6 days) was administered, followed by oral prednisone (75 mg/day) with subsequent tapering until suspension at 12 weeks. L. Diamanti (&) G. Berzero P. Bini S. Ravaglia E. Marchioni Neurology Department, IRCCS National Neurological Institute C. Mondino, University of Pavia, via Mondino 2, 27100 Pavia, Italy e-mail: luca.diamanti@mondino.it

Ear lobe angioleiomyoma and aggressive keloid

Sir, Angioleiomyoma is a rare, benign smooth muscle tumor originating from the tunica media of blood vessels. It may be localized anywhere in the body. Ear lobe angioleiomyoma is rarely diagnosed before surgery. The usual treatment is surgical excision. Ear lobe keloids are very common. Often, this entity comes as the result of ear piercing. The question of coexistence of an angioleiomyoma with an aggressive keloid is unusual. In February 2008, a 12-year-old female presented a nodular lesion of the right ear lobe. The patient referred previous ear piercing history at both earlobes without familiarity for keloids. A similar lesion had been excised at the same site in 2001. The histological diagnosis was “vascular leiomyoma.” The lesion recurred in April 2003; a second excision was performed and the histology was the same as the first one. Between April 2003 and February 2008, a new lesion appeared at the same site. In February 2008, it was ovalshaped, with well-defined margins, and painless. This new local recurrence was excised with 0.3 cm clear margins and a postauricular flap was performed for right ear lobe reconstruction. Histology showed “remarkable nodular fibrosis with keloid-like aspects at the periphery; lesion completely excised.” In May 2009, a new recurrence occurred at the junction between the new ear lobe and preauricular region (Fig. 1). A second patient, 24 years old female, in December 2011 presented a lesion at the left ear lobe site. A nodular lesion was first noted in August 2007, adjacent to the site of a previous ear piercing. The lesion was round-shaped and painless. After its first excision (2007), the histology was “cutaneous leiomyoma incompletely excised; the inferior margin of the excision is still involved.” In December 2007, she presented a recurrence and a second excision was performed; histology reported “cutaneous angioleiomyoma” again, with “unclear deep excision margins.” In September 2010, a new recurrence appeared at the scar site. A wide surgical excision was performed again; histology reported “hypertrophic scar tissue with keloid focal features.”All the procedures were performed by the same general surgeon. In September 2011, the scar became hypertrophic, then she came to our clinic. We applied the same protocol for both patients consisting in intralesional injections of triamcinolone acetonide 40 mg/ml diluted 1:1 in saline solution and “U-shaped” Zimmer splint ear lobe compression (Fig. 2). The incidence range of angioleiomyoma is between the third and sixth decade of life, with a female prevalence. The lesion is usually a unique lesion, small, round, firm, skin-colored, and well-encapsulated [1, 2]. On the other hand, ear lobe keloid is very common. Often, this entity comes as the result of ear piercing. The exact pathogenesis of keloids is unknown. Most important factors involved in keloid formation are chronic inflammation, infection, excessive wound tension, foreign material, or other impurities in earrings [3, 4]. Many options have been proposed for keloid treatment: simple excision, intralesional injection of corticosteroids, application of pressure, and application of silicone gel or patches. The occurrence of an angioleiomyoma that ends into an aggressive keloid is extremely unusual. Luo and Pan [5] studied leiomyomas, keloids, surgical scars, and peritoneal adhesions to identify genes that could individually distinguish these fibrotic disorders despite differences in the nature of their development and growth. Leiomyomas in Caucasians compared with keloids in African-Americans showed a limited difference in their gene expression profile. This suggested the existence of a comparable environment for leiomyomas and keloids. Their results indicated that the molecular features S. Razzano (*) : E. Di Sergio Naples, Italy e-mail: razzanosergio@gmail.com

Multiagent imaging: from the pathophysiologic basis to clinical characterization and radionuclide therapy

The remarkable growth of nuclear medicine in the past 20 years is attributable to a number of factors, including the clinical recognition that imaging with [F]FDG, touted as the ‘‘molecule of the millennium’’ [1], improves diagnosis and staging, especially when it is used with devices that provide anatomic reference for the metabolic images. Furthermore, the growth of FDG PET/CT has been paralleled by an evolution of other applications of ‘‘molecular imaging’’ for both diagnostic and therapeutic purposes [1]. This issue of Clinical and Translational Imaging focuses on the imaging of multiple parameters (achieved either by imaging with multiple agents or by imaging at multiple time points) as a means of better characterizing the presence or severity of a disorder. In the opening article, Ciarmiello et al. [2] provide a comprehensive review of the complex pathophysiology of degenerative brain disorders. In this regard, both PET and SPECT imaging use a wide range of tracers to track pathophysiological processes in the healthy and diseased brain, especially for the purpose of investigating the pathophysiological aspects of neurodegenerative disorders. This area of investigation is extremely important considering the aging of the global population and the high prevalence of brain disorders, such as Alzheimer’s disease and Parkinson’s disease, in elderly persons. Utilizing molecular imaging in routine clinical practice may overcome the limitations of a diagnostic approach based solely on clinical judgment and structural imaging. These molecular imaging techniques will foster the development of new drugs whose effects on specific pathways can be monitored, and compared to clinical outcomes. Strauss and Fox explore new techniques that expand the applications of approved radiopharmaceuticals in patients with heart failure and atherosclerosis [3]. Their article focuses mainly on the evaluation of mitochondrial function and sympathetic innervation in patients with heart failure. The new applications they discuss, by providing functional information with high predictive value, allow identification of heart failure patients at high risk of clinical events. Another area of growing interest is linked to the possibility of directly imaging and evaluating focal vascular inflammation, microcalcification and calcification in patients with dyslipidemia. Imaging-based characterization of inflammation, or early phases of calcification in atheromas, is expected to stimulate the development of therapeutic strategies that are more personalized than those based on traditional measurements of lipid levels in patients with dyslipidemia. Characterization of atheromas, especially in the coronary and carotid arteries, may be the imaging approach of choice to permit effective pharmacologic therapy geared at reducing the incidence and severity of clinical events. Palestro et al. [4] discuss the current role of molecular imaging with single-photon and positron-emitting tracers in the evaluation of inflammation and infection. After reviewing the clinical role of well-established imaging procedures based on approved radiopharmaceuticals (chiefly, labeled autologous leukocytes and [F]FDG, even though there is still a role for Ga-citrate scintigraphy), the authors describe ongoing investigations of tracers, such as radiolabeled antibiotics—these were originally expected to be ‘‘infection-specific’’ imaging agents, but to G. Mariani (&) Regional Center of Nuclear Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy e-mail: giuliano.mariani@med.unipi.it

Letter to the Editor concerning Tsuchiya K et al. “Dosimetric comparison between intensity-modulated radiotherapy and standard wedged tangential technique for whole-breast radiotherapy in Asian women with relatively small breast volumes”

With great interest, we read the recent article by Tsuchiya et al. [1]. In this paper, the authors tried to identify, in the adjuvant setting after breast-conserving surgery, the optimal radiation technique for selected 25 small breast glands (median volume, 552.6 cc), comparing the dose distribution obtained with the standard wedge tangential technique (SWT), tangential-field intensity-modulated radiation therapy (T-IMRT), and 3–4 field IMRT techniques (3FIMRT or 4F-IMRT). An improved dose distribution, a shorter treatment time, and a reduction of Radiation Therapy Oncology Group (RTOG) acute high-grade skin toxicity with the T-IMRT technique [2, 3], which can be considered a simplified form of IMRT based on two tangential fields with sub-segments, have been demonstrated [4]. In their paper, Tsuchiya et al. stated that T-IMRT can be appropriate in particular for irradiation of small breasts, because of an improvement in dose homogeneity and in the dose received by 2 % of the volume (Dmax), reducing the bilateral lung mean dose and the V20 ipsilateral lung volume, compared with the other reported techniques [1]. In our unpublished data on 30 selected patients, we have pointed out that T-IMRT leads to reducing the cutaneous acute high-grade toxicity according to the RTOG scale even if the volume of our Italian breast cancer patients was higher than the Asian one (mean 910 cc, median 775 cc). In our clinical records, the tangential technique with 6 MV photons, comparing the standard wedge tangential technique (SWT) versus T-IMRT, was used, and several dosimetric parameters for planning target volume (PTV) and organs at risks (OARs) were analyzed [3]. The collapsed cone (CC) dose calculation algorithm was applied instead of the pencil beam classic (PBC) calculation model, and a statistical analysis was performed with Student t test (p \ 0.05). T-IMRT was superior to the SWT in reducing the percentage of the PTV receiving more than 110 % (V110 %) and 107 % (V107 %) prescribed dose as well as Dmax. The reduction of V110 %, V107 %, and Dmax was 50, 30, and 3 %, respectively, without compromising PTV coverage (no significant reduction of V95 % and D98) [5]. Comparing T-IMRT with SWT, our data showed no significant dosimetric differences for the heart (Dmean, V10, V20, V30 and V50) and lung (Dmax, Dmean, V10, V20, V30 and V50) but a significant reduction of hot spots, calculated as Dmax and V50. A significantly lower dose with T-IMRT (5 % reduction for Dmean) was recorded for the controlateral breast. Furthermore, a comparison between the ipsilateral lung dose distributions obtained with CC versus PBC, for T-IMRT only, showed that the use of PBC undervalues M. G. Ruo Redda (&) S. M. Anglesio S. Allis R. Verna A. Girardi E. Trevisiol A. Reali Department of Oncology, Radiation Oncology, University of Turin, S. Luigi Gonzaga Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy e-mail: mariagrazia.ruoredda@unito.it

Is a policy of watch and wait after a complete response following neoadjuvant treatment for locally advanced rectal adenocarcinoma justified? Should we reset the limit?

Radical surgery has been considered, in the past century, the unique and more effective therapeutic option for locally advanced rectal adenocarcinoma. Standardization of surgical technique [1] has reduced the local recurrence rates to one digit percentages, and the addition of radiation therapy treatments combined with less toxic chemotherapy regimens either preor post-operatively has significantly improved the shortand long-term outcomes of these patients. The systematic use of neoadjuvant therapy has led to the common observation that at least 20–30 % of patients (depending on the CHT regimen used and the timing of surgery) are completely free of tumor (CR: ypT0ypN0) in the resected specimens [2, 3]. Despite these encouraging results, we continue to operate on these patients with a low-mortality rate but with a significant percentage of functional sequelae (low anterior resection syndrome, leaks, stenosis, sexual and urinary problems, need for a diverting stoma). These complications occur more frequently than usually reported in the surgical literature, especially when the postoperative evaluation is performed by a Registered Nurse or a surgeon not involved with the operation [4]. If we all agree that small T1 lesions without particularly aggressive features can be safely treated by wide local excision (either transanal or better via TEM, Transanal Endoscopic Microsurgery) [5] why should we modify our thinking and treat the patients who have reached a complete response after the preoperative treatment in a different way? Pioneristic work [6] has demonstrated that in patients who respond to the neoadjuvant treatment, a policy of intense observation without surgery is possible and not followed by an increase in cancer related mortality. The main difficulty in accepting this ‘‘obvious’’ policy, by the surgical community, has been that, so far, no test has shown to be 100 % accurate in identifying a complete response to the preoperative treatment, thus in discriminating which patient to observe from which patient to operate [7]. Another important issue that has recently emerged is that the arbitrarily chosen 6-week waiting period (after the completion of the neoadjuvant treatment and the operation), if prolonged up to 8 or 12 weeks brings a consistent increase in the percentage of complete responders up to 30 % and above [8]. This observation can be explained by the prolonged effect of the radiation therapy subministered to the tumor bed. At our institution we have developed a prospective observational protocol, IRB approved, for patients with locally advanced non-metastatic extraperitoneal rectal adenocarcinomas consisting of re-evaluation at 6 weeks after the end of ERT and then at 12 weeks for patients C. E. Vitelli (&) F. Stipa Department of Surgery, Azienda Ospedaliera San Giovanni Addolorata-Roma, Via dell’Amba Aradam 9, 00184 Rome, Italy e-mail: cevitelli@me.com

Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis

Encephalitis associated with anti-N-Methyl-D-Aspartate Receptor (NMDAR) antibodies is an autoimmune encephalopathy often associated with teratoma [1]. Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system (CNS) associated with antibodies against aquaporin 4 (AQP4) [2]. Here, we report the case of a patient who developed limbic encephalitis (LE) followed by NMO, whose serum harbored anti-NMDAR and anti-AQP4 IgG antibodies. A 50-year-old woman presented with subacute, shortterm memory loss, confusion, and behavioral changes. Routine blood tests, an infectious disease screening, an electroencephalogram (EEG) and cerebral spinal fluid (CSF) tests were all negative, whereas a brain MRI showed a T2-weighted, hyperintense medial temporal cortex. A pelvic mass was detected by computed tomography (CT) scan. Two months later, she underwent a hystero-adnexectomy with the removal of an ovarian teratoma. A diagnosis of paraneoplastic LE was made. Tests for classical onconeural antibodies (Hu, Ri, Ma2, CV2/CMRP5, amphiphysin, Yo) proved negative. Her memory deficit started to improve 4 months after surgery, when she received repeated courses of low-dose oral steroids. One month later, she had only residual retrograde amnesia (Fig. 1e). Five months later, she developed drowsiness, cervical itching, and impaired gait. Within 2 weeks, she had developed paraplegia and MRI showed multiple T2weighted hyperintense lesions in the pons, hypothalamus, medulla oblongata, and cervical spine (Fig. 1a–c). A CSF analysis proved negative (normal white cell count and proteins, and absence of IgG intrathecal synthesis). Plasmaexchange and high-dose intravenous steroids were initiated, resulting in a slow improvement of strength. Nine months later, she presented with left-eye optic neuritis. High-dose intravenous steroids were partially effective. Three months later, a relapse occurred with weakness of the right limbs. An MRI disclosed new lesions in the pons and dorsal spine (Fig. 1d). Her serum and CSF were tested for AQP4-IgG-Ab by indirect immunofluorescence on a commercial assay (Euroimmun, Lubeck, Germany) [3], proving positive on serum (titer 1:100). The test was extended to NMDAR-IgG-Ab, also proving positive on serum (1:32) and on CSF. The patient was treated with plasma-exchange and oral steroids, with benefit. Three months later, her CSF analysis revealed a normal white cell count and increased protein content (84 mg/dl); matching oligoclonal bands were detected in the CSF and serum. Human leukocyte typing disclosed the presence of the class I allele B8 and class II DR3-DQ2 (DRB1*03-DQB1*02). AQP4-IgG-Aband NMDAR-IgG-Ab-positivity were both confirmed, but a decrease in serum Ab titer was shown (both Abs serum titer 1:10; NMDAR-Ab CSF titer 1:3, 2); VGCC-, AMPAR-, GABAbR-, LGI1and CASPR2-Abs tested negative. Treatment with azathioprine was started. Eight months later, her conditions were stable. This patient presented with LE followed by NMO 1 year later, and tested positive for AQP4and NMDAR-Abs. To M. Zoccarato M. F. Pelizza B. Giometto L. Zuliani (&) Department of Neurology, Ospedale Ca’Foncello, Azienda Unita Locale Socio-Sanitaria 9 Treviso, Piazza Ospedale 1, 31100 Treviso, Italy e-mail: luigizuliani77@gmail.com

Allogeneic hematopoietic stem cell collection from elderly related donors: a retrospective multicenter study on mobilization and collection efficiency

Correspondence: Franco Maria Dallavalle Via Vochieri, 51 15121 Alessandria, Italy E-mail: fdallavalle@ospedale.al.it SUMMARY In literature several data are reported showing that CD34+ cell collection efficiency decreases gradually with the increasing in donor age. We have therefore retrospectively analyzed data on 81 healthy donors older than 65 years from eight Italian transplant centers undergoing a total of 142 apheresis procedures. Data related to CD34+ cell mobilization in peripheral blood, collection and complication during procedures were recorded. Standard mobilization regimen was granulocyte colony-stimulating factor at 10 μg/kg/die for 4 days. On Day 5, median number of peripheral CD34+ cells was 42/ mL. Median number of total CD34+ cells collected was 3.35x106/kg in a median of 2 aphereses. Adverse events were recorded in 34.8% of procedures but were mostly mild. Our data show that mobilization of donors older than 65 can be safe and effective in the majority of cases. Allogeneic hematopoietic stem cell collection from elderly related donors: a retrospective multicenter study on mobilization and collection efficiency

Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukaemia: a pilot study of a monocentric experience

Correspondence: Rosa Fanci Department of Haematology Careggi University Hospital of Florence, Italy E-mail: rosa.fanci@unifi.it SUMMARY The aim of this study was to evaluate the posaconazole (PCZ) plasma levels in the presence of patient-specific factors and the possible correlation between plasma levels and the clinical outcome in acute myeloid leukaemia (AML) patients. Acceptable levels for prophylaxis are ≥0.5 mg/L, although levels >0.7 mg/L have been recommended. Twenty-two AML patients in first-induction were included, receiving posaconazole as primary prophylaxis (200 mg/tid). The PCZ mean levels in 15 samples, obtained after 5-7 days, were 0.49±0.6 mg/L and in 34, obtained within 8-15 days, were 1.03±0.78 mg/L. The failure to reach adequate levels was related mainly to the use of proton-pump inhibitors or to poor compliance. Antifungal therapy was needed in 27% of patients, all with inadequate levels. No breakthrough aspergillosis was documented. In our experience, therapeutic drug monitoring seemed helpful to identify PCZ low concentrations and to optimise the treatment strategy. Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukaemia: a pilot study of a monocentric experience

Adenocarcinoma arising from a long-standing Kock pouch

Dear Editor: Ulcerative colitis (UC) is a chronic inflammatory bowel disease involving the all colon and rectumwith different extent. It is well known and widely accepted that surgical treatment is necessary to manage refractory forms and severe clinical symptoms and to prevent colonic cancer. The risk of primary colonic cancer is higher the longer interval fromUC diagnosis has passed. Proctocolectomy represents the surgical choice for these patients, and until development of ileal pouch anal anastomosis (IPAA), the continent Kock pouch has represented the only continent solution that, avoiding the formation of terminal ileostomy, has improved patient’s quality of life. Because of its relatively common complications, mainly associated to a loss of function due to nipple valve slippage, Kock pouch has been afterwards supplanted by IPAA that restores the bowel continuity maintaining the physiological sphincters function. We would like to report a new case of a primary adenocarcinoma arising from a long-standing Kock pouch in a 56-yearold woman. She had a proctocolectomy with pouch formation in 1985 for severe pancolitis in ulcerative colitis associated to erythema nodosum. Despite medical treatments and a previous diverting ileostomy, she experienced a progressive deterioration of her clinical symptoms confirmed by endoscopic and histological findings. At the time of surgery, a severe inflammation involved the all rectum. Therefore, a proctocolectomy wasmandatory. The restorative proctocolectomywith an IPAA was avoided because of patient’s pelvic floor weakness. Due to her high motivation of having a better body image and quality of life, a continent Kock ileostomy was given avoiding a terminal ileostomy. The histopathology report on surgical specimen confirmed the diagnosis of ulcerative colitis without dysplasia or cancer. Since the operation, the pouch function has always been satisfactory without any complications; therefore, she has never had pouch revision nor endoscopic surveillance. Twenty-eight years later, the patient complained of mild discomfort at the stoma site and difficulty in pouch intubating associated to bloating, abdominal tenderness, and need of Valsalva to empty the pouch. The stoma was not explorable because of a retracted and tender distal area. It admitted just the tip of the fifth finger and the exploration was painful. A little polypoid lesion (1.5×1×0.5 cm) was noted on the right side of the mucocutaneous junction of the stoma. Clinical examination was otherwise unremarkable. Excision biopsy under local anesthesia was performed, and the histology revealed high-grade dysplasia with focal area of intestinal type mucinous adenocarcinoma with dermal infiltration (CK 20+ and CD X2+). Imaging by CT, MRI, and PET-TC scanning showed a concentric thickening of 6 mm of the distal part of the stoma characterized by high metabolic activity. There was no suspicion of regional node involvement or evidence of metastases. Blood tests and neoplastic markers were negative. An excision of the pouch together with 10 cm distal ileum segment was performed. The pouch appeared dilated, but otherwise normal and no abnormalities of the valves were obvious. Macroscopically, the tract of the exteriorized bowel showed a thick retracting area with a reduced compliance of the ileum wall. Nodules enlargement were also noted at the time of surgery. An end ileostomy was fashioned on the contralateral side of the abdomen as oncologically I. Giannini (*) Department of Emergency and Organ Transplantation, General Surgery and Liver transplantation Unit, University Aldo Moro of Bari, Policlinico. Piazza G Cesare, 11, 70124 Bari, Italy e-mail: ivanagi83@yahoo.it

Special issue on advances in Learning Classifier Systems

Learning Classifier Systems (LCS) constitute a uniquely adaptable class of learning framework existing at the intersection of machine learning and evolutionary computation. Fundamentally, an LCS combines genetic search with an appropriate learning strategy to evolve a rule set which collectively describes a temporal or spatial problem. Since their conceptualization, a variety of algorithmic architectures and mechanisms have been introduced with the objective of improved functionality or application to new problem domains. As technology advances, the power and versatility of LCS algorithms makes them increasingly appealing. Since 1992, the International Workshop on Learning Classifier Systems (IWLCS) has sought to promote the ongoing development of LCS architecture, application, and theory. Beginning in 2003, the IWLCS has been held annually, in association with the Genetic and Evolutionary Computation Conference (GECCO). This special issue includes original works as well as selected and revised papers from the 13th and 14th IWLCS, held in Portland, USA, during GECCO 2010, and Dublin, IR, during GECCO 2011. Over the last few years, there has been tremendous progress in (1) the systematic design of novel LCSs that can deal with additional problem topologies, (2) theoretical analyses incorporated to better understand and improve existing systems and (3) applications within important domains. The works collected in this special issue extend this trend, illustrating the maturity of LCSs and their applicability to hard real-world problems that currently elude solution. In Production System Rules as Protein Complexes from Genetic Regulatory Networks: An Initial Study, Bull presents a new type of production system rules, by introducing a new, indirect encoding that views rules as protein complexes produced by the temporal behavior of an artificial genetic regulatory network. The experimental analysis shows that the new innovative approach has potential, and opens up different lines for future research. Taking a look back to the origins of LCSs, in Risk Neutrality in Learning Classifier Systems Smith develops a novel model of risk-neutral reinforcement learning in a traditional Bucket Brigade credit-allocation market which is adjusted by a genetic algorithm. The work revises two important aspects in LCSs: default hierarchies and long chains of coupled classifiers. The new model is extensively discussed, reviving some ideas present in the first LCSs proposals by Holland. In Analysing BioHEL Using Challenging Boolean Functions, the issue moves to different systematic analysis of current LCSs that enable a better understanding of the systems and give light to future improvements. In this paper, Franco et al. examine how BioHEL, a hierarchical evolutionary learning system specifically designed to cope with large-scale datasets, behaves on a family of Boolean functions whose complexity is varied along different dimensions. The experimental analysis shows the D. Loiacono Politecnico di Milano, P.zza Leonardo Da Vinci, 32, 20133 Milan, Italy e-mail: loiacono@elet.polimi.it

Foreword to special issue on “Myocarditis”

William Osler, with a very actual sentence, stated, back in year 1892, in its Medicine textbook: ‘‘There are three phases to treatment: diagnosis, diagnosis and diagnosis’’ [1]. This sentence clearly highlights that the best clinical management is based upon the most accurate diagnosis. Historically myocarditis has being considered a rare and poorly understood condition, a conundrum with polymorphic clinical presentation and variable prognosis ranging from spontaneous resolution to progressive heart failure and death. The first comprehensive review with a modern approach to etiopathogenesis was published in 1980 by Woodroof JF, who highlighted the possible etiological role of Coxsackie viruses and of the immune system in the progression of cardiac damage, with possible evolution to a dilated cardiomyopathy [2]. A major advance in diagnosis was the refinement of the endomyocardial biopsy technique using the King’s bioptome by Richardson [3]. Another important step was the development of a consensus pathological classification and histological definition of myocarditis by endomyocardial biopsy, known as the Dallas criteria [4]. Meanwhile, the first experimental observations were made by several investigators, suggesting a possible involvement of autoimmune mechanisms to cardiac autoantigens; in particular, a mouse model for myosin-induced autoimmune myocarditis was described by the Neu et al. [5]. In addition, various groups in the late 80s and early 90s reported the presence of circulating anti-heart autoantibodies against myosin as well as other autoantigens in acute and chronic myocarditis or dilated cardiomyopathy, in keeping with the hypothesis of autoimmunity being involved in a subset of patients [6–14]. A retrospective multicenter registry from the USA coordinated by Cooper et al. [15] reported the efficacy of immunosuppressive therapy in a rare but lethal form of myocarditis, e.g., giant cell myocarditis. On these premises, the multicenter Myocarditis Treatment Trial was designed using the Dallas criteria to recruit myocarditis patients to 6 months immunosuppression; the therapy with azathioprine and prednisone or cyclosporine A and prednisone was well tolerated, and no significant effect on survival was observed, although the study was not powered to detect differences in survival [16]. The results of the trial had a profoundly negative effect in the next decade on the use of endomyocardial biopsy to detect and treat myocarditis. However, researchers developed new diagnostic tools to be added to standard histology, in particular immunohistochemistry, to increase sensitivity of endomyocardial biopsy particularly in focal and chronic myocarditis and characterize the number and type of infiltrating inflammatory cells, and molecular detection of genomic material of infectious agents mainly by polymerase chain reaction (PCR), to diagnose infectious, particularly viral myocarditis [17–24]. This work leads to another major step forward, e.g., the 1995 WHO classification of cardiomyopathies, with the acknowledgment that myocarditis is diagnosed on endomyocardial biopsy by established histological, immunological and immunohistochemical criteria; molecular techniques on EMB were recommended to identify viral etiology [25]. In the WHO classification, infectious, autoimmune and idiopathic forms of myocarditis are recognized that may lead to dilated cardiomyopathy [25]. Using serum cardiac autoantibody testing as well as histology, immunohistology and viral PCR on endomyocardial biopsy, it is nowadays possible to define distinct etiopathogenetic A. L. P. Caforio (&) Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences, Centro ‘‘V. Gallucci’’, University of Padova-Policlinico, Via Giustiniani, 2, 35128 Padua, Italy e-mail: alida.caforio@unipd.it

Letter to the Editor of European Archives of Otorhinolaryngology

We read the interesting Review Article by Slootweg et al. [1] recently published in this Journal. We concur on the importance of an accurate morphology definition of sinonasal cancers (SNC), which is crucial not only for therapeutic decisions but also from the etiologic point of view. In fact, sinonasal carcinomas are strongly associated with occupational exposures, in particular wood and leather dusts and nickel compounds [2]. In Italy since 2008 incidence and etiology of primary epithelial tumors of nasal cavity and paranasal sinuses are surveyed through a nationwide cancer registry. The Lombardy Registry of Sinonasal Cancers was established at the end of 2007 in the most populated (almost 10 million residents at the 2011 census) and industrialized Italian region [3]. It collects all epithelial SNC cases occurring among residents in the region at the time of first diagnosis. The primary sources of information on SNC cases are the departments of pathology, otolaryngology, maxillofacial surgery, and radiotherapy in over 100 hospitals. Histological types are defined according to the World Health Organization (WHO) Classification [4]. Occupational exposure to selected agents is collected through a standardized questionnaire administered to patients or their next of kins by trained interviewers. In the period 2008–2012 we recorded 255 SNC cases with median age at diagnosis of 68 years, 167 (65.5 %) among males, and 88 (34.5 %) among females. Using the European population as standard, the SNC incidence rates (9million) are 6.8 (95 % CI 5.7–8.2) in men and 2.6 (95 % CI 1.9–3.4) in women. The anatomical site mostly affected was the nasal cavity, with 54 cases in males (32.3 %) and 32 (36.4 %) in females, followed by the maxillary sinus, 35 cases (21.0 %) in males and 25 (28.4 %) in females. The ethmoidal sinus was rarely involved in females (7 cases, 8.0 %) while there were 37 cases (22.2 %) in males. The most frequent morphology was squamous cell carcinoma, with a similar distribution across gender, 73 cases (43.7 %) in males and 41 (46.6 %) in females. Conversely, adenocarcinomas were twice as frequent in men (53 cases, 31.7 %) than in women (13 cases, 14.8 %). The majority of adenocarcinomas were intestinal-type adenocarcinomas (ITAC), 37 (22.2 %) in men and 8 (9.1 %) in women. There was a strong association between anatomical site and morphology. Out of 114 squamous cell carcinomas, 52 (45.6 %) originated from the nasal cavity, while among 66 adenocarcinoma cases 27 (40.9 %) were located in the ethmoidal sinus. The higher rates in men and the different distribution of SNC site and morphology between men and women most probably reflect differences in previous exposure to carcinogens. In fact, among the 66 subjects with adenocarcinoma, occupational exposure was recorded for the majority (50, or 75.8 %). Of these, 33 (50 %) had been ever exposed to wood dust and 19 (28.8 %) to leather dust. Conversely, the proportion of subjects ever exposed was about 10 % for squamous cell carcinoma and about 20 % for other morphologies. Although lower, the proportion of subjects with squamous cell carcinoma or other C. Mensi (&) L. Riboldi C. Sieno P. A. Bertazzi D. Consonni Department of Preventive Medicine, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Via San Barnaba 8, 20122 Milan, Italy e-mail: carolina.mensi@unimi.it

Sensitivity and feasibility of lung ultrasound in bronchiolitis—reply to the correspondence letter by Catalano

We thank Dr Catalano et al. for their interest on our article. The comment raises two important issues, one regarding the test sensitivity and the second, more general, on test feasibility. Assuming the final diagnosis as a gold standard, lung ultrasound (LUS) showed an excellent sensitivity (47/52 vs 38/52 of chest x-ray, 90 vs 73 %), but we have to consider the observational characteristics of the study design, performed in a real-world setting with real patients, real problems, and real doctors, with clinically driven indication to chest xrays. This is typical of an observational effectiveness study; it is not an efficacy study, evaluating the technique under ideal conditions, and the observed results can be more directly relevant to clinical practice but also vulnerable to selection bias [1]. The authors raise concerns about the equipment setting and rationale for chest x-ray prescription. We reported this information in the Methods section: chest x-ray was always requested by the attending physician on the basis of the clinical picture; the equipment used for the lung ultrasound was a Toshiba Nemio machine, equipped with a high-resolution linear probe with frequencies ranging from 6 to 12 MHz. Regarding the second issue on the practical appeal of the method, we reported our gratifying experience in the demanding theater of a neonatal intensive care unit, consistent with the international consensus that the method is simple, safe, and sensitive—when challenged under controlled conditions versus appropriate gold standards [5]. Dr Catalano argues that lung ultrasound relying on artifacts, such as B-lines, is not an evidence-based best-practice imaging clue. We agree with that: LUS is not always able to provide a detailed anatomical definition, especially when we consider B-lines. However, we believe that the usefulness of LUS relies in being an additional imaging tool for the evaluation of the lung, which is quick, bedside, low-cost, non-ionizing, and very sensitive to detect the loss of air content. Of course, LUS should be integrated with other imaging modalities, when a detailed anatomical definition is needed. It is also true that every new diagnostic tool always raises many uncertainties when it is proposed. Given the high versatility and potential clinical implications of adding ultrasound to the regular imaging equipment, we believe it is of importance to deepen the knowledge of this technique to better understand its strengths and limitations. Cardiologists who experienced lung ultrasound as an adjunct to much more technically demanding echocardiography say that “from a technical viewpoint, in the echocardiographic cursus studiorum where 2D echo represents the elementary school, Doppler echo the secondary school, and stress echo University, B-lines correspond to kindergarten [3].” We also concur with Daniel Lichtenstein, who recently stated (Montecarlo Lung Ultrasound School 2013) that it takes 20 s to make a lung scan with V. A. Caiulo (*) School of Ultrasound of Italian Federation of Pediatricians, Piazza Angeli 3, 72100 Brindisi, Italy e-mail: antoniocaiulo@inwind.it

The Origin of the Genetic Code: Matter of Metabolism or Physicochemical Determinism?

In the research field on the origin of the genetic code two lines of thought are evident. The first puts at the core of the origin of the genetic code the physicochemical properties of amino acids (1967; Woese et al. 1966; Jungck 1978; Weber and Lacey 1978; Lacey and Mullins 1983; Di Giulio 1989a, b; Taylor and Coates 1989; Di Giulio 1996; Freeland and Hurst 1998; Lacey et al. 1992). Indeed, the physicochemical theory of the origin of the genetic code suggests that these properties have been the main selective pressure that determined the organisation of the genetic code (Sonneborn 1965; Woese et al. 1966; Fitch and Upper 1987; Di Giulio 1997). A prediction in part equivalent is also made by the stereochemical theory of the origin of the genetic code that maintains that interactions between codons or anticodons and amino acids have been the main forces that organised the genetic code (Woese 1967; Shimizu 1982; Szathmary 1993; Yarus 1998; Yarus et al. 2009). Therefore, also for the stereochemical hypothesis the physicochemical properties of amino acids were essential in organising the code. On the other hand, the second line of thought considers the metabolism and the biosynthetic relationships between amino acids as the main force that defined the evolutionary organisation of the genetic code (Wong 1975, 2005; Di Giulio 2008a), with the properties of amino acids having only a subsidiary role in this organisation (Wong 1980; Di Giulio 1989a). The current special issue of the Journal of Molecular Evolution, dedicated to the Evolution of the Genetic Code, presents four papers that summarise this field of study at the moment and bring some insight into these two lines of thought. Naturally, whether the physicochemical properties of amino acids would reflect the structure of proteins, that is to say their function, then this would not be incompatible with the coevolution theory of the genetic code, because the protein structure, by means of the physicochemical properties of amino acids, might have been the main selective pressure that determined the genetic code organisation. Obviously, this would also imply a correlation between the biosynthetic relationships of amino acids and their physicochemical properties, in addition to that with the structure of the genetic code, as some works seem to indicate (Di Giulio 1991, 1996). One of the works presented in this special issue by Francis (2013) is inclined to maintain a similar position. Indeed, the title of this paper is: ‘Evolution of the genetic code by incorporation of amino acids that improved or changed protein function’. Furthermore, Francis (2013) considers the hypothesis that very early on the genetic code used only codons of the GNC kind (Ikehara 2002; Trifonov 2004; Francis 2011), a code completely compatible also with the coevolution theory (Di Giulio 2008a). However, the observation that the properties of amino acids are mirrored in the genetic code organisation does not necessarily imply their determining role in the genetic code organisation, unless one does not validate that the level reached by the minimisation of physicochemical distances between amino acids in the genetic code structure is very elevated. This, at the moment, does not seem to be the case (Wong 1980; Di Giulio 1989a; Di Giulio et al. 1994; Di M. Di Giulio (&) Laboratory for Molecular Evolution, Institute of Genetics and Biophysics ‘Adriano Buzzati Traverso’, CNR, Via P. Castellino, 111, 80131 Naples, Napoli, Italy e-mail: massimo.digiulio@igb.cnr.it; digiulio@igb.cnr.it

Vertebral artery dissection during Kung-Fu training

Objective We describe a case of vertebral artery dissection during Kung-Fu practice. Materials and methods We describe a case of a 26-year-old male with no significant pathologies in his medical history. The patient was a non-smoker, did not drink alcohol, as well as did not take any kind of drug. He had no family history of neurological problems. The patient was a KungFu practitioner and was subjected to an annual medical examination for competitive sports, which never revealed anything pathological. During a training session, the patient made a quick movement with his head and trunk. The movement was performed in an uncoordinated way, in contrast to what usually happens in kung fu where the movements are characterized by excellent coordination. This incoordination led him to lose his balance and fall backwards, without head trauma. Subsequently, the patient stood up without any trouble, finishing his training. No pain to the neck or head was reported. Driving back home, the patient realized that he did not see well, and decided to go to the nearest Emergency Department. There, a brain CT scan and a neurological evaluation were performed, detecting no abnormalities. Therefore, he was discharged. The next morning, due to an unusual headache and to the persistence of visual impairment, he decided to come to our Emergency Department. We performed a neurological assessment, which showed a complete homonymous hemianopia of the right side. The patient was, therefore, subjected to brain CT scan, which showed a left occipital ischemic lesion. He was admitted to the Stroke Unit. During the hospitalization, Doppler ultrasound of supra aortic vessels showed the dissection of the left vertebral artery. The patient underwent cerebral angiography, which confirmed the dissection of the distal part of the left vertebral artery (Fig. 1–9). The possibility of being affected by Ehlers–Danlos’s syndrome, as well as Marfan’s syndrome and osteogenesis imperfecta, was excluded [1]. No history of migraine [2]. Hyperhomocysteinemia and MTHFR mutations were excluded [3]. Major trauma to the skull or chest was excluded. We also excluded whiplash injury and chiropractic manipulation as possible etiologies. An oral anticoagulant therapy was prescribed. An angiography, performed approximately 2 months after the onset of symptoms, showed the results of the dissection. Few cases of vertebral artery dissection during sport practices have been described in literature. None of these concerned the Kung-Fu [4, 5]. Discussion and conclusion The case described shows that even a simple movement of the head, already carried out several times in the past, can lead to the dissection of supra-aortic vessels [6]. We believe that it is important to remember that a sudden movement of the head can lead to a vessel dissection and that this can happen also without the patient experiencing any pain. F. Pacei (&) IRCCS Policlinico San Donato, P.za Malan 1, 20097 San Donato Milanese, MI, Italy e-mail: federico.pacei@gmail.com

Clinical and neuropathological findings in Hashimoto’s encephalopathy: a case report

Hashimoto’s encephalopathy (HE) is a controversial autoimmune condition of the central nervous system (CNS) characterized by focal and/or diffuse symptoms concomitant with raised levels of anti-thyroid antibodies, in particular anti-thyroperoxidase (TPO) and/or anti-thyroglobulin (TG) antibodies [1]. Hereby, we provide the full clinical and neuropathological description of an HE patient with a rapid and fatal course. A 67-year-old man with autoimmune hypothyroidism taking L-thyroxine 100 lg/day came to our observation because of 1-month history of apathy and speech difficulties. At admission in the neurological ward, fluent aphasia, disorientation, and spontaneous diffuse myoclonic jerks were present. Cranial CT and brain MRI were unremarkable. EEG evidenced rare diffuse theta-delta bursts. On laboratory investigations, we detected only a markedly raised titer of serum anti-TPO antibodies (3,790 UI/ml). CSF analysis disclosed very high protein concentration (126 mg/dL) with moderate alteration of blood–brain barrier permeability. Virological analyses were all negative. Total tau CSF concentration was normal, whereas the 14-33 protein was present in traces. To rule out a neurological paraneoplastic syndrome, the patient’s serum was analyzed by an indirect immunofluorescence assay on monkey cerebellum slides. We evidenced a Tr-like pattern, characterized by a prominent staining of cytoplasm and dendrites of Purkinje cells, but with no positive dots in the molecular layer (Fig. 1). No paraneoplastic antibody specificity (Hu, Yo, Ri, amphiphysin, Ma2, Ta) was detected by dot blot. Serum anti-VGKC and anti-NMDA-R antibodies were absent. A total body contrast-enhanced CT ruled out occult neoplasms. Given the subacute encephalopathy picture with no evident causes and the very raised serum titer of anti-TPO antibodies, a presumptive diagnosis of HE was made. A high-dose systemic methylprednisolone pulse (1,000 mg/ day) was started. After 5 days from steroid initiation, the patient was intubated and transferred to the intensive care unit (ICU) because of a refractory convulsive status epilepticus. Thiopentone was administered to get a suppression-burst pattern on EEG recordings. After 1 week the patient’s clinical conditions markedly ameliorated and no seizure relapses were observed. Therefore, he was readmitted to our neurologic ward. In the following 5 days, diffuse myoclonic jerks progressively increased, leading to convulsive status epilepticus. The patient entered again the ICU to employ intravenous thiopentone. A new brain MRI study evidenced diffuse hyperintensity of cortical white matter of parietal lobes in T2 and FLAIR scans with no contrast enhancement in T1 sequences. MRI signs of bilateral hippocampal sclerosis were also present. The patient’s neurologic status deteriorated in spite of a 10-day systemic methylprednisolone (1,000 mg/day) and 5-day intravenous human immunoglobulin pulse (400 mg/kg/ day). Exitus occurred from a multiorgan failure syndrome after 3 weeks. The autopsy procedure was limited to the intracranial content, since the remote suspect of a prion disease. On gross inspection, cortical gyri were slightly flattened. On microscopic examination, areas of neuropil vacuolation with congestion and swollen endothelial cells D. Imperiale (&) R. Testi A. Romito S. Taraglio Centro Regionale Diagnosi ed Osservazione Malattie Prioniche DOMP, ASL To2, Via Cibrario 72, 10144 Turin, Italy e-mail: daniele.imperiale@aslto2.piemonte.it

Cocaine-induced cluster-like headache

Cluster headache (CH) is the paradigm of trigeminal autonomic cephalalgias (TACs). According to the guidelines of the International Classification of Headache Disorders [1], CH is characterized by attacks of severe, strictly unilateral pain which may be orbital, supraorbital, temporal or any combination of these sites, lasting 15–180 min and occurring from once every other day to eight times per day. The pain is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, myosis, ptosis and/or eyelid oedema and/or with restlessness/agitation [1]. However, there have been some cases where, although the headache had clinical features that mimicked primary CH, even in the typical time pattern and response to treatment, they were of secondary origin [2] and thus named cluster-like headache (CLH). A recent review reported that the most frequent pathologies associated with CLH were of vascular origin (38.5 %), followed by tumours (25.7 %) and inflammatory/infectious diseases (13.5 %), where iatrogenic or drug-related conditions represented 4.7 % of the CLH [3]. Cocaine is involved in several neurological complications: ischaemic stroke, transient focal deficits, dizziness, seizures and even headache [4]. Headache usually has migrainous features in cocaine abusers, even if cocainerelated cases of cluster-like headache and orofacial pain have occasionally been reported [5]. Herein, we report a case where cocaine abuse gave rise to head and facial pain, accompanied by autonomic features, mimicking CH. In November 2010, a 24-year-old woman, smoker, had a neurological evaluation for right zygomatic and periorbital pain which was so severe and recurrent as to make her return to the Emergency Department of Campo di Marte Hospital in Lucca five times in 1 week. The patient complained of 1 or 2 daily pain attacks, mostly in the evening (about 8:00–9:00 p.m.), associated with rhinorrhea, lacrimation, conjunctival injection and reduced palpebral opening (ptosis) on the right of her face and reported having had two similar, less painful, episodes on the left side. Each pain crisis lasted 45–180 min, with severe, throbbing and burning pain. She was restless and extremely nervous during the attacks and reported having had a nosebleed three times before the onset of facial pain in the last week. Both neurological examination and CT scan were unremarkable, as was brain MRI. Treatment with i.v. ketorolac, ibuprofen, tramadol and diclofenac had no effect. Only i.v. paracetamol (1,000 mg/day) and i.m. dexamethasone (8 mg/day), administered in the Emergency Department, seemed to provide partial relief, even though a spontaneous cessation of the attack could not be ruled out. Although some of the facial pain features were consistent with CH, according to the HIS diagnostic criteria, they had some atypical characteristics, i.e. nose G. Cafforio (&) M. Mazzoni Neurological Department, Campo di Marte Hospital, Via dell’Ospedale, Lucca, Italy e-mail: gcafforio@libero.it