CASE REPORTterapeutica.ro/img/rev/pdf/26/2014-2_.pdf · Negulescu Cristina, Drăgănescu Anca,...

2EDITORIAL2EDITORIAL245 The European 2The European 22HIV/AIDS22 & Infectious 2Diseases Academy2Diseases Academy25 Years and on-going25 Years and on-going22!2Streinu-Cercel A2Streinu-Cercel A22.2REVIEW2REVIEW247 Influenza infection and neurologic 2Influenza infection and neurologic 2complications2complications2Vișan Angelica, Luminos Monica, 2Vișan Angelica, Luminos Monica, 2Negulescu Cristina, Drăgănescu Anca, 2Negulescu Cristina, Drăgănescu Anca, 2Bilasco Anuţa, Vasile Magdalena, Măntescu 2Bilasco Anuţa, Vasile Magdalena, Măntescu 2Ruxandra, Merișescu Mădălina, Slavu 2Ruxandra, Merișescu Mădălina, Slavu 2Diana, Dogaru Cornelia, Streinu-Cercel A.2Diana, Dogaru Cornelia, Streinu-Cercel A.2ORIGINAL PAPERS2ORIGINAL PAPERS256 Inappropriate use of 2Inappropriate use of 22PPI22s to patients 2admitted into a non ICU gastroenterology 2admitted into a non ICU gastroenterology 2department2department2Neag Maria, Bocșan Corina, Popa Adina, 2Neag Maria, Bocșan Corina, Popa Adina, 2Câmpean R., Mircea P.A.2Câmpean R., Mircea P.A.261 Assessing the effectiveness and safety 2Assessing the effectiveness and safety 2of pharmacological therapy in children 2of pharmacological therapy in children 2diagnosed with attention deficit and 2diagnosed with attention deficit and 2hyperactivity disorders2hyperactivity disorders2Daviţoiu Ana Maria, Truţă Elena, 2Daviţoiu Ana Maria, Truţă Elena, 2Negulescu Cristina, Constantin Laura, 2Negulescu Cristina, Constantin Laura, 2Stoica Alexandra, Pleşca Anca Doina2Stoica Alexandra, Pleşca Anca Doina2THERAPEUTICAL PRACTICE2THERAPEUTICAL PRACTICE22682Prediction scores and complexity 2Prediction scores and complexity 2of physical therapy approach in the 2of physical therapy approach in the 2Intensive Care Unit of the Clinical 2Intensive Care Unit of the Clinical 2Emergency Hospital Bucharest2Emergency Hospital Bucharest2Popescu G., Macovei R.Al., Ilie Mădălina, 2Popescu G., Macovei R.Al., Ilie Mădălina, 2Constantinescu G., Stănciulescu Elena-2Constantinescu G., Stănciulescu Elena-2Luminița, Pătru Cristina, Păun M.Al., 2Luminița, Pătru Cristina, Păun M.Al., 2Grințescu Ioana Cristina, Grințescu 2Grințescu Ioana Cristina, Grințescu 22Ioana Marina22722Assessment of prognostic factors in 2Assessment of prognostic factors in 2myelodysplastic syndromes2myelodysplastic syndromes2Georgescu Daniela, Patrinoiu Oana, 2Georgescu Daniela, Patrinoiu Oana, 2Popescu Mihaela, Ciuhu Anda Natalia2Popescu Mihaela, Ciuhu Anda Natalia22CASE REPORT22782Gastrointestinal stromal tumour: 2Gastrointestinal stromal tumour: 2predicting the risk of recurrence of 2predicting the risk of recurrence of 22primary tumours2Săvulescu F., Duțu C., Trifu V., 2Săvulescu F., Duțu C., Trifu V., 2Darmanescu Monica, Surdeanu D., 2Darmanescu Monica, Surdeanu D., 22Merticariu B., Cirlan C.22832Therapeutic success in chronic myeloid 2Therapeutic success in chronic myeloid 2leukaemia - accelerated phase at onset2leukaemia - accelerated phase at onset2Patrinoiu Oana, Georgescu Daniela2Patrinoiu Oana, Georgescu Daniela2

Vol. XVIII Number 2 June 2014

National Institute of Infectious Diseases "Prof. Dr. Matei Balş"

Romanian Society of Pharmacology, Therapeuticsand Clinical Toxicology

Romanian Academy ofMedical Sciences

University of Medicine and Pharmacy "Carol Davila"

Journal published in cooperation with:

CNCSIS Category: B+ Code: 605

NLM (National Medical Library)SCOPUSEBSCOhostIndexCopernicusgetCITED

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Founders

Emanoil Manolescu Mircea Angelescu Liviu Ioan Miclea

Editor-in-Chief TherapeuticsAdrian Streinu-Cercel (Professor, Member of Academy of Medical Science, Head of Department of Infectious Diseases, National Institute

of Infectious Diseases "Prof. Dr. Matei Balş", University of Medicine and Pharmacy Carol Davila Bucharest)

Editor-in-Chief Clinical Pharmacology and ToxicologyVictor A. Voicu (Professor, Member of Romanian Academy, Head of Department of Pharmacology, Toxicology and Clinical Psychopharmacology,

University of Medicine and Pharmacy Carol Davila Bucharest)

Associate EditorMonica Luminos (Associate Professor, National Institute of Infectious Diseases "Prof. Dr. Matei Balş", University of Medicine and Pharmacy

Carol Davila Bucharest)

International Scientific Board

Laure Aurelian (Professor, Senior Associate, The Johns Hopkins School of Public Health), • Hege Christensen (Professor, School of Pharmacy, Uni-versity of Oslo, Norway), • Jaime Kapitulnik (Professor, The Hebrew University of Jerusalem, Israel), • Momir Mikov (Senior Lecturer, School of Pharmacy, University of Otago, New Zealand), • Stanislav Yanev (Professor, Head of Department Drug and Toxicology, Bulgarian Academy of Science, Bulgaria), • Olavi Pelkonen (Professor, Head of the Department of Pharmacology and Toxicology, University of Oulu, Finland), • Olivier Patey (Professor, Chef de service des maladies infectieuses et tropicales CHI, Villeneuve-Saint Georges, France), • George C. Rodgers (Professor of Pediatrics, Pharmacology and Toxicology, University of Louisville, Kentucky, USA), • Robert Smith (Professor, Brown Medical School, U.K), • Jean Paul Stahl (Professor, Rédacteur en chef de Médecine et Maladies Infectieuses, Elsevier Maison, Grenoble, France), • Michel Urbain (Chief of Research Department, Societe de Etude et de Research Biologique, Paris, France), • Andrei Iagăru (Assistant Professor, Department of Nuclear Medicine, Stanford University, USA) • Serafim Kastanakis (Professor, University of Crete, Greece)

Romanian Scientific BoardIoana Alina Anca (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Eduard Apetrei (Professor, University of Medicine and

Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), • Ştefan Sorin Aramă (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Constantin Arion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), • Anca Buzoianu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca) • Carmen Dorobăţ (Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), • Constantin Dumitrache (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Carol Davila Bucharest), • Leonida Gherasim (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), • Ioan Hăulică (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Gr.T. Popa, Iassy), • Daniela Ion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Ion Fulga (Professor, Head of Department of Pharmacotherapy and Pharmacology, University of Medicine and Pharmacy Carol Davila Bucharest), • Sorin Leucuţa (Professor, University of Medicine and Pharmacy Oradea), • Radu Macovei (Professor, Head of Department of ICU-Toxicology, University of Medicine and Pharmacy Carol Davila Bucharest), • Mihai Gafencu (Assistant Professor, University of Medicine and Pharmacy Victor Babeş Timişoara), • Nicolae Miu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca), • Ostin C. Mungiu (Professor, Head of Department of Pharmacology and Clinical Toxicology, University of Medicine and Pharmacy Gr.T. Popa, Iassy), • Lucian Negruţiu (Professor, University of Medicine and Pharmacy Victor Babeş Timişoara), • Florian Popa (Professor, Chancellor of University of Medicine and Pharmacy Carol Davila Bucharest), • Irinel Popescu (Professor, Head of Department of Surgery and Liver Transplant, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science), • Laurenţiu Mircea Popescu (Professor, Member of Romanian Academy, Head of Department of Celular Biology, University of Medicine and Pharmacy Carol Davila Bucharest), • Valeriu Popescu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Science), • Florica Stăniceanu (Professor, Univeristy of Medicine and Pharmacy Carol Davila Bucharest), • Dan Tulbure (Professor, Head of Department of ICU, University of Medicine and Pharmacy Carol Davila Bucharest), • Doina Ţăţulescu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca), • Coriolan Ulmeanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Doina Velican (Researcher, Member of Romanian Academy of Medical Science), • Florin Căruntu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Adrian Gabriel Popescu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Anca Drăgănescu (Pediatrician, INBI Prof. Dr. Matei Bals, Bucharest) • Paraschiva Postolache (Associate Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), • Alexandru Rafila (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Adriana Hristea (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Gabriela Leşanu (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) • Ion Lică (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), • Raluca Papacocea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), • Maria Pasca (Associate Professor, University of Medicine and Pharmacy Targu Mures)• Voichiţa Lăzureanu (Assistant Professor, University of Medicine and Pharmacy Victor Babeş Timişoara), • Anca Macovei (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), • Anca Streinu-Cercel (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), • Andrei Tica (Associate Professor, University of Medicine and Pharmacy Craiova) • Laura Topor (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) • Mihail Tudosie (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) • Ionel Alexandru Checheriță (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) • Mihai Săndulescu (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) • Toma Papacocea (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest)

General Registrar Of Editorial BoardVictoria Aramă (Professor, University of Medicine and Pharmacy Carol Davila Bucharest)

Issue EditorElisabeta Otilia Benea (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Oana Streinu-Cercel Ana-Maria Tudor Alexandra Mărdărescu

Publishing EditorMihaela Cristina Negulescu

Editorial Office Institutul Naţional de Boli Infecţioase Prof. Dr. Matei Balş, Pavilionul IV, Etaj 41 Dr. Calistrat Grozovici Str., Sector 2, Bucureşti, C.P. 021105, O.P. 10

E-mail: [email protected] [email protected]

Published by SC Editura Rp. SRLCUI RO9954898, RC J40/7184/1997Address: 6 Codrii Neamțului Str., Bl. PM 26bis, Sc. A, Et. 8, Ap. 36, sector 3, Bucharest, Romania Tel/Fax: 031.80.40.513; 0724.356.578 E-mail: [email protected]: www.terapeutica.ro

ISSN 2066-0170

XVIII, Vol.18, Number 2/2014 45

President of the European HIV/AIDS &Infectious Diseases Academy

Streinu-Cercel A.

THE EUROPEAN HIV/AIDS & INFECTIOUS DISEASES ACADEMY - 5 YEARS AND ON-GOING!

Therapeutics, Pharmacology and Clinical ToxicologyVol XVIII, Number 2, June 2014Pages: 45-46 © Copyright reserved 2014

The European HIV/AIDS & Infectious Diseases Academy launched in Bucharest/Romania in the summer of 2009 celebrates its fifth anniversary. The Academy has been created as an educational and research institution for defining clinical, epidemiological and logistic particularities in HIV infection for Central and South-East Europe, aiming to optimize its management.

The last decade marked an evolution in the HIV/AIDS treatment methods. The universal access to ARV therapy entails improvement of the human capacity, of the infrastructure, of equipment availability, as well as systems and planning. At global level there are few countries with lengthy experience in the field, while developing countries are in demand of training and system organizing programs. The aim of the European HIV/AIDS & Infectious Diseases Academy located in Bucharest/Romania is to answer these challenges, offering direct access to the theory and practice (state-of-the-art treatment and care) to national and international professionals.

The Central and South-East European founding countries and affiliates to the HIV/AIDS Academy are: Albania, Belarus, Bulgaria, Czech Republic, Croatia, Estonia, Hungary, Latvia, Lithuania, Republic of Moldova, Romania, and Ukraine. Serbia has joined the group starting 2013.

A number of experts from these countries have been identified and have joined the Experts Group who will elaborate a common strategy for the Central and East-European countries in the field of fighting HIV/AIDS and infectious diseases. At this point almost 50 members from the affiliate countries have joined the Experts Group and this number is expected to increase over time as activities develop within the departments of the Academy: research, education, and advocacy.

The European Academy of HIV/AIDS and Infectious Diseases, as a component of the National Institute for Infectious Diseases “Prof. Dr. Matei Bals”, is offering a variety of programs of training and education bearing the immense advantage of providing direct access to patients care activities, to experts, to the cutting edge equipment and to the most advanced procedures.

The courses and trainings benefit from the certification of the Romanian Ministry of Health, University of Medicine and Pharmacy „Carol Davila” Bucharest, the Medical Sciences Academy, and the College of Physicians - Romania.

Here are some of the Post-graduate courses provided:• Educational Courses in support of the National HIV/AIDS Strategy – in collaboration with selected Health

Professional Associations;• Academicals Post-graduate Training for Adherence to ARV Therapy - for Clinical MDs and psychologists;• HIV infection, ARV therapy for Children;• HIV infection, ARV therapy for Adults and Teenagers;• GCP Course for Clinical Research Professionals -The London Institute for Clinical Research;• Project Management Course for Clinical Trials -The London Institute for Clinical Research;• Basic Research Methodology – Baylor College of Medicine;• Bi-annual HIV Resistance Seminar and expert meeting;• Post-graduate Management Course in Clinical Studies – in cooperation with the Foundation for Development

and Management Gdansk (GFKM), Poland and the University of Medicine and Pharmacy “ Carol Davila” Bucharest

• Invasive fungal infections• NeuroAIDS Course • HIV-associated Osteo-Renal Disorders training course• Update in infectious diseases treatment – training in collaboration with partners of the Academy• Course for medical nurses - organized by Synevo Central Lab

Experts used the opportunity of ceremony of launching the Academy facilities in Bucharest in June 2009 to meet launching the Academy facilities in Bucharest in June 2009 to meet launchingand discuss the way forward at international level. Stated objective of the meeting were to define regional areas of cooperation in relation to HIV/AIDS treatment, care and support and to discuss and agree upon specific mechanisms the European Academy can use to support activities in the respective areas of cooperation. Participants included treatment and social experts from 10 countries, representatives of European community networks, private sector and international programs (UNAIDS).z

The following topics were proposed for research projects, which are evaluated by an international Experts Evaluation Committee for granting future financial resources: Starting ARTV at Naïve Patients (Albania); CNS and

EDITORIAL

Therapeutics, Pharmacology and Clinical Toxicology46

How to Avoid Metabolic Clinical Adverse Events (Romania); Management of HIV Co-infection with HBV and HCV (Bulgaria); Prevention of Vertical Transmission (Ukraine ); Adherence to the Antiretroviral Therapy (Romania ); Man Having Sex with Men (Czech Republic ); Management of MDR TB Co-infection (Romania); Travel Medicine and HIV (Croatia); HIV and the Metabolic Syndrome (Romania); HIV Co-infection with Parasites (Croatia); HIV Treatment and Cardiovascular Risks (Romania); Co-infections with STDs and Herpes Viruses (Romania); HIV-infected Patients Models of Care (Romania); Epidemiological Aspects in Central and Eastern Europe (Romania); Monitoring Fatty Liver in Naïve HIV Patients and HAART (Romania); Management of IDUs (Latvia); Survey of HBV, HCV, HDV viruses with HIV Co-infection (Romania); Quality of Life in HIV-infected Adults ( Romania); Psychiatric Disorders in HIV-Infected Patients (Romania).

Several Experts Group meetings took place in the last years in different countries: Paris (2008), Bucharest (June 2009, October 2009, February 2010), Sofia (November 2010), Belgrade (October 2011). The 7th Experts Group Meeting took place in Sibiu/Romania end of May 2014, to share achievements and further plans, as well as to celebrate the fifth anniversary of the European Academy.

During the Experts Group Meeting several project proposals developed under the above-mentioned topics have been presented. Out of these, the following have received funding:

• “Post-graduate Training on Adherence to the Antiretroviral Therapy in HIV Positive Patients” - targeted on teams of MDs and psychologists working with HIV-positive patients in Romania, Albania and Republic of Moldova;

• Pilot Project on Prevention and Monitoring of HIV-related Cardio-Metabolic Risks;• HIV-associated Osteo-Renal Disorders;• HIV-associated Neurocognitive Disorders (NeuroAIDS) National Program;• Cross-border Management of Infectious Diseases (Romania, Republic of Moldova and Ukraine);• „Program of Medical Communication and Information in the Area of Severe Infections and Sepsis”;• ‘’Street Art”, developed in main cities since January 2014;

In the same time, several Romanian domestic and international scientific activities have been developed under the aegis of the European Academy. Below are some of the scientific events that took place in the last years:

• Regional HIV Meeting (Saudi Arabia, Bulgaria, Croatia, Serbia, Romania, Russia), 28-29.11, 2012• JUSTRI Paediatric Meeting, 6-7.09, 2013;• ECDC-EMCDDA Consultation Meeting: 3rd Meeting on detecting and responding outbreaks of HIV among

people who inject drugs (18-19.11, 2013);• The 6th and respectively the 7th National Congress on HIV/AIDS –with international participation (Sibiu/

Romania, May 17-19, 2012 and respectively May 29-31, 2014); • The Medical Summer School with international participation “TARV between Past and Present”( Gura

Humorului/Romania, June 21-23, 2012); • The Summer Medical School “ ART…….in anti-infectious therapy, ART…and anti-infectious therapy”, , Iasi/

Romania, June 13-15, 2013; • The 2nd and the 3rd editions of the National Symposium “Management of the Infectious Diseases Critical

Patient” MaPaCI 2 and respectively MaPaCI 3 (Tg. Mures/Romania, July 19-21, 2012 and respectively April 24-26, 2014);

• The 3rd edition of the International Summer School (Constanta/Romania, September 3-7, 2012); “Traveler’s Health Issues”, Constanta, 2011, 2013;

• Medical Summer School “Infectious Pathology – interdisciplinary perspective in the global era”, Iasi/Romania, June 19-21, 2014;

• TB/HIV Constanta, September 26-27, 2014. Since 2013 the National Research Database (Baza Națională de date de Cercetare – BNC) has been launched

and is available on-line. BNC is a multidisciplinary on-line platform integrating state-of-the-art information regarding projected research plans, ongoing research studies, and results of completed research projects. It was created through project POSDRU/86/1.2/S64124, and is implemented by the National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, with the purpose of improving access to research data, as well as post-graduate education and training in all fields connected to medicine and infectious diseases (www.bnc.cercetaremedicala.ro).

Regarding publishing, the European Academy has the support of two journals: GERMS, a new on-line journal, available since December 2011 (www.germs.ro). GERMS is the official on-line English language journal of the European Academy and is mainly dedicated to international articles. The Board includes internationally recognized experts (see www.germs.ro)

The Journal publishes articles on a wide range of topics, describing research results in all areas connected to microorganisms, including, but not limited to: prevention, pathogenesis, clinical description, optimal practices of diagnosis and treatment of infectious diseases, microbiology, immunology, epidemiology, public health, evaluation of current and novel treatments, updates in infectious diseases, etc.

Also, since February 2010 the Therapeutics Pharmacology and Clinical Toxicology Journal, has become the journal of the European Academy (www.terapeutica.ro).

The European HIV/AIDS & Infectious Diseases Academy has been ISO 9001:2000 certified, as part of the re-certifying process undergone by the National Institute for Infectious Diseases “Prof. Dr. Matei Bals” (INMB) during 2010. The European Academy benefits from the expertise and experience of the highly specialized HIV/AIDS experts from the INMB, internationally recognized by WHO and ECDC.

For more details and updates a web page is available both in English and Romanian at: www.aidsacademy.org


Angelica Vișan1 Dr. Calistrat Grozovici St., Bucharest, Romaniae-mail: [email protected]

Abstract. Purpose: Influenza infection is associated with a wide range of neurologic complications, that imposes a recognized burden of central nervous system diseases. The emergence of influenza A H1N1 virus has been linked to important neurological involvement. Scope: Our objective with this paper was to make a review of the neurological manifestations related to influenza A H1N1 virus in different countries of the world, so as to highlight the variety of clinical aspects of the pandemic virus. We will present the investigations used, but also the hypothesis of the pathogenic mechanisms involved in each case. Conclusions: Neurological manifestations of influenza A H1N1 virus infection appear to be variable in severity, from febrile seizures to encephalitis with malignant clinical course, complicated by high morbidity and mortality. Since the H1N1 influenza virus was not detected in the cerebrospinal fluid of the patients with this diagnosis, the emerging view is that the host immune response plays a key role in pathogenesis. This review can contribute to establish future management of neurological complications, especially when influenza continues to be a real threat in our life.Key words: Influenza A H1N1 infection, neurologic complications, pathogenesis, cytokinee, biomarkers

1. National Institute of Infectious Diseases “Prof. Dr. Matei Balș”, Bucharest, Romania2. University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania

Vișan Angelica1,2, Luminos Monica1,2, Negulescu Cristina1, Drăgănescu Anca1, Bilasco Anuţa1, Vasile Magdalena1, Măntescu Ruxandra1, Merișescu Mădălina2 , Slavu Diana1, Dogaru Cornelia1, Streinu-Cercel A.1,2

INFLUENZA INFECTION AND NEUROLOGIC COMPLICATIONS

REVIEWTherapeutics, Pharmacology and Clinical ToxicologyVol XVIII, Number 2, June 2014Pages: 47-55 © Copyright reserved 2014

Introduction

Respiratory tract infections are the leading cause of morbidity in children. Viral infections are responsi-

ble for the majority of respiratory tract infections, amongst which influenza infection plays an important role [1].

Influenza viruses belong to the Orthomyxoviridae family and are classified depending on their molecular and biological characteristics in influenza A, B and C. In-fluenza A and B infections occur in seasonal outbreaks and influenza C plays a small role in humans [2].

In addition to seasonal outbreaks, influenza pandem-ics appear at large and unpredictable intervals (every 20-40 years). They are caused by new influenza A viruses which are antigenically distinct from seasonal influenza A. The spectrum of clinical manifestations during pan-demics can be similar to that of seasonal influenza, but sometimes severe clinical manifestations are more likely to occur in pandemic influenza infection.

Centers for Disease Control and Prevention (CDC) of The United States established the following case definitions [3]:

• Influenza-like illness (ILI) is defined as fever (temperature of 37.8C or greater) with cough or

sore throat in the absence of a known cause other than influenza;

• A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratory-confirmed H1N1 influenza A virus detection by real-time reverse transcriptase (rRT)-PCR or culture;

• Mild or uncomplicated disease is defined by fever, chills, muscle pain, headache, cough, sore throat, malaise, sometimes diarrhea and vomiting, but no shortness of breath and little change in chronic health conditions;

• Progressive illness is characterized by typical symptoms plus signs or symptoms caused by: cardio-pulmonary insufficiency (tachypnea, hypoxia, labored breathing in children, chest pain, hypotension), central nervous system (CNS) impairment (confusion, altered mental status), severe dehydration or exacerbations of chronic conditions;

• Severe or complicated illness is characterized by signs of lower respiratory tract disease (hypoxia requiring supplemental oxygen, abnormal chest radiograph, mechanical ventilation), CNS findings (encephalitis, encephalopathy), complications of hypotension (shock, organ failure), myocarditis or rhabdomyolysis, or invasive secondary bacterial infection.


Predictors of outcome are older age, the presence of preexisting conditions and a requirement for mechanical ventilation. All of these were associated with a higher risk of mortality. Encephalitis is an independent predictor of mortality [3].

Diagnostic assays – Real-time reverse transcriptase (rRT)-PCR is the most sensitive and specific test for the diagnosis of influenza virus infection.

Several rapid antigen tests are able to distinguish between influenza A and B viruses, but they are not able to distinguish between seasonal and pandemic strains of H1N1 influenza A. It was suggested that clinicians should consider using rapid influenza antigen tests as part of their evaluation of patients suspected of having influenza, but the results need to be interpreted with caution, because a negative result does not rule out infection. Confirmation of pandemic H1N1 influenza A infection can be made only by RT-PCR or culture [3].

Complications – The most common complications of influenza in children are otitis media, lower respiratory tract involvement: interstitial pneumonia, laryngotracheitis (croup), bronchitis or bronchiolitis. Other complications are less frequent: CNS involvement, myositis, myocarditis, bacterial coinfection and even toxic shock syndrome associated with S. aureus superinfection of influenza [4].

Neurological complications were described in variable proportions during each influenza season. The most prevalent neurological manifestations during the twelve flu pandemics recorded in the 20th and 21st century included delirium, encephalitis, ocular abnormalities, amyotrophy, myelopathy, radiculopathy, ataxia and seizures [5].

The most severe influenza pandemic, the one to which all other pandemics have been compared, was the pandemic in 1918, “the Spanish flu”.

The medical literature of the time published soon after observations regarding the neurological manifestations related to the evolution of influenza

infection during the pandemic. The British Royal Society of Medicine, in “Discussion on Influenza”, in 1919, noticed the relationship between the neurological illness and the pandemic. E.B. Turner postulated that influenza “attacked more particularly the nerve centers”, because he observed “very pronounced nerve sequelae”. W.H. Hamer also noticed that, although rare, neurological manifestations appeared shortly following the outbreaks of influenza infection. A. Abraham made laboratory researches and he noted that there were no cases of meningitis, since he didn’t find anomalies in cerebral-spinal fluids. B.H. Spilsbury published his pathological findings from central nervous system tissue where he mentioned that there were “degenerative changes in the nerve cells of the motor nuclei in the pons, in some of which chromatolysis and pigmentation were found”, “general congestion of the brain”, “but no inflammation in the brain or meninges”. Encephalitis lethargica with its post-encephalitic Parkinsonism has been closely associated with the 1918 flu pandemic [5].

Since that time, researchers from all over the world have focused on the pathogenic mechanisms of the neurological complications of the influenza viruses. The objectives were to discover the possibilities of the direct invasion of the virus in the CNS and the modalities of immune reaction of the host in general and of the CNS, against influenza infection.

In late March 2009, in Mexico, a new outbreak of influenza A infection, H1N1 type was detected. Soon after, the influenza virus spread in many countries and in June 2009 The World Health Organization raised its alert level to the highest, phase 6, indicating widespread transmission on at least two continents [6]. In July, CDC already reported neurological complications related to influenza infection.

Despite the fact that the pandemic was declared to be over in August 2010, there are still isolated cases of infection with the pandemic influenza AH1N1 virus, some of them being actually extremely severe.

Our objective with this paper was to make a review of the neurological manifestations related to influenza A H1N1 virus in different countries of the world, so as to

Year of pandemic/epidemic Virus Neurologic manifestationPandemic -1918 H1N1 Delirium, cycloplegia, encephalitis

lethargicaPandemic - 1957 H2N2 Encephalitis, seizures, muscle paraplysis, gbsPandemic - 1968 H3N2 Amyothrophy, ms flares, encephalitis,

encephalopathy, myelopathy, gbsPandemic - 1977 H1N1 Unknown Epidemic – 1979/ Finland H3N2 Encephalitis, seizures, relapsing deliriumEpidemic 1994 -1995/ Japan H1N1 and H3N2 Encephalitis, encephalopathy, seizuresEpidemic 1997 and 2001 /Hong Kong

H5N1 Neurotropism in animals (laboratory discovered)

Pandemic 2006 H5N1 UnknownPandemic 2009 H1N1 Encephalopathy, seizures, ataxia

TABLE I – by Julia Henry – Neurological manifestations associated to influenza pandemics in the last century [5]


highlight the variety of clinical aspects of the pandemic virus. We will present the investigations used, but also the pathogenic mechanisms involved in each case. This review can contribute to establish future management of neurological complications, especially when influenza continues to be a real threat in our life.

Influenza A H1N1 was associated with a wide spectrum of neurological manifestations [7]:

• Febrile seizures;• Influenza-associated encephalopathy or

encephalitis (IAEE);• Acute necrotizing encephalopathy of childhood

(ANEC);• Reye syndrome;• Acute disseminating encephalomyelitis (ADEM);• Guillain-Barre syndrome;• Transverse myelitis.

The following definitions were used in this review:• Neurological manifestation associated with

pandemic influenza – seizures or encephalopathy within 5 days from the onset of influenza symptoms;

• Encephalopathy – altered mental status or consciousness or personality compared to premorbid state for 24 hours or more;

• Encephalitis – encephalopathy plus 2 of the fallowing: fever>38C, pleocytosis in the cerebrospinal fluid (CSF) or neuro-imaging showing evidence of infection or inflammation;

• Influenza-associated encephalopathy or encephalitis - encephalopathy/ encephalitis – not caused by other etiologies, except influenza, after complete investigation [7].

Pandemic influenza virus A H1N1 was found in many countries, but neurological manifestations were different both as type and severity.

Neurologic manifestations of influenza A H1N1 virus in children

I. Landau et. all published a retrospective study made in Israel, in a university tertiary - care hospital in Tel Aviv, regarding all children with laboratory-confirmed influenza A H1N1 accompanied by neurological complications [8].

• 74 children were hospitalized during 1 October 2009 – 31 January 2010 with confirmed influenza A H1N1infection. Among them, 14 children exhibited associated neurological complications. Seizures comprised the most frequent neurological complication, occurring in 10 patients. The other 4 patients had: transverse myelitis, myositis, behavioral changes with expressive aphasia or syncope.

• The incidence of neurologic complications in this study was higher than in previously reported influenza-related cases, but neurologic presentations were relatively mild and with favorable outcome. The child with transverse myelitis remained with weakness in his left arm, despite the long treatment of rehabilitation [8].

II. In Malaysia was conducted a retrospective review of the national database by which the subjects were prospectively recruited during the pandemic influenza, from 15th June 2009 till 30th November 2009. The aim of the study was to describe the characteristics of neurological

manifestations and complications in a national pediatric cohort with pandemic influenza A H1N1 [7].

• Among all 1254 children confirmed with pandemic influenza A H1N1, 103 (8.3%) presented neurologic manifestations: 69 cases – febrile seizures, 16 cases – exacerbations of seizures in children with an underlying epilepsy, 14 cases – influenza associated encephalopathy/encephalitis (IAEE) and 4 cases – acute necrotizing encephalopathy of child hood (ANEC). The incidence of neurological complications from the pandemic virus was 10 fold higher than the rate of seasonal influenza.

• The most severe form of IAEE is ANEC. This disease is characterized by sudden onset of fever, seizures, coma and even death within a few days. There are no specific diagnostic markers, although some children had elevated liver enzymes and deranged coagulation profile. CSF was normal in all 4 cases (without pleocytosis or raised proteins, influenza virus PCR – negative).

• A distinctive radiologic feature of ANEC is bilateral and symmetrical thalamic lesions, occasionally involving the putamen, periventricular white matter, cerebellum, medulla as well as brainstem tegmentum.

• ANEC is associated with high mortality and morbidity, with potentially severe neurologic sequelae in survivors. Two of the patients with ANEC died and two suffered moderate and respectively severe neurological sequelae.

• All these patients were given intravenous methylprednisolon and immunoglobulin.

• Postulated pathogenesis of central nervous system involvement in influenza infection is direct viral invasion and viral-induced inflammatory process.

1. The detection of viral RNA in the CSF could indicate the evidence of viral penetration into the CNS. But viral positivity was very rare demonstrated. In this study, all children with IAEE or ANEC showed no evidence of viral neuro-invasion, with negative test for viral PCR of CSF specimens.

2. The second hypothesis suggested that in genetically susceptible children, overwhelming cytokine release from virus stimulated glial cells may be responsible for the neurotoxic effect. The genetic predisposition which has been reported to cause IAEE includes polymorphism of a mitochondrial enzyme, carnitine palmytoyl transferase II. Many investigators showed the phenomenon of hypercytokinemia, which is not associated with CSF pleocytosis. Studies demonstrated that children with IAEE or ANEC have raised concentrations of pro-inflammatory cytokines and their receptors (such as TNF-α, IL-6 and soluble TNF-receptor 1) in plasma and CSF. Histopathological examination in a fatal case of IAEE described vasogenic brain edema with generalized destruction of vascular endothelial cells caused by high levels of cytokines. The high level of


mitochondrial enzyme cytocrome c oxidase represents the most accurate predictor for endothelial apoptosis in severe influenza associated encephalopathy [7].

III. In China, in the province Shenzhen, from the onset of pandemic till December 2009 more than 1200 individuals have been tested positive for the novel A H1N1virus and three fatal cases have been documented. Among these, two cases were in children who developed neurological complications [9].

• Case 1 – a 9-year-old boy, admitted for high fever which persisted for two days, increased weakness, profuse vomiting and diarrhea, and altered mental status. He received antiviral treatment, but his mental status rapidly deteriorated. He was mechanically ventilated, but died soon, because he developed pneumonia, multiorgan failure and diffuse intravascular coagulation.

• Case 2 – an 11-year-old boy, admitted for a 3-day history of fever, cough, vomiting, abdominal pain and headache. Soon after admission, the patient had a seizure consisting of episodic eye rolling and tongue thrusting. Afterwards, he developed visual hallucinations, difficulty in responding to questions and in following commands. Initially, he received supplemental oxygen for mild hypoxia and hypopnea, but after a short time he required mechanical ventilation. Electroencephalography (EEG) was consistent with encephalopathy. The patient died of ARDS and neurological complications.

• Cytokine dysregulation (cytokine storm) is known to be implicated in severe clinical manifestations like ARDS ( acute respiratory distress syndrome), MSOF(multiple system organ failure), lymphopenia and hemophagocytosis. Investigators measured the levels of 10 cytokines and chemokines as described by Lee et all. (2007). The results were compared with the values of the patients with mild A H1N1 infection and healthy controls.

• The levels of IL-6, TNFα, IL-8 and MCP-1 (monocyte chemoattractant protein-1) were significantly increased;

• On the contrary, the levels of IP-10 (interferon inducible protein-10), IL-12 and RANTES (regulated upon activation, normal cell-expressed and secreted) were significantly decreased. For example: the normal value for RANTES is 750( in healthy volunteers); the value 250 was found in mild forms of influenza disease; patients who died had an undetectable value of RANTES. Early reports demonstrated that monocytes and macrophages infected with influenza A virus are able to secrete RANTES, which preferentially favored the recruitment of blood mononuclear cell population to the site of infection. In addition to the chemotactic activity, it was also involved in direct antiviral activity by inducing NO (nitric oxide) synthesis in macrophages. The authors suggest that the decreased level of RANTES might play a critical role in the pathogenesis of the patients with severe influenza infection.

• Other cytokines and chemokines (IL-1β, IFN-γ, IL-10) were detected at very low levels or were undetectable, similar to the reference.* This study highlights the importance of cytokine

storm in death associated to novel influenza in young individuals [9].

IV. Influenza A H1N1 virus was present also in Japan and neurological manifestations were carefully observed.

• Tomiyasu et al. published a study with the purpose to investigate the changes in the concentrations of brain metabolites in children with acute encephalopathy (AE), using single-voxel magnetic resonance spectroscopy (MRS).

• Proton MR spectroscopy (MRS) is a powerful tool for noninvasive monitoring of changes in brain metabolite concentrations and might be useful for the early diagnosis of AE.

• The subjects were 10 children with AE caused by influenza A H1N1 virus. The symptoms were seizures, disturbance of consciousness, abnormal behavior. In that medical center, MRS has been integrated into routine clinical MR examinations of the brain.

• Using MRS they studied the basal ganglia (BG) as a representative sample of the gray matter, and the centrum semiovale (CS) as a representative sample of the white matter.

• The MRS data was recorded during three time periods: 1). Initial neurological symptoms at presentation and at the start of the treatment (days 1-3 of admission) 2). After short-term follow-up (days 2-11) 3). After Long-term follow-up (days 18-20).

• The model spectra consisted of 16 reference compounds: alanine, aspartate (Asp), creatine (Cr), phosphorylcreatine (PCr), ϓ-aminobutyrate (GABA), glucose (Glc), glutamate (Glu), glutamine (Gln), glycerol phosphorylcholine (GPC), phosphorylcholine (PCh), myo-inositol (mIns), lactate (Lac), N-acetylaspartate (NAA), N-acetyl-aspartyl-glutamate (NAAG), scyllo-inositol and taurine (Tau).

• These major metabolites are thought to be significant markers of the state of the CNS. In MRS, NAA is considered to be a marker of neuronal density or mitochondrial metabolic function; Cr level is relatively stable in various diseases and can be used as a reference for other metabolites and mIns is a glial marker. Glutamate is known to act as an excitatory neurotransmitter. The release of large amounts of Glutamate from the presynaptic cells into the extracellular space results in calcium ions entering cells, causing neuronal damage and/or cell death. Moreover, the excess of Glu is taken up by astrocytic cells with the goal of converting it to Gln, resulting in cell swelling and edema.

• Taurine represents the most abundant free amino-acid, making-up about 0.1% of body weight and it is found in all cell types of the CNS. There are many physiological functions related to Tau, but its roles are not completely defined. Tau acts as an


antioxidant to protect neurons from free radical-mediated cellular damage. Tau is present in high concentrations in several proinfalmmatory cells and after cellular damage. In IAEE, free radicals cause nonspecific oxidative injury, and cysteine acts as a free radical scavenger. Tau is a cysteine-derived product that is produced by sulfur oxidization via hypotaurine. This might be the reason for the high concentrations of Tau present in the AE patients during the follow-up period. Tau protects against Glu-induced neuronal excito-toxicity.* All patients included in this study had a good

outcome, without sequelae and were discharged within 1 month of admission. Some of them had cerebral edema at presentation but none of them had cerebral necrosis.

* There were no significant differences in the concentrations of the major metabolites between the patients and the controls and between the first or second MRS period. This corresponded with the diagnosis of the patients group, of mild A H1N1- related Acute Encephalitis.

* The only exception was the increased level of Tau observed in the BG in the second period. It is still unclear whether the Tau elevation is generally found in Acute Encephalitis or is specific to A H1N1-related cases.

* This study launches the great challenge of researching brain metabolites variations in severe cases of AE, more exactly in ANEC, but also in AE of different etiologies.

V. Another case, also from Japan (Kumakura et al) presented an 8-year-old girl diagnosed with acute necrotizing encephalopathy associated with pandemic influenza A, without neurological sequelae.

• One day before admission, she developed fever and cough and on the day of admission, she had a high-grade fever (40ºC) and a generalized tonic-clonic seizure of about 30 seconds. The deterioration of her consciousness progressed rapidly, and she presented delirium, stupor, anisocoria and unstable blood pressure. The rapid antigen test from the nasal swab was positive for influenza A virus. Subsequently, PCR was performed and confirmed the presence of pandemic A H1N1 influenza virus. CT scan and MRI were normal. Cerebrospinal fluid analysis showed: 1 cell/mm3, proteins =17.3 mg/dl, IL-6=143 pg/ml (normal range <3.2 pg/dl), index Ig G=0.63 (normal range<0.70);

• About 4 hours after her seizure, she started treatment with oseltamivir, pulse therapy with methylprednisolone (30 mg/kg/day x 3 days) and high doses of intravenous immunoglobulin (1g/kg/day x 2 days). A CT scan was made again 12 hours after the seizure and revealed a low density area in the thalamus bilaterally and upper brainstem tegmentum. MRI was repeated at about 20 hours after the seizure and established the diagnosis of influenza A acute necrotizing encephalopathy.

• The outcome was favorable and she gradually

recovered. In only 2 days, she was able to respond to verbal commands and in 6 days, she was able to read. After 16 days she walked again without assistance. MRI performed 6 months later showed a deposition of hemosiderin at the center of the thalamus bilaterally and no atrophy.

• Chen et al. reported that the thermolabile phenotype of carnitine palmitoyltransferase II, such as the cystine-isoleucine-methionine haplotype was evident in patients with influenza-associated encephalopathy. The analysis showed that the little girl had that kind of haplotype. Even if this idea seems to be speculative, the thermolabile carnitine palmitoyltransferase II phenotype with decreased enzymatic activities may reduce the utilization of mitochondrial fuel during high-grade fever. The impaired mitochondrial β-oxidation and the synthesis of adenosine triphosphatin in the cerebral microvascular endothelial cells can be responsible for the increasing permeability of the vascular wall and the development of brain edema.

• Early intervention with pulse methylprednisolone may be efficient in suppressing the inflammatory response. When the patient becomes afebrile in a short time, the activity of carnitine palmitoyltranferase is recovered and the prognosis is better.

• For this reason, the transient disorder in energy metabolism present in patients with this phenotype can benefit from adjuvant therapeutic strategies: 1) prompt hypothermic therapy, 2) the administration of L-carnitine for the activation of long-chair fatty acid β-oxidation, 3) the administration of glucose to increase the rate of the citric acid cycle [11].

VI. Wendy et al. from USA published an article where she demonstrated the importance of prompt control of fever in obtaining a favorable outcome. They presented the case of a 4-year-old girl with the diagnosis of acute necrotizing encephalopathy (ANE) who was treated with controlled hypothermia in addition to the standard protocol [12].

• With a 3-days history of cough, rhinorrhea and high persistent fever, she became lethargic, with confusion, visual hallucinations and seizures. After clinical examination, the diagnosis was “febrile seizure” and because the rapid antigen test from nasopharyngeal swab was positive for influenza A infection, the patient received a prescription with oseltamivir and ibuprofen. 12 hours later, the neurologic status worsened: she presented increased sleepiness in alternation with excessive irritability, disorientation, altered state of consciousness and complex partial seizures. The little girl was admitted and cranial MRI revealed multifocal supratentorial and infratentorial bilateral areas of restricted diffusion, particularly within the pontine gray matter, left cerebellum, bilateral thalamus, where there were also hemorrhagic lesions.

• She was treated with a 5-day course of 30 mg/kg/day of solumedrol, a standard 5-day course


of oseltamivir and intravenous immunoglobulin. In addition they intubated her and cooled her temperature to 34°C for 48 hours, using an Arctic Sun 2000 Targeted Temperature Management by Medivance, with the monitoring of her temperature by en esophageal sensor. After 48 hours of induced hypothermia, she was rewarmed slowly, at a rate of 0.1C/hour, for 36 hours, until her temperature became 37.6°C.

• The patient was hospitalized for 18 days and then she was transferred to a rehabilitation clinic. After 6 months, she was able to walk and to talk, with a complete restored cognitive status.

• This case emphasizes the role of cytokines in the pathogenesis of the neurological complications in influenza infection. Preliminary data showed that patients with acute necrotizing encephalopathy (ANE) do not present elevated levels of viral particles in their respiratory secretions, but that they have an exaggerated immune response to the virus. High levels of IL-6, IL-10 and TNF-α were measured in serum and cerebrospinal fluid of patients with ANE. There are some authors who reported favorable outcomes after early treatment with anti cytokines agents [Munakata M. et al, 2000]. Therapeutic hypothermia represents a possible approach to anti cytokines therapy, because it was demonstrated that it is followed by decreasing levels of IL-6.

• Since the pathophysiology of ANE is mediated by proinflammatory cytokines, the treatment should be focused to block this response. Mizuguchi et al. reported favorable outcomes in ANE using ulinastatin, a urinary trypsin inhibitor approved for use in Japan for the treatment of pancreatitis and septic shock [12].

VII. Interesting cases with neurologic complications of influenza infection are also reported from Europe. In Switzerland it was published the case of a 2.5 – year – old girl. The onset of her disease was 24 hours before admission, with an isolated febrile episode and dry cough. The next day, she became hypotonic and she was not able to walk, so she was admitted to a hospital [13].

• On the first examination, the child was afebrile, conscious, but irritable and she could not speak. The vital signs were normal. In the next few hours her neurologic status worsened, she developed behavioral changes, alternating periods of agitation and apathy, followed by decreased consciousness and she had to be intubated. CT scan was normal and CSF was normal too, excepting a mild pleocytosis (8 cells/mm3). Subsequently, a brain MRI was performed and showed a well-defined lesion in the splenium of corpus callosum and an additional area of restricted diffusion at the level of the right dentate nucleus.

• Laboratory work-up was completed and all blood tests were normal. PCR for influenza A from the nasopharyngeal swab was positive.

• The evolution was favorable and she was extubated after 48 hours. The little child became conscious again, but the hypotonic syndrome and

ataxia with truncal tremor still persisted. She was able to articulate isolate words only after 5 days, while in this interval she was totally mute. Ataxia disappeared within days, but dysarthria and difficulty in words finding lasted longer. The fully recovery was registered after a month.

• This was not the only case of reversible lesion of the splenium of the corpus callosum in individuals with mild form of IAEE. This pattern of lesion could be another specific clinical-radiological picture adding to the large spectrum of influenza neurological complications. Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) has distinctive features: a monophasic course with dramatic onset and quick recovery, CSF with minimal pleocytosis and specific lesion on MRI, showing transient splenial involvement.

• The pathogenic mechanism seems to be the inflammatory cytokine-mediated response, rather than a direct viral invasion. This hypothesis is supported by raised concentrations of IL-6, TNF-α and their receptors in IAEE. This “cytokine storm” with a rapid onset may determine the dysfunction of the brain-blood barrier and the brain edema.

• A specific feature of this case was the coexistence of cerebellar involvement and the lesion of the dentate nucleus, as well as the truncal ataxia and transient mutism. This was the first case reported until that moment, with encephalitis and concomitant cerebellitis [13].

Neurologic complications of influenza in adultsEven if the neurologic manifestations caused by

influenza virus are more frequent in children than in adults, we found several interesting cases reported in adults (patients between 20 - 50 years), without chronic diseases or any immunosuppression, with particular clinical and imagistic features.

I. In Italy, Cortese et al. studied the case of a 30-year-old previously healthy man who developed acute severe demyelinating polyradiculopathy during influenza A (H1N1) 2009 infection [14]. The authors emphasize the importance of the molecular study, because they discovered a mutation of the hemagglutinin gene of the virus, a substitution at position 222, which has been reported to be o factor of increased virulence, manifested by severe respiratory infection, but never before with neurological involvement.

• The patient was admitted for high fever (39°C) and headache, followed in the next 12 hours by the rapid onset and progression of neurological symptoms: gait unsteadiness, weakness of lower limbs, without sensory symptoms or urinary problems. In only a few hours, he developed flaccid tetraparesis, speech and swallowing difficulties and then he was intubated due to respiratory failure. Neurological examination confirmed a striking concomitant involvement of peripheral spinal and cranial nerves, flaccid tetraplegia with abolished deep tendon reflexes, bilateral eyelid ptosis, facial weakness and dysphagia.

• The first CSF analysis was normal, but the


second, performed after 2 days, revealed albuminocytological dissociation (high protein level, without increased number of cells).

• The viral load of influenza virus was 1x 104 virus RNA copies/ml in nasopharyngeal secretions and 1 x 105 virus RNA copies/ml in bronchoalveolar lavage (BAL) fluid.

• Sequencing of the hemagglutinin gene of the virus showed the presence of D222E substitution.

• The diagnosis was para-infectious Guillain-Barre syndrome (GBS) and the patient received: intravenous immunoglobulins – 0.4g/kg/day for 5 days, Ceftriaxon - 1g/day for 7 days and Oseltamivir 75 mg x2/day for 5 days. The evolution was favorable with rapid neurological improvement, concomitant with the disappearance of the virus from the nasal swab and the BAL. He was extubated after a week and after another week he started to walk again. He needed 2 weeks for the complete motor and cranial nerve recovery.

• The particularities of this case are: 1) the identification of a mutated hemagglutinin gene of the pandemic virus, associated with severe respiratory infections admitted to intensive care units; 2) the appearance of the respiratory and neurological symptoms almost concomitantly; 3) the clinical and neurological improvement concomitant with the disappearance of the virus from the respiratory secretions.

• Molecular mimicry and a cross reactive immune response seem to play a major role in the pathogenesis of GBS. The possible hypothesis would be that the short interval between respiratory and neurological symptoms could be explained by a strong response to influenza A (H1N1) strain.

II. An unusual case of neurological involvement was reported again from Italy, by Locuratolo N. [15].

• A 51-year-old man who was admitted for fever, rhinorrhea and behavioral changes, developed in the next 24 hours high fever (39.9°C) and a severe neurological syndrome, with altered mental status, nuchal rigidity, opisthotonus, conjugate eye deviation to the right and recurrent focal motor seizures with secondary generalization. He was intubated, under sedation with Propofol and Phenytoin.

• The EEG showed epileptic discharges over the left frontal region;

• MRI – (FLAIR, DWI) – revealed a slight area of increased signal in the left medial frontal cortex extending to the frontal-polar area and insula. MR angiography was conclusive for severe hypoperfusion in the left frontal-temporal region.

• CSF was normal, acellular, with normal glucose and protein levels. Bacterial, fungal and viral cultures were negative.

• PCR from the nasopharyngeal swab was positive for A H1N1 – influenza virus.

• The outcome was favorable with normal neurological examination by day five.

• In this case, the rapid onset of encephalopathy in

association with a brain imaging pattern of acute vasogenic edema and favorable outcome, support the diagnosis of PRES - posterior reversible encephalopathy syndrome. PRES is a clinical-radiological entity caused by different systemic conditions: hypertensive encephalopathy, autoimmune diseases, eclampsia, transplant, chemotherapy, sepsis or shock. Clinical symptoms and imaging abnormalities are usual, but not always reversible.

• The pathophysiological mechanism underlying PRES seems to be vasoconstriction and hypoperfusion resulting in ischemia, demonstrated by MR- angiography and by the increased incidence of stroke in adults during epidemics. Influenza infection may modulate endothelial function, contributing to thrombotic diathesis or may exert an effect on atherosclerosis through massive production of proinflammatory cytokines or immune complexes.

• Brain edema in PRES is localized predominantly in the parietal-occipital regions and less frequently in frontal-temporal and cerebellar areas. Vasogenic edema usually has a favorable outcome, as opposed to cytotoxic edema. Focal hypoperfusion suggesting vasculopathy may reflect direct endothelial viral involvement or, more likely, a secondary response to the viral-triggered immune-related systemic process [15].

III. From Taiwan, Ying-Chu Chen reported a case of a H1N1 associated-encephalopathy/encephalitis with severe neurological sequelae [16].

• A 40-year-old man was admitted after 4 hours of violent, generalized tremors and clumsiness involving his right side limbs. Two days before admission the patient had high fever (39°C), sore throat, mild headache, repetitive vomiting and diarrhea. The general medical practitioner recommended for these symptoms acetaminophen, but the fever persisted.

• CT scan of the brain revealed patchy hypodense lesions of the vertex area.

• CSF analysis showed mild pleocytosis: 13 cell/mm³, proteins = 48mg/dl, glucose = 97mg/dl, lactate = 3.72 mmol/l.

• On admission to the intensive care unit with the diagnosis of encephalitis, the neurological status rapidly deteriorated. He developed paroxysmal truncal spasms associated to the severe tremor and he became irritable and confused. He had tachycardia (122/min – heart rate) and hyperventilation and went into respiratory failure and shock. Neurological examination revealed upper right limb tonic flexion, right inferior limb tonic extension, hyperreflexia and bilateral Babinski sign. He required intubation, mechanical ventilation and infusion of Norepinephrine.

• EEG showed a diffuse slowing of cortical activity.• MRI revealed cortical and subcortical areas of

hyperintensity, localized bilaterally in the frontal-parietal area, with spared deep brain structures.

• PCR –A H1N1 influenza virus from


nasopharyngeal swab was positive; all other serological and molecular tests, from blood and CSF were negative.

• The treatment administrated consisted of: Oseltamivir, Acyclovir, Vancomycin, Ceftiaxon, Minocycline and Propofol (to control the violent tremors).

• The temperature and vital parameters returned to normal after 3 days. The patient survived with neurological sequelae: right hemiplegia, left limb rigidity with severe action tremors, slow psychomotor processing and apathy.

• This case presented with various neurological signs involving both pyramidal and extrapyramidal system, as well as cortical lesions. These clinical features are unusual and the extrapyramidal sequelae of this patient remind us about the presentation of encephalitis letargica after the influenza pandemic in 1918.

• The imaging findings are also unusual because the majority of neurological complications of influenza reported in adults had no abnormalities on CT or MRI. Severe cerebral lesions are characteristic for IAEE or ANEC, clinical forms described in children.

• Because extrapyramidal signs cannot be explained by the lesions found on the MRI image at that moment, it is assumed that new or extensive brain damage occurred after the first MRI examination. For this reason it is important to monitor the imagistic aspects during the evolution of a patient with neurological symptoms [16].

IV. Finally, we present two cases from USA, of two young adults, 26 and respective 29-year-old, both with obesity, who were admitted with the diagnosis of H1N1-associated acute respiratory distress syndrome and renal failure. They developed malignant cerebral edema and died.

• The neurological deterioration and cerebral edema occurred in the context of hyponatremia caused by acute renal failure. These two patients exhibited a transtentorial brain herniation syndrome, including a unilateral third nerve palsy (dilated and unresponsive pupil), elevated intracranial pressure and coma, secondary to the development of acute and diffuse cerebral edema.

• The causes of brain edema are multiple, but two important mechanism are: cytotoxic edema (related to hypoxic-ischemic injury and hyponatremia) and to vasogenic edema (in the context of the systemic inflammatory state, where cytokines lead to increased permeability of the blood-brain-barrier).

• Severe infection with A H1N1 virus has the ability to alter serum Na homeostasis and brain oxygenation, because of the effects on the kidney and lung, generating a high risk for the development of cerebral edema, especially in the presence of altered blood-brain-barrier. For this reason, hyponatremia should be aggressively treated and hypoxia should be avoided.

• Despite the therapeutic measures administrated, including Mannitol and hypertonic saline boluses

and even external ventricular drain, these two patients died [17].

Discussions

In this review I have chosen to present different cases from around the world, some of the most representative examples of neurological complications due to AH1N1 virus. Each of them represents a real lesson which the last pandemic left us:

A. A H1N1 virus turned out to be more aggressive as compared to seasonal flu viruses;

B. Although Influenza associated encephalopathy/encephalitis (IAEE) and acute necrotizing encephalitis of childhood (ANEC) were considered specific forms of neurological complications in children, they can also be found in adults;

C. IAEE seems to develop in individuals with certain genetic predisposition (ex. Patients with carnitine palmitoyltraspherase thermolabile fenotype);

D. Despite clinical and radiological evidence of central nervous system involvement, evidence of the presence of influenza virus in the CSF was rarely demonstrated. In all cases presented here, PCR for AH1N1 from the CSF was negative. (If all these researchers from around the world never found this virus in the CSF maybe it wasn’t there!);

E. Nowadays all scientists are extremely focused on the ``cytokine storm``, which seems to hold the answer to understanding the complex phenomena that occurs in the central nervous system. Brain lesions are extremely severe and many of them lead to dramatic consequences;

F. Laboratory investigations should include: genetic analysis, serum and CSF specific cytokine level and level of brain metabolites;

G. Radiologic monitoring is very important in evaluating patients with neurological complications and understanding the evolution of brain lesions;

H. Therapeutic strategy should include: hypothermia, glucose, Mannitol, Oseltamivir, IVIG, Methilprednisolone pulse-therapy, L-carnitine and maybe, after more studies, anti-citokine agents.

Conclusion

Influenza associated central nervous system dysfunction comes in great variety, from mild or moderate, to malignant forms, with lethal or high neurological sequelae potential. This is just one of the reasons which make Influenza pandemic a major priority for the medical community [18].

References

1. Nicholson KG, Wood JM. Influenza, The Lancet Nov. 2003, vol.362, Issue 9397, pg. 1733-1745.

2. Fraaij PLA, Heikkinen T. Seasonal influenza: The burden of disease in children, Vaccine 2011, 29:7524-7528.3. Thorner AR, Hirsch MS. Clinical manifestations and diagnosis of pandemic AH1N1 influenza (“swine influeza), UpToDate June 2013.


4. Munoz FM, Mallory GB. Clinical features and diadnosis of seasonal influenza in children, UpToDate 2013.5. Henry J, Smeyne RJ. Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries, Parkinsonism and Related Disorders 2010, 16:566-571.6. Thorner AR, Hirsch MS. Epidemiology of pandemic H1N1 influenza(“swine influenza”), UpToDate, april 2014.7. Ismail HIM, The CM. Neurologic manifestations and complications of pandemic influenza A H1N1in Malaysian children: What have we learnt from the ordeal?, Brain &Development xxx(2014)xxx-xxx.8. Landau YE, Grisaru-Soen G. Pediatric Neurologic Complications Associated with Influenza A H1N1, Pediatr Neurol 2011, 44:47-51.9. Cheng XW, Lu J. Three fatal cases of pandemic 2009 influenza A virus infection in Shenzhen are associated with cytokine storm, Respiratory Physiology& Neurobiology 2011, 175:185-187.10. Tomiyasu M, Aida N. Monitoring the brain metabolites of children with acute encephalopathy caused by the H1N1 virus responsible for the 2009 influenza pandemic: a quantitative in vivo H MR spectroscopy study, Magnetic Resonance Imaging 2012, 30:1527-1533.11. Kumakura A, Iida C. Pandemic Influenza A-Associated Acute Necrotizing Encephalopathy without Neurologic Sequelae, Pediatric Neurology 2011, 45:344-346.

12. Wendy S, Vargas MD. Favorable Outcomes in Acute Necrotizing Encephalopathy in a Child Treated with

Hypothermia, Pediatric Neurology 2012, 46:387-389.

13. Fluss J, Ferey S. Mild influenza-associated encephalopathy/encephalitis with a reversible splenial lesion in a Caucasian child with additional cerebellar features, European Journal of Paediatric Neurology 2010, 14:97-100.

14. Cortese A, Baldanti F. Guillain-Barre syndrome associated with the D222E variant of the 2009 pandemic influenza A H1N1 virus: Case report and review of the literature, Journal of the Neurological Sciences 2012, 312:173-176.

15. Locuratolo N, Mannareli D. Unusual posterior reversible encephalopathy syndrome in a case of influenza A H1N1 infection, Journal of the Neurological Sciences 2012, 321:114-116.

16. Chen YC, Lo CP. Novel influenza A(H1N1)- associated encephalopathy/encephalitis with severe neurological sequelae and unique image features – A case report, Journal of the Neurological Sciences 2010, 298:110-113.

17. Kahle KT, Walcott BP. Cerebral edema and a transtentorial brain herniation syndrome associated with pandemic swine influenza A(H1N1) virus infection, Journal of Clinical Neuroscience 2011, 18:1245-1248.

18. Anonymous. Pandemic influenza – a priority for the neurological community, The Lancet Neurology 2009-10-01, vol. 8, Issue 10, pg. 869-869.


Corina Bocșan e-mail: [email protected]

Abstract. It is a fact that more frequent evidences are showing that proton pump inhibitors (PPIs) are used improperly. This contributes, on one hand, to the increase of the cost of health care services, and on the other hand, is impairing the safety and quality of patients’ lives. The aim of this study was to identify whether, in a non ICU ward, PPIs are used with respect for the current clinical guidelines. The research is based on the assessment of therapeutic schemes of 98 patients which were hospitalized in a non-ICU ward, summarizing 236 days of treatment with PPIs. PPI administration was analyzed in related to indication, dose, route of administration and drug interactions. We also tried to determine if there is a potential cost of PPI therapy which could, potentially, be saved. We have found that that PPIs were unnecessarily administered in 8.05% of days, having inadequate doses in 21.61% of days, there have been interactions for 1.69% of days, and route of administration was inadequate for 10.17 % of days. By comparing the total cost with the potential total cost, the first was found as significantly higher. So, PPIs are being used inappropriately to some of the patients admitted to non-ICU ward. A solution for improving PPI therapy might be to include a clinical pharmacologist as part of the medical team and follow minimal prescribing rules.Key words. Proton pump inhibitors, overprescribing, clinical pharmacologist, cost

1. 1st Medical Clinic, Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Romania2. Department of Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania3. Department of Clinical Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania4. Bio-statistics consultant

Neag Maria1, Bocșan Corina2, Popa Adina3, Câmpean R.4, Mircea P.A.1

INAPPROPRIATE USE OF PPIS TO PATIENTS ADMITTED INTO A NON ICU GASTROENTEROLOGY DEPARTMENT


Introduction

Discovery ATP-ase enzyme H+/K+ and introduction of the first proton pump inhibitor to treat

disorders caused by stomach acid have marked a real success in gastroenterology [1, 2]. Currently, proton pump inhibitors are the most effective medication in reducing gastric acid secretion [3].

Proton pump inhibitors that have been used are derivatives of pyridyl-methyl-sulfinil benzimidazole and they act by inhibiting ATP-ase H+/K+, covalently binding to it. Through reaction between CO2 and H2O, under the action of carbonic anhydrase, H+ and HCO3_ are formed. ATP-ase H+/K+ perform the influx of H+ ions and efflux of K+ ions, and the H+ ion is coupled with Cl-introduced by ion exchange with HCO3_ [4, 5, 6].

PPI use is widespread and growing worldwide, with annual sales in excess over U.S. $ 25 billion [3]. In an era of heated controversy and debates on health reform-related costs in the healthcare system, it is important to address all sources of expenditure to the system. In particular, the efficacy and safety of PPI contribute to overuse this therapeutic class [7]. Studies conducted

in the United States and Europe continues to report a PPI overprescribing both in hospital and ambulatory [8]. Approximately 50-60% of gastric acid secretion inhibitory medication prescribed for hospitalized patients is without adequate indication [9]. Here, clinical pharmacologist can have a positive impact. By including these specialists in medical team, may be reduced the cost of drug therapy and patient safety can be improved. In Romania, specializing in clinical pharmacology exists, but in hospitals there are no posts for this specialty. Consequently, clinical pharmacologists work either in research or in industry. This study intends to demonstrate the importance of including a clinical pharmacologist as part of medical teams as contributive solution to optimize and reduce costs of drug therapy for patients with digestive pathology.

Objectives

In this study we aim to evaluate the use of PPI in patients hospitalized in a clinic gastroenterology department, in terms of indications, dosage and administration. At the same time we assessed the extent to which clinical pharmacologist can help to improve prescribing therapeutic substances in this class.

ORIGINAL PAPER


MethodMedical methodologyMedicinal therapies of 98 patients have been studied

by a clinical pharmacologist. Patients were hospitalized in a department of gastroenterology, non-ICU, of Clinical Emergency County Hospital Cluj.

We considered proper use of PPIs:A. Use as directedAppropriate indications for PPI have been considered

under the following conditions:• Erosive esophagitis treatment;• Treatment of symptoms of gastroesophageal

reflux disease (GERD);• Eradication of Helicobacter pylori (HP);• Treatment of duodenal ulcer;• Treatment of gastric ulcer;• Treatment of Zollinger-Ellison syndrome;• Treatment of ulcers induced by non-steroidal anti-

inflammatory drugs (NSAIDs);• Suspicion of bleeding in the upper gastrointestinal

tract;• Prevention of gastrointestinal bleeding ulcers;• Prevention of ulcers caused by NSAIDs if:

* The patient has a history of complicated ulcer;* Use several NSAIDs including aspirin;* The use of high doses of NSAIDs;* Concomitant use of anticoagulants;* Old age;* Concomitant use of corticosteroids. [7, 8, 10, 11].

B. Method of administration of PPIs: corresponding indication dose, frequency of administration, optimum route of administration, duration of therapy according to clinical guidelines: Order no. 1216/2010 for the approval of Medical Practice Guidelines for Specialty Gastroenterology, American College of Gastroenterology guidelines, monographs of each substance [8, 12, 13, 14, 15]. Most used PPI for the hospitalized patients were: omeprazole, pantoprazole, esomeprazole. These were administered either ways, orally or by parenteral use (iv).

Statistical Analysis

In order to prove the hypothesis of the study, two characteristics of the group have been considered. We aim to demonstrate that there is a potential cost of treatment that can be saved.

Characteristics of the studya) Variable that measures the impact on patients

exposed to PPIs.• Usefulness of the drug - according to clinical

guidelines.• Dose - dose too high or too low relative to the

patient's diagnosis.• Possible interactions of PPI with other drugs

administrated simultaneously.• Untreated problem - there was a problem that

required treatment with PPIs, but it was ignored.• Route of administration - oral or parenteral (iv).All the above variables are Boolean ones, having

only two values 0 or 1, 1 representing the presence of medication error and 0 absence of it.

b) Variables that quantifies the effect of improper use of PPI therapy, quantifying the potentially cost saving.

• Potential cost saved achieved by assessing dose, route of administration, usefulness or interactions.

• Hospital cost: cost incurred by the hospital.• Patient cost: cost incurred by the patient,

deducted cost based on the patient's medical history in conjunction with price information published on the website of the Ministry of Health.

• Total Cost: The sum of hospital cost and patient cost.

All the above variables, related to costs, are quantitative ones.

Study sample

The 98 patients were treated with PPI during 236 days, on average 2.4 days / patient. Statistical unit of study (observation study) is “the day of hospitalization”. A patient can produce multiple days of hospitalization, each day being measured using all variables described above. Day of hospitalization is the cost producer.

1. Method1.1. Assumptions and descriptive results.The metric of survey is represented by the comparison

of the total cost of treatment with PPIs and total cost, excluding the potential cost savings. This test is designed to validate or invalidate working hypothesis. The metric will compare the actual cost versus actual cost less the amount that can be saved through proper use of PPIs (inappropriate use represents fundamental assumption we wish to be tested).

Type of test. Pair-test to compare differences between mean

Statistical hypothesisH0 (null hypothesis): Average total cost equals

average total cost potential.H1 (alternative hypothesis): Average total cost is

greater than average total cost potential.Note. Given the alternative hypothesis formulation,

unilateral paired t-test will be use. This choice is justified because the actual total cost is greater than the potential total cost as shown in Table I:

Total cost Potential total costAverage 14.79 6.05

Standard deviation 23.17 11.49

Table I. Indicators for central tendency and deviation for Real Average Total Cost and Potential Average Total Cost


In accordance with clinical guidelines, either of the American College of Gastroenterology or those existing in Romania, of the 236 days of hospitalization in which the patients received PPIs, in 19 days the treatment was unnecessary, in 51 days doses of PPIs were inadequate (too big/too small), in 4 days were identified interactions between PPIs and medication given simultaneously, in 14 days there were problems that needed treatment with PPIs but they were ignored and in 24 days the administration route of PPIs was inadequate (see Table II).

1.2. Inferential results.In the absence of no previous specifications, the

standard 5% risk level (0.05) will be chosen.Results of unilateral t test (one-tail) pairs are shown

in Table III

Discussion

Due that PPIs is one of the most frequently prescribed medication, we considered important to evaluate the use of this therapeutic class, from the point of view of clinical pharmacologist. PPIs have been used to the 98 patients in 236 days and the medication errors were identified in 112 days, which means a summarized rate of 47.45%. A similar study on elderly patients highlighted a percentage of PPIs incorrect use of 61% [16].We present in Table IV some examples of errors.

The results are showing that the most common error encountered when using PPI medication is related to dose, 21.61% according to our study. This error can be avoided if it is taken into account the relevant specifications of

the products monographs of the American College of Gastroenterology guidelines or those in Romania, where doses of PPIs are indicated for each part of the digestive pathology (gastro esophageal reflux disease, peptic ulcer, acute gastritis, etc.). In this, it is stated that, in patients with indication for PPIs therapy they are prescribed in minimum effective dose [17].

Wrong dose is coming on the second place, in descending order of frequency of occurrence, by wrong route of administration, unnecessary recommended drug, problem untreated and lowest frequency, drug interactions.

In the study there is a tendency to use PPI by injection against oral PPI although the efficacy of this class of drugs is the same regardless of the route of administration (oral or parenteral) and preparations administered parenterally cost is much higher than the oral (33 RON vs. 0.83 RON) [18]. A study in the UK shows

that only 26.4% of the administered iv PPI are without prescription error (correct indication, correct dose, frequency of proper administration) [19]. Another study that has been conducted in a university hospital in the United States showed that 76% of the PPI administered iv. did not qualify for this route of administration [20].

For a correct use of PPIs in hospitalized patients would be useful associating a clinical pharmacologist to the medical team and following a few basic prescribing rules related to:

a) Drug indication: is the drug appropriate for the patient?

b) Similar drugs: is patient using a drug with the same action?

c) Dose: the dosing regimen is right? (dose, frequency of administration)?

Type of error Presence of error Absence of errorUnnecessary drug 19 days (8.05%) 217 days (91.95%)Inadequate doses 51 days (21.61%) 185 days (78.39%)Possible interactions 4 days (1.69%) 232 days (98.31%)Problem untreated 14 days (5.93%) 222 days (94.07%)Wrong route of administration 24 days (10.17%) 212 days (89.83%)

Table II. The incidence of medication errors, identified by groups of errors

Total cost Potential Total costAverage 14.79 6.05Dispersion (spread) 537.02 131.93Standard deviation 23.17 11.49Sample size 236 236H0 (difference between actual average costs-potential) 0Statistical t (calculated) 7.62Theoretic t (unilateral) 1.652177009p-value, P(T<=t) (unilateral) 0.00 << 0.05

Table III. Summary of statistical testing (unilateral)


d) Duration: duration of therapy is correct?e) Cost: evaluating the cost / efficiency? [21, 22].However, the prolonged use of PPIs has also potential

side effects: vitamin B12 deficiency, iron deficiency, osteoporosis risk, risk of infections (e.g. Clostridium difficile infection), pneumonia, bone fractures, and their presence correlates with the rising cost from health system [7, 9, 23, 24, 25].

ConclusionsBased on data analysis we ordered, the study

hypothesis is validated. Thus, the total cost can be accepted as being statistically significantly higher than the potential total cost. The source of this difference was found in the fact that PPIs are used inappropriately for hospitalized patients in non-ICU ward. This misuse has a particularly negative impact on treatment costs and, to a lesser extent, on patient safety.

Therefore, our recommendation is to include a clinical pharmacologist in medical team. As the owner of accumulation of information and knowledge, this kind of professional can optimize the cost, safety and quality of patients’ life.

References

1. Shin JM,Vagin O, Munson K, Kidd M, Modlin IM, Sachs G. Molecular mechanisms in therapy of acid-related diseases. Cell Mol Life Sci. 2008; 65(2):264–281.

2. Madanick RD. Proton pump inhibitor side effects and drug interactions:Much ado about nothing? Cleveland Clinic Journal 2011;1(78): 39-49.

3. Ahrens D, Chenot JF, Behrens G, Grimmsmann T, Kochen M. Appropriateness of treatment recommendations for PPI in hospital discharge letters.

Eur J Clin Pharmacol 2010; 66:1265–1271.4. Shin JM, Sachs G. Long lasting inhibitors of

the gastric H,K-ATPase. Expert Rev Clin Pharmacol. 2009;2(5):461–468.

5. Shin JM, Sachs G. Pharmacology of Proton Pump Inhibitors. Curr Gastroenterol Rep. 2008;10(6):528–534.

6. Mejia A. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol. 2009 ;2(3): 295–314.

7. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol.2012;5(4):219-32.

8. Eid SM, Boueiz A, Paranji S, Mativo C, Landis R, Abougergi MS. Patterns and Predictors of Proton Pump Inhibitor Overuse among Academic and Non-Academic Hospitalists. Intern Med 2012;49: 2561-2568.

9. Ali T, Roberts DN, Tierney WM. Long-term Safety Concerns with Proton Pump Inhibitors. Am J Med. 2009;122(10):896-903.

10. Echevarría EM, Pereira JA, Torralba M, Arriola PG, Martín DP, Mateos J and Zapata R. Assessing the use of proton pump inhibitors in an internal medicine department. Rev Esp Enferm Dig. 2008;2(100):76-81.

11. Nasser SC, Nassif JG, Dimassi HI. Clinical and cost impact of intravenous proton pump inhibitor use in non-ICU patients. World J Gastroenterol. 2010;16(8):982-6.

12. http://www.ms.gov.ro/index.php?pag=181&pg=213. DeVault K, Kastell D. Updated Guidelines for

the Diagnosis and Treatment of Gastroesophageal Reflux Disease. Am J Gastroenterol 2005;100:190-200.

14. Lanza F, Chan F, Quigley E. Guidelines for Prevention of NSAID-Related Ulcer Complications.

Type of error Example of error Correcting the error

Unnecessary drug

Administration of pantoprazole and omeprazole together. Pantoprazole injectable, 2 x 40 mg/day, to a patient without digestive symptoms and no signs of gastrointestinal bleeding

Administration of a proton pump inhibitor alone. Minimum oral dose administration of PPI prophylactically until elucidate the diagnosis

Inadequate doses

Dose of pantoprazole 20 mg/day for peptic ulcer (diagnosis sustained by upper gastrointestinal endoscopy) or Controloc 2 x 40 mg/day prophylactic in patients with cirrhosis or chronic pancreatitis

Pantoprazole 40 mg/day for 4-8 weeks. Pantoprazole 20 mg/day

Wrong route of administration

Patient with dyspepsia receives injectable pantoprazole even though has in therapeutic plan also oral medication

Administration of pantoprazole or other PPI orally. The efficiency of PPI administered parenterally is the same as the ones being administered orally

Problem untreated

During hospitalization acute gastritis diagnosis is put both clinically and endoscopically, but patient remains without further treatment. Therapeutic recommendation is being offered only at discharge

Recommendation of antisecretory therapy immediately after diagnosis

Drug InteractionsWere administered omeprazole and sucralfate. There are possible interactions between the two medicinal substances, sucralfate activating it when the pH is below 4

Only the administration of PPI

Table IV. Examples of medication errors


Am.J.Gastroenterol 2009; 104:728 – 738.15. http://www.drugs.com16. Hamzat H, Sun H, Ford J, MacLeod J, Soiza R,

Mangoni A. Inappropriate Prescribing of Proton Pump Inhibitors in Older Patients: Effects of an Educational Strategy. Drugs & Aging; 2012:29(8):681-690.

17. Heidelbaugh J, Metz D, Yang Y. Proton pu,p inhibitors: are they overutilised in clinical practice and do they pose significant risk? Int J Clin Pract 2012;66(6):582-591.

18. Pang S, Graham D. A clinical guide to using intravenous proton-pump inhibitors in reflux and peptic ulcers. Ther Adv Gastroenterol 2010; 3(1): 11-22.

19. Craig D, Thimappa R, Anand V, Sebastian S. Inappropriate utilization of intravenous proton pump inhibitors in hospital practice—a prospective study of the extent of the problem and predictive factors. Q J Med 2010; 103:327–335.

20. Hoover JG, Schumaker AL, Franklin KJ. Use

of intravenous proton-pump inhibitors in a teaching hospital practice. Dig Dis Sci. 2009;54(9):1947-52.

21. Aronson JK. Medication errors: what they are, how they happen, and how to avoid them. QJM. 2009;102(8):513-21.

22. Aronson JK. Balanced prescribing – principles and challenges. Br J Clin Pharmacol 2012;74(4):566–72.

23. Coté GA, Howden CW. Potential adverse effects of proton pump inhibitors. Curr Gastroenterol Rep. 2008;10(3):208-14.

24. Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ. 2012;344:e372.

25. Durand C, Willet K, Desilets A. Proton Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a Problem? Clinical Medicine Insights: Gastroenterology 2012;5:65-76.


Ana Maria Davițoiu21 Basarabia Blvd, Bucharest, Romaniae-mail: [email protected]

Abstract. Deficit Hyperactivity Disorder (ADHD) is considered to be a neurodevelopment condition with a worldwide prevalence between 3-10 % in children1 with symptoms that could continue into adolescence for 50-80% of cases and into adulthood for as many as 30 – 50 % of cases. The purpose of the research was to evaluate the efficacy and safety of pharmacological treatment in attention deficit hyperactivity children. A retrospective clinical research in 73 patients was designed and carried out at “Victor Gomoiu” Clinical Pediatric Hospital. The data was obtained from patients medical records. The study duration was 15 months from Jan 2013 to March 2014. The medical treatment was analysed: type of drugs given, dosage, pharmaceutical formulation, length of treatment. We also analysed the types of non-medical treatments associated: psychological therapy, logopedic therapy, occupational and cognitive stimulation therapy, other types of therapy. Monthly monitoring and identification of adverse events was done for each patient by analysing the type of medication given, adverse event onset, severity, dose optimization, withdrawal from treatment or change of medication. Data was stratified for three age groups: preschool children (< 7years old), 12 to 18 - year-olds and 7 to 11 - year- olds. Combined therapy (both medical and psychological) gave results but without being able to determine the measure in which either the psychological, pharmacological or combined treatment have influenced the end result. Early detection and management of side effects (dose optimization, change of medication, drug combinations that diminish or even eliminate the side effects, treatment interruption) improve compliance and adherence towards the given medical treatment but also improve the quality of life.Key words: ADHD; efficacy; safety; pharmacological and non-pharmacologycal treatment

1. Clinical Emergency Children’s Hospital “Victor Gomoiu”, Bucharest, Romania2. University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania3. Clinical Emergency Hospital, Bucharest, Romania4. National Institute of Infectious Diseases "Prof. Dr. Matei Balș", Bucharest, Romania

Daviţoiu Ana Maria1,2, Truţă Elena3, Negulescu Cristina4, Constantin Laura3, Stoica Alexandra3, Pleşca Anca Doina1,2

ASSESSING THE EFFECTIVENESS AND SAFETY OF PHARMACOLOGICAL THERAPY IN CHILDREN DIAGNOSED WITH ATTENTION DEFICIT AND HYPERACTIVITY DISORDERS

ORIGINAL PAPERTherapeutics, Pharmacology and Clinical ToxicologyVol XVIII, Number 2, June 2014Pages: 61-67 © Copyright reserved 2014

Introduction

Attention Deficit Hyperactivity Disorder (ADHD) is considered to be a neurodevelopment

condition with a worldwide prevalence between 3 - 10% in children with symptoms that could continue into adolescence for 50 - 80% of cases and into adulthood for as many as 30 – 50 % of cases (Kristensen H.A., et al, 2014). The persistence of ADHD in these age groups was once debated between clinicians and researchers but it is a well-established fact now. Symptom severity decrease with time but patients continue to experience elevated levels of inattention, hyperactivity and impulsivity compared to typically developing peers. There seem to be three patterns of ADHD manifestations in patients:

one consisting mostly of inattention, the second mostly of hyperactivity and/or impulsivity and the third type being a combination between these two. The findings are consistent with the current available guidelines: DSM V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) the 2013 update to the American Psychiatric Association's (APA) and the International Statistical Classification of Diseases and Related Health Problems (ICD 10) a medical classification list established by the World Health Organization (WHO).

EtiologyADHD is thought to be caused by abnormalities

of neurotransmitter functions, which regulate the amount of dopamine and norepinephrine in the frontal lobe (Bron T.I., et al, 2014). Both are catecholamine-structured compounds that play an important role in the functionality of the sympathetic nervous system. Dopamine plays an important part in behaviours such


as learning, motivation, goals, drives and emotions while norepinephrine is involved in maintaining the organism in a state of alertness and awareness through detection of the correct stimuli that start the process. Other studies demonstrated increases in dopamine D2/D3 receptor activity in striatal regions in adolescence with ADHD (Ernst M., et al., 1999). The physiopathology of ADHD is complex and not fully understood but the genetic aspects account for around 75% of the disorder symptomatology. Other two important factors are the external ones and the social related ones. The genetic research for ADHD summarises a list of candidate genes that could be responsible for the disorder but most likely, there is a combination of genes linked to ADHD, which are involved in the function of several neurotransmitters (Voeller K.K.S., 2004). Other recent studies have shown a co-occurrence of ADHD and obesity in children due to common risk alleles. There is evidence that obesity genes such as FTO gene, which codes for the enzyme alpha-ketoglutarate - dependent dioxygenase, may affect ADHD risk. There is no clear picture concerning specific biomarkers, which could detect from early on a tendency towards developing ADHD in young patients but recent studies highlight that adiponectin and in particular, its high molecular weight form may be a possible marker for ADHD. The mechanisms underlying the association between adiponectin levels and psychiatric symptoms are largely unknown (Mavroconstanti T., et al, 2014). Early findings using magnetic resonance imaging (MRI) reported morphological differences in brain regions innervated by dopamine containing neurons in young patients with ADHD. Similar studies showed that children with ADHD have smaller volumes of total brain matter and subcortical regions but it is not clear yet whether these differences persist into adulthood or are simply a delayed maturation process. The most noticeable differences in ADHD compared to controls were found in the cerebellar regions, the splenium of the corpus callosum, total and right cerebral volumes and right caudate nucleus. The literature does not specify how abnormal childhood brain volumetric translates into adulthood. No difference between ADHD patients and healthy subjects were observed for total brain volume, grey matter or white matter volume (Marten A., et al, 2014).

More and more evidence suggests a possible attentional phenotypic pattern for ADHD children. It seems that compared to typically developing peers, ADHD children are slower and less accurate in responding to invalidly cued left targets than compared to right ones.

Another difference was noted through positron emission tomography (PET) which showed that ADHD patients had an overall deficit in cerebral glucose metabolism compared to control subjects (Marten A., et al, 2014).

It is not surprising regarding the genetic nature of ADHD, that 25% of patients will have a parent who met the former diagnostic criteria for ADHD as well. Aside the genetic factors, social-environmental ones also play a very important part. Increased rates of attention deficit and hyperactivity have been observed in children who were raised in institutions. The educational background as well as the family upbringing influences the symptomatology but it also could affect the way a proper

diagnosis will be given depending on the severity of the behaviour. There is growing concern that patients could be over-diagnosed due to a faulty therapeutic evaluation, which can lead also to inadequate therapy.

External factors have also been linked to ADHD or ADHD like behaviours. Some of these include multiple pre- and perinatal factors: foetal alcohol syndrome, maternal smoking, metabolic disorders of the mother (diabetes, phenylketonuria), injury to the medial temporal lobe during early development, hyperbilirubinemia (jaundice) in the newborn period, iron deficiency, hypoxia, particularly in the foetus or infant.

The risk of co morbidity is high in patients with ADHD. The most common condition in adult ADHD is Major Depressive Disorder (MDD), which was associated with smaller volumes of total and left hippocampus in subjects.

Developmental coordination disorder (DCD) is another neurodevelopmental disorder frequently associated with children with ADHD and it affects their ability to perform everyday tasks. There is a heightened risk of psychological distress for these patients, which can lead to more health problems than in children with ADHD only. Research indicates that the co morbidity between ADHD and DCD is very high, a “pure” ADHD being rather an exception than a rule (Missiuna C., et al, 2014).

ADHD has been also associated with autism spectrum disorders, epilepsy, anxiety, thus patients with such co morbidities experience a greater social, cognitive and psychological impairment.

TreatmentControlled studies proved a lower efficacy only

with behavioural therapy as compared to those where a medical treatment was associated. Combined therapy leads to variable results. The type of therapeutic approach depends on the patient’s age, severity of symptoms and other known associated conditions.

Non-medical treatmentThere are different types of approaches but the best

thing for a young patient is to understand the condition, a step which can be done through counselling including through cognitive-behavioural therapy (ex: goal-setting, role-play, self-monitoring). The main aspect resides in organisation, routine and structure. The behaviour during school hours should be carefully monitored through noise and visual stimuli control, by establishing an adequate deadline for tasks, a diversity and innovation in them and also though the teacher’s proximity and influence.

If difficulties persist in the home environment, parents are encouraged to seek additional professional help including through behavioural management techniques. Children with mostly hyperactive and impulsive type ADHD are often helped at home by having an organised schedule, established limits and through adequate parenting approaches.

It has been reported that patients with ADHD tend to be bored more easily and because of this fact, immediate rewards are preferred compared to delay ones, even if this choice would reduce overall size of the rewards.

Medical treatmentA measure of ADHD and the responsiveness to


medication is through the electroencephalogram (EEG) which in ADHD has a consistent pattern of low frequency activity. In the diagnosis of ADHD, theta waves play an important role, being significantly increased in frontal regions in ADHD groups compared to the control group (Tye C., et al, 2014). The purpose of pharmacotherapy is to reduce symptoms and to bring the condition to a stable state, this being the case of long term ADHD with symptoms from moderate to severe. Studies have shown that ADHD is an independent risk factor for smoking with increased chances for an individual to start smoking earlier in life and with a higher risk of dependency. Although a precise mechanism has not been described, researchers consider that dopamine dysfunctions in the reinforcement processes might be a possible cause (Kollins S.H., et al, 2014). Besides smoking tendencies, individuals with ADHD are also at higher risk for substance abuse (Charach A., et al., 2011) and the use of psychostimulant drugs is controversial in patients that also have a substance-abusing problem.

The two main drugs prescribed in Romania are methylphenidate (MPH) and atomoxetine. MPH is a CNS stimulant, chemically related to amphetamine and by stimulating the central nervous system; it increases attention, alertness and lowers fatigue (Daviţoiu A., ş.a., 2014). The long-term effects of MPH are unknown and treatment duration should not surpass 12 months, unless the physician considers there is an overall therapeutic benefit. Treatment for patients under 6 years old is not recommended. MPH is prescribed also off-label in MDD (major depressive disorder), in obesity, lethargy and bipolar disorders. Generally it is recommended for the last dose to be given at least 4 hours before going to bed, due to side effects (***., 2012). Sleep problems or difficulties with sleep onset and maintenance are reported within the use of psychostimulants. This problem can be also due to ADHD itself and it is often associated with anxiety or other behaviour disorders (parent reported prevalence ranging from 55% to 74%). Melatonin is prescribed in these cases, only for sleep onset while other drugs are prescribed also for a range of emotional and behavioural symptoms (clonidine/tricyclic antidepressants) (Efron D., et al., 2014). Atomoxetine is a selective norepinephrine reuptake inhibitor, used in the treatment of ADHD and has demonstrated efficacy, being preferred in individuals with co morbid anxiety, substance abuse, increased mood lability or tics. The mechanism of Atomoxetine is not completely understood but it acts as an indirect agonist of catecholamine signalling in the prefrontal cortex, modifying the signals to noise ratios, which are thought to influence the symptoms in the disorder. Benefits have been observed as early as one week after reaching therapeutic dose but evidence suggests that full effects may be observed after 6 weeks from the start of the treatment. Although ADHD was initially considered a developmental disorder, recent findings lean towards the idea of a disruptive disorder. Many researchers consider ADHD to be over diagnosed, especially due to inadequate diagnosis criteria (Leuchter A.F., et al., 2014).

ObjectiveThis retrospective study of 73 paediatric patients was

carried out in the Clinical Emergency Children’s Hospital “Victor Gomoiu” in Bucharest and its main purpose was to evaluate the safety and effectiveness of treatment in children diagnosed with ADHD. The duration of the study was of 15 months, between January 2013 and March 2014. The study received approval from the Institutional Ethics Committee, and both parties (patients and their legal guardians) gave their consent to take part in the study by signing an Informed Consent Form.

Materials and methodsThe study participants were ambulatory patients of

the Emergency Children’s Hospital “Victor Gomoiu”. The study data was obtained from medical records pertaining to a variety of paediatric patients diagnosed with ADHD as well as other associated illnesses. Demographic features such as: age, sex, family background and social background were also recorded.

Subjects included in the study were paediatric patients diagnosed with ADHD according to DSM IV or DSM V or ICD-10 that tested positive for at least 3 out of 9 symptoms of inattention, at least 2 out of 5 symptoms of hyperactivity and at least one criteria out of 4 for impulsivity. The final diagnosis meant that symptoms should be present and identifiable for a minimum of 6 moths, and the condition should manifest in at least one of the following backgrounds: social, family or school. Autism, psychical illnesses and Down Syndrome were considered inclusion criteria.

There were no established exclusion criteria. The children’s symptoms were included in one of

the following categories: attention deficit, hyperactivity or a combination of the two. The children selected in the study received medical treatment or other types of therapy, depending on the doctor’s decision. The neuropsychiatric development was established by IQ measurement and by using the Portage Scale.

The Childhood Autism Rating Scale (CARS) was used to evaluate the symptoms of Autism. Other assessments were done to collect information regarding the quality of life as per the following procedures which will be discussed further on.

The medical treatment was analysed: type of drugs given, dosage, pharmaceutical formulation, length of treatment. We also analysed the types of non-medical treatments associated: psychological therapy, logopedic therapy, occupational and cognitive stimulation therapy, other types of therapy. Their inclusion in the overall treatment was the doctor’s personal decision.

Monthly monitoring and identification of adverse events was done for each patient by analysing the type of medication given, adverse event onset, severity, dose optimization, withdrawal from treatment or change of medication.

Data was stratified for three age groups: preschool children (< 7years old), 12 to 18-year-olds and 7 to 11 - year-olds.

Results and discussions Applying non-medical treatment or medical

treatment in children diagnosed with ADHD, has the end purpose of reducing symptom severity and improving the


performance and task accomplishment at school, amongst family or any other social environment that the child is part of (Klassen AF et al, 2004). ADHD syndrome was diagnosed in 73 cases, out of which 63 patients (83.5%) had comorbidities. Only 10 patients appeared to be diagnosed with “pure” ADHD. The number of comorbidities was between 1 and 4 (Figure 1) out of which the most common

Figure 1. Comorbidities per age groups

Figure 2. Gender of study participants diagnosed with ADHD

were intellectual disability (ID), speech impediments and autism spectrum disorders (ASD).

Out of all study participants, 73.6% were males and 26.3% females (Figure 2). The average age for was 9.3 years (age range between 5 to 16 years) years for males and for females 8.7 years (age range between 3 to 13 years).

Demographic, socio-economic and clinical characteristics of children with ADHD as well as their families are presented in Table I.

We couldn’t establish a connection between socio economic influences, antecedents and ADHD subtype. XVIII The most frequent subtype of ADHD among subjects, in all three groups, was the Combined Type (Figure 3), followed by the Predominant Inattentive and the Hyperactive-Impulsive type.

Figure 3. ADHD subtype amongst the three age groups


Feature Number %

Family statusNuclear family (two-parent family) 38 52.05Single-parent family 22 30.13Maternal assistant 5 6.84Personal caregiver 8 10.95EducationNormal school/ kindergarten 68 93.15 Special school/ Special classes 5 6.8Mistakes in educational assessment 20 27.39GenderMale 53 73.6Female 20 26.7Age≤ 7 years 14 19,177 - 11 years 16 58.912 - 18 years 43 21.19ADHD subtypeADHD, Combined Type 42 57.53%ADHD, Predominantly Hyperactive-Impulsive Type 13 17.8%ADHD, Predominantly Inattentive Type 18 24.65%Types of associated illnesses Intellectual disability 46 63.01Speech impediments 19 26.02Autism spectrum disorders 10 13.69Down’s syndrome 1 1.36Conduct disorder 10 13.69Neurological disorders 7 9.58Others 5 6.84AntecedentsParent with ADHD 1 1.36Prenatal seizures 3 4.1

Table I. Demographic, socio-economic and clinical status of children diagnosed with ADHD as well as their families

All age groups were confronted with socio economic issues: single-parent families (30.13%), personal caregivers (10.95%), maternal assistants (6.8%), all of these influencing the quality of life.

Initial treatment consisted in psychotherapy for preschool children. For the other age groups, the initial approach was a pharmacological one. The types of drugs administered were either Methylphenidate (71.4% -79.6%) or Atomoxetine (20.9% - 28.5%) – Figure 4.

The quality of life had suffered a severe impact for 50% of preschool children and for 60.4% of children between 7 and 11 years of age. For the other 50% of preschool children, 23.5% of the 7 to 11-year-olds and 100% of the 12 to 18-year-olds, the impact was of moderate proportions. 16.27% of the 7 to 11-year-olds, had the quality of life slightly affected by their condition.

Figure 4. Pharmacological treatment for ADHD in the three age groups


The treatment improved the quality of life for 50% of preschool children and for 9.3% of children between 7-11 years old. For the rest of the children, there were no improvements concerning this issue.

Adverse events (AE) were reported in all three age groups: 25%, 23% and 30% - see Figure 5. The AE

reported amongst preschool children (a total of 14 children – 2 girls 14.28% and 12 boys – 85%) were sleep disorders (two cases – 14.28%) and convulsive episodes (one case – 7.1%). The two patients that were treated with methylphenidate, had sleep induction and sleep maintenance problems. The convulsive episode appeared after two months from the initial treatment with Atomoxetine and lead to the following therapeutic measures: discontinuity of Atomoxetine administration, the treatment of convulsions and continuity in cognitive behavioural therapies.

The total number of children with ages between 12 to 18 was 16: 4 girls, 12 boys with an average age of 13 years for girls and 14, 08 years for boys. The AE that were reported in this age group are presented in Figure 6. Five children that were receiving pharmacological treatment had an adverse event (31.25%). For these patients, symptoms appeared after treatment with Methylphenidate (2 patients - 12.5%) and after treatment with Atomoxetine (3 patients – 18.75%). Other adverse events reported were: headaches (1 subject) and ECG

alterations associated with convulsive episode (1 subject) – for patients treated with Methylphenidate and loss of appetite (2 subjects), anxiety (1 subject) and gynecomastia (1 subject) for patients treated with Atomoxetine.

The AE reported in the 7 to 11 - year-olds group were the following: motor tics and twitches (1 subject), sinus tachycardia (1 subject), enuresis (2 subjects), diurnal enuresis (1 subject), headaches (1 subject), sleep disorders (2 subjects) and drowsiness (1 subject) – Figure 7.

In most cases (88.37% for 7 to 11 - year olds and 87.5% for 12 to 18 - year-olds) ADHD was diagnosed for the first time (“de novo”) in children. Late diagnoses of this condition as well as a faulty education (20-27.39%) lead to increased rates of treatment abandonment and also difficulties in fitting in the family, school and other social environments.

Conclusions Combined therapy (both medical and psychological)

gave results but without being able to determine the measure in which either the psychological, pharmacological or combined treatment have influenced the end result.

Association between pharmacological and non-pharmacological treatment as well as family support contributed to the child’s well-being and state of health.

A big contribution to a positive outcome in ADHD treatment belongs to a wide range of parties: medical specialists (the general practitioner, the pediatric doctor, the neuropsychiatrist), the psychologist, family members as well as the social environment surrounding the child.

We notice the absence of a National Therapeutic Guideline in our country as well as a common disinterest manifested by parents in following educational programmes and behavioural trainings for parents with children diagnosed with ADHD: manuals, videos on behavioral techniques and statements of other parents sharing positive experiences as an outcome, tips regarding practicing a balanced and a healthy diet with high quality nutrients, recommended regular exercises for children and teenagers diagnosed with ADHD as well as supervision of eating habits and the amount of fluids ingested and the relationship to ADHD. Fatty acid supplements are not recommended as a way of treatment.

Figure 5. Adverse events reported in preschool children

Figure 6. Adverse events reported in 12 to 18-year-olds

Figure 7. Adverse events reported in 7 to 11-year-olds


Thus, the number of educational errors could be reduced or even be eliminated.

Training programs for schoolteachers would also improve the quality of life of children diagnosed with ADHD. The frequency of these trainings for both parents and teachers would delay the initiation of a pharmacological treatment, reducing thus the prevalence of adverse events and the costs of the treatment.

For a better assessment of safety and efficacy of pharmacological treatment in children diagnosed with ADHD, this study should be extended to other medical centres, interested in understanding better this condition. This would be a great contribution in solving the frequent impediments related to this disorder.

Early detection and management of side effects (dose optimization, change of medication, drug combinations that diminish or even eliminate the side effects, treatment interruption) improve compliance and adherence towards the given medical treatment but also improve the quality of life.

It is recommended, as a safety measure, to apply cognitive behavioural therapy as an elective treatment before any pharmacological approach - for preschool children and children younger than 12 years of age. In the case of teenagers, pharmacological treatment is recommended as a primary therapeutic measure.

Acknowledgement: This paper is partly supported by the Sectorial Operational Programe Human Resources Development (SOPHRD), financed by the European Social Fund and the Romanian Governmentunder the contract number 141531.References

1. Bron T.I., Bijlenga D.A., Boonstra M. OROS – methylphenidate efficacy on specific executive functioning deficits in adults with ADHD: A randomized, placebo-controlled cross-over study. European Neuropsychopharmacology 2014; 24:519-528.

2. Charach A., Dashti B., Carson P., Booker L., Lim C.G., Lillie E., Yeung E., Ma J., Raina P., Schachar R. Effectiveness of Treatment in At-Risk Preschoolers. Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment. Attention Deficit Hyperactivity Disorder. Agency for Healthcare Research and Quality (US) 2011 Oct.

3. Daviţoiu A., Pleşca A.D., Truţă E., Constantin L., Stoica A. Farmacoterapia la pacienţii cu ADHD: eficienţă şi siguranţă. Congresul Naţional de Farmacie, Ediţia XV 2014.

4. Efron D., Lycett K., Sciberras E. Use of sleep medication in children with ADHD. Sleep Medicina 2014; 15:472-475.

5. Ernst M., Zametkin A.J., Matochik J.A., Pascualvaca D., Jons P.H., Cohen R.M. High midbrain [18F] DOPA accumulation in children with attention deficit hyperactivity disorder. American Journal of Psychiatry 1999; 156:1209 – 1215.

6. Klassen A.F., Miller A., Fine S. Health - Related Quality of Life in Children and Adolescents Who Have a Diagnosis of Attention - Deficit/Hyperactivity Disorder Pediatrics 2004; 114:e541.

7. Kollins S.H., R. Adcock A. ADHD, altered dopamine neurotransmission, and disrupted reinforcement processes: Implications for smoking and nicotine dependence. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 52:70-78.

8. Kristensen H.A., Parker J.D.A., Taylor R.N. The relationship between trait emotional intelligence and ADHD symptoms in adolescence and young adults. Personality and Individual Differences 2014; 36-41.

9. Leuchter A.F., Mc Gough J.J., Korb A.S. Neurophysiologic predictors of response to atomoxetine in young adults with ADHD: a pilot project, Journal of Psychiatric Research 2014; XXX:1-8.

10. Marten A., Onnink H., Zwiers M.P., Hoogman M. Brain alterations in adult ADHD: Effects of gender, treatment and comorbid depression, European Neuropsychopharmacology 2014; 24:397 – 409.

11. Mavroconstanti T., Halmǿy A., Haavik J. Decreased serum levels of adiponectin in adult attention deficit hyperactivity disoerder, Psychiatry Research 2014; 216:123-130.

12. Missiuna C., Cairney J., Pollock N., Campbell W., Russel J.D. Psychological distress in children with developmental coordination disorder and attention-deficit hyperactivity disorder. Research in developmental disabilities 2014; 35:1198-1207.

13. Missiuna Ch, Cairney J., Pollock N., Campbell W., Russel D., Macdonald K., Schmidt L., Heath N., Veldhuizen S., Cousins M. Psychological distress in children with developmental coordination disorder and attention - deficit hyperactivity disorder. Research in development disabilities 2014; 35:1198 - 1207.

14. Sibley M.H., Kuriyan A.B., Evans S.W. Pharmacological and psychosocial treatments for adolescents with ADHD: An updated systematic review of the literature. Clinical Psychology Review 2014; 34:218-232.

15. Silk T.J., Newman D.P., Ranmalee E. Influence of methylphenidate on spatial attention asymmetry in adolescents with attention deficit hyperactivity disorder (ADHD), Neuropsychologia 2014; 56:178-183.

16. Tye C., Rijsdijk F., Mc Loughlin G. Genetic overlap between ADHD symptoms and EEG theta power, Brain and cognition 2014; 87:168-172.

17. Voeller K.K.S., Attention-Deficit Hyperactivity Disorder (ADHD) J Child Neurol. 2004; 19 (10):798-814.

18. ***. Merck 8th, edition 2006. 19. ***. RCP - Medikinet®, 3 octobre 2012.20. ***. RCP – Strattera®, Aprilie 2008.


Elena-Luminiţa Stănciulescu 8 Calea Floreasca, Bucharest, Romaniae-mail: [email protected]

Abstract. Evaluation scores of critically ill patients began to develop in the ‘70s, in an attempt to create a real model to allow the quantification of disease severity, outcomes, prognosis and mortality rate of hospitalized patients in ICU. Over time many such scores were developed, some of them have lost practical value, being no longer in use, others are important tools in assessing critically ill patients.There are basically four areas of application of these scores: research and clinical trials - for this purpose, scores serve as common, standardized tools of patient comparison, as a common language for researchers and clinicians, who may thus decide how the results of clinical research can influence their daily practice; administrative field - refers to the capital allocation depending on the disease severity, to cost-effectiveness analysis; performance assessment field: comparative performance assessment of ICU from year to year is important, as well as, individual performance assessment; assessment of individual prognosis and treatment protocols or decisions. There are four known validated prediction scores: APACHE (Acute Physiology and Chronic Health Evaluation), SAPS (Simplified Acute Physiology Score), MPM (Mortality Prediction Model) and SOFA (Sequential Organ Failure Assessment) score. A prediction score (severity score) represents a numerical value, composed of a variety of clinical parameters, quantifying the severity of the disease. This can be introduced into a mathematical equation, the result reflecting the probability of clinical course, usually the mortality rate. There is an obvious correlation between the severity of the prediction score, length of ICU stay and the complexity of physical therapy. This study aims to demonstrate the importance of starting prompt physical therapy in critically ill patients with high severity scores, significantly influencing individual recovery and prognosis.Keywords: prediction scores, intensive care, physical therapy

1. University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania2. Clinical Emergency Hospital Bucharest, Romania

Popescu G.1, Macovei R.Al.1, Ilie Mădălina1, Constantinescu G.2, Stănciulescu Elena-Luminița1, Pătru Cristina2, Păun M.Al.1, Grințescu Ioana Cristina2, Grințescu Ioana Marina1

PREDICTION SCORES AND COMPLEXITY OF PHYSICAL THERAPY APPROACH IN THE INTENSIVE CARE UNIT OF THE CLINICAL EMERGENCY HOSPITAL BUCHAREST

Therapeutics, Pharmacology and Clinical ToxicologyVol XVIII, Number 2, June 2014Pages: 68-71© Copyright reserved 2014

Introduction Evaluation systems of critically ill patients began

to develop in the 70s, in an attempt to create a real model to allow the quantification of disease severity, development opportunities, prognosis and mortality rate of hospitalized patients in ICU. Over time, many such systems were developed, some of them have lost practical value, being no longer in use, others are important tools in assessing critical patient.

There are basically four areas of application of these systems:

• research and clinical trials: for this purpose scores serve as common, standardized tools for

patient comparison, as a common language for researchers and clinicians, who may thus decide how the results of clinical research can influence their daily practice.Thus, only evaluation systems that are approved and published in specialized literature should be used.

• administrative field refers to the capital allocation depending on the severity of disease, to the possibility of evaluation of these administrative decisions, to the cost-effectiveness analysis.

• performance assessment field: comparative performance assessment of ICU is important each and every year, as well as, individual performance assessment.

• individual prognosis assessment field and treatment protocols or decisions.

There are known four validated prediction scores: APACHE (Acute Physiology and Chronic Health Evaluation), SAPS (Simplified Acute Physiology

THERAPEUTICAL PRACTICE


Score), MPM (Mortality Prediction Model) and SOFA (Sequential Organ Failure Assessment) score.

A prediction score (severity score) represents a numerical value, formed from a variety of clinical parameters, quantifying the severity of the disease. It can be included in a mathematical equation whose result reflects the probability of clinical evolution, usually the mortality rate.

The relation between the severity score and the evolution is empirically determined from many databases. Prediction scores from ICU cannot be used for patients outside the ICU.

There are two major principles to consider in the evaluation of a prediction score. First, an instrument should measure an important result. Most of the ICU scores quantify intra-hospital mortality, while others measure long term mortality and functional status. Second, an instrument should be easy to use because data gathering from critically ill patients might be time-consuming and expensive.

The accuracy of risk scores in predicting mortality and calibration are the characteristics used in the evaluation of a prediction system:

The accuracy of the score in predicting mortality describes the precision of a certain prediction. For instance, if an evaluation system predicts 70% mortality,

the accuracy of the score in predicting mortality is perfect if the noticed mortality is 70%.

Calibration describes the way in which the instrument functions on a large scale of predicted mortalities. Using the above example, a prediction instrument would be extremely well calibrated if it had the same accuracy for 90%, 50% and 20% mortality.

ICU scores

Widespread in the USA[1], the APACHE score is frequently used in the Intensive Care Unit of the Clinical Emergency Hospital Bucharest. Practically, it is the first risk score with an adapted pattern for the critically ill patient, whatever his/her specific diagnosis. It was published in 1981 by Knaus et al, allowing patient classification by intra-hospital mortality risk. Its most recent version is APACHE IV.

The APACHE score requires the introduction of clinical variables which then generate a severity score. The resulting severity score is integrated into a regression equation which leads to a mortality prediction. The required variables are different depending on the version, but the generally used parameters are: age, diagnosis, previous treatment and a certain number of acute and chronic physiologic variables. The APACHE

APACHE II (physiological variables) (A)

Physiological variables 4 3 2 1 0 1 2 3 4

Rectal TºC ≥41 39-40.9 38.5-38.9 36-38.4 34-35.9 32-33.9 30-31.9 ≤29.9Mean Arterial Pressure (mmHg)

≥160 130-159 110-129 70-109 50-69 ≤49

Pulse (beats/min) ≥180 140-179 110-139 70-109 55-69 40-54 ≤39

Respiratory Rate (breaths/min) ≥50 35-49 25-34 12-24 10-11 6-9 ≤5

PaO2* (mmHg) ≥500 350-499 200-349 <200

AaDO2** (mmHg) >70 61-70 55-60 <55

Arterial pH ≥7.7 7.6-7.69 7.5-7.59 7.33-7.49 7.25-7.32 7.15-7.24 <7.15Serum Na+ (mmol/l) ≥180 160-179 155-159 150-154 130-149 120-129 111-119 ≤110

Serum K+ (mmol/l) ≥7 6-6.9 5.5-5.9 3.5-5.4 3-3.4 2.5-2.9 <2.5

Serum Creatinine (micromol/l) ≥3.5 2-3.4 1.5-1.9 0.6-1.4 <0.6

Haematocrit (%) ≥60 50-59.9 46-49.9 30-45.9 20-29.9 <20White Blood Count (x109/l) ≥40 20-39.9 15-19.9 3-14.9 1-2.9 <1

GCS Score = 15 – actual GCS Serum HCO3 (mmol/l) ≥52 41-51.9 32-40.9 22-31.9 18-21.9 15-17.9 <15

Table I. A = Total physiological variables score points; * If FiO2≥50% record AaDO2; ** If FiO2<50% record PaO2; B = Age points


score uses the most distant values compared to normal that are registered in the first 24 hours after admission to the ICU.

Exactly like in most prediction models, APACHE requires periodic retesting, review and update because

its accuracy diminishes as treatments and other factors influence mortality.

Most frequently mentioned are APACHE II and III, though APACHE IV was also validated.

In the case of APACHE I there are 34 physiological parameters taken into account, each one of them being evaluated from 0 to 4 points, according to the degree of deviation from normal, one way or the other. The addition result represents the acute physiologic score, based on which there are four categories of patients, from A to D, according to the death risk.

A very important progress brought by the introduction of this score was the improvement of possibilities to demonstrate the efficiency of newer therapies, based on non-randomized studies, allowing patient stratification in groups of different disease severity levels and comparing these two groups.

Practically, this score isn’t used anymore, being replaced with a new version developed by the same authors and published in 1985 as APACHE II

APACHE II score has three components: acute physiologic score (A), age score (B), chronic condition evaluation score (C) [2].

The acute physiology score has 12 physiological parameters, each one of them having 4 levels of deviation from normal, either increasing or decreasing being evaluated from 0 to 4; the sum represents the acute physiology score.

The variables used to calculate the APACHE II severity score are mentioned in the table 1. Though the APACHE II severity score is based on the worst values of variables during the first 24 hours following the ICU admission, it seems like an acceptable alternative[3]. APACHE II is not perfect. The progress cannot be correctly anticipated for certain specific subgroups (for example liver failure, sepsis), because a discrepancy in mortality prediction for patients in ICU that are transfered in the outpatient department has been noted[4,5].

If the patient is known to have multiple organ dysfunction or immune suppression, record as follows :

Non-surgical patients or surgical postoperative emergency status – 5 points.

Elective postoperative patients -2 points.APACHE II = A + B + C [6] APACHE II score results from adding the points

from each section: acute physiology score, age points and chronic health points, global score being from 0 to 67 points [2].

The score is calculated in the first 24 hours from admission in the ICU and evaluated in evolution through periodical calculation.

Points 0 2 3 5 6Age ≤44 years 45-54 55-64 65-74 ≥75

Table II. C = Chronic Condition points

The APACHE II Score database was of 5030 patients admitted to 13 units of Intensive Care over a three year duration. A correlation between the mortality rate, ICU length of stay and the APACHE score was demonstrated[2].

Physical therapy for the critically ill patient in the ICUICU patient recovery treatment covers respectively:

• Patient’s regular position changes from one side to another to prevent pressure/bed-sores and subsequent ulcers.

• Respiratory physical therapy to prevent respiratory complications.

• Physical therapy for maintaining muscular flexibility and joint mobility.

• Physical therapy for stimulating the nervous tissue unaltered by disease and to facilitate its overtaking of the functions of altered brain structures.

• Patient’s cognitive stimulation (close friends’ visits, music, image panels that would help integrate him/her into the environment, make him/her aware of the day, the hour and the place he lives in, personal data, family photos).

Objectives of physical therapy:• Prevention and treatment of respiratory

complications• Spasticity prophylaxis or treatment• Prophylaxis or treatment of joint aches, ankylosis• Maintenance of optimal arterial, venous and

lymphatic circulation• Preventing bed-sores• Stimulation of the nervous tissue in cortical areas

unaltered by disease and facilitating its overtaking of the functions of altered brain structures.

Techniques for reaching these objectives:• Neuro-proprioceptive facilitation techniques:

Kabath technique, Bobath • Sensorial stimulation techniques • Passive, slow, superior and inferior limb

mobilization in bed• Patient mobilization in sitting or standing position

Respiratory physiotherapy consists of:• Postural drainage - patient positioning is based

on pulmonary injury, thus providing an optimal ventilation of the area and bronchial secretions drainage (if needed)

• Thoracic manual techniques of percussion and vibration during postural drainage

• Increase in tidal volume using manual thoracic compressions

• Abdominal breathing stimulation techniques• Cough stimulation maneuvers


• Subcutaneous soft tissue light thoracic massage (it reduces local edema, restores normal rib breathing mobility).

Results of physical therapy correlated with icu scoresIn our ICU units a protocol of early initiation of

physical therapy has been instituted, with adjustments being made for disease characteristics and severity.

The moment of physical therapy initiation is important: patients with similar APACHE scores at ICU admission in our hospital had better outcomes, and shorter ICU stay if physical therapy was initiated early.

Patients who did not benefit from physical therapy at the same time as disease specific intensive care had a higher mortality.

Conclusions There is an obvious correlation between

prediction score severity, ICU and hospital length of stay and the complexity of physical therapy.

Early physical therapy is essential for patients with high severity scores, thus significantly influencing recovery and individual prognostic.

References

1. Cowen JS, Kelley MA. Errors and bias in using predictive scoring systems. Crit Care Clin 1994; 10:53.

2. Knaus W.A.et al. APACHE II - A severity of disease classification system, Crit. Care Med.1985;13 (10):818-829.

3. Ho KM, Dobb GJ, Knuiman M, et al. A comparison of admission and worst 24-hour Acute Physiology and Chronic Health Evaluation II scores in predicting hospital mortality: a retrospective cohort study. Crit Care 2006; 10:R4.

4. Escarce JJ, Kelley MA. Admission source to the medical intensive care unit predicts hospital death independent of APACHE II score. JAMA 1990; 264:2389.

5. Capuzzo M, Valpondi V, Sgarbi A, et al. Validation of severity scoring systems SAPS II and APACHE II in a single-center population. Intensive Care Med 2000; 26:1779.

6. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13(10):818-29.


Daniela Georgescu19-21 Șos. Ștefan cel Mare, Bucharest, Romaniae-mail: [email protected]

Abstract. Myelodysplastic syndromes (MDSs) represent a heterogeneous group of bone marrow conditions characterized by peripheral blood cytopenias and increased risk for evolution to acute leukemia. An accurate risk group classification constitutes the start point for the establishment of the therapeutic attitude in MDS pathology. The prognostic relies on different risk models, some of them being disease related: French-American-British system (FAB), World Health Organization classification, International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), MD Anderson Scoring System (MDACC), while others being patient and comorbidities related: MDS- specific Comorbidity Index (MDS-CI). In 2012, Peter L. Greenberg and collaborators published in Blood the Revised International Scoring System (R-IPSS) that included MDS patients in five risk groups, based on cytogenetic changes. The evolution of patients with low risk MDS is heterogeneous and in most cases influenced by an associated pathology, considering that myelodysplasia occurs more frequently in elder people. By correlating the data in literature, a risk group classification was applied in the case of a 65 years old male patient, based on several of the above mentioned models. The patient was diagnosed with MDS in 2009 - refractory cytopenia with multilineage dysplasia and ringed sideroblasts (WHO 2008) in the Haematology Clinic of “Colentina” Hospital, Bucharest. At admission the patient presented a normal karyotype and he was classified in Intermediate 1 risk group (IPSS Int-1); Intermediate risk (WPSS); Low risk (MDACC); Low risk (MDS-CI). Our patient soon became transfusion dependent, with a requirement of 3 units of packed red blood cells per month and repeated hospital admissions. He also developed progressive left-ventricular dysfunction secondary to severe anaemia and recurrent transfusions. After approximately four years, in May 2013, the patient’s reclassification based on risk models indicated an intermediate risk (WPSS), the same as that at the moment of the diagnosis, but the associated comorbidities (transfusion dependency and heart failure) shifted him to a higher risk group, according MDS Co-morbidities Index (MDS-CI Int-High Risk), with low chances of survival, confirmed by his death shortly after, due to staphylococcal endocarditis but no leukemic transformation. Considering these events it becomes clearer that for MDS patients staged in low and intermediate risk groups, comorbidities represent an independent risk factor which entails a reassessment of the current prognostic systems. Keywords: Myelodysplastic syndromes (MDS), risk models, WHO, IPSS, WPSS, MDACC, MDS-CI, R-IPSS prognostic scoring systems

1. “Colentina” Clinical Hospital, Haematology Clinic, Bucharest 2. “Sfantul Luca” Hospital, Oncology and Palliative Care Department, Bucharest

Georgescu Daniela1, Patrinoiu Oana1, Popescu Mihaela1, Ciuhu Anda Natalia2

ASSESSMENT OF PROGNOSTIC FACTORS IN MYELODYSPLASTIC SYNDROMES


Introduction

Myelodysplastic syndromes (MDSs) are a heterogeneous group of stem cell clonal

disorders characterised by ineffective hematopoiesis and predilection for acute leukaemia (AL) transformation. The diagnosis is set based on the patient’s history and the changes in the peripheral blood; it requires cytological +/- immunohistochemistry examination of the peripheral blood and bone marrow which is

the essential part of the diagnosis [1]. Cytogenetic and molecular examinations contribute to the understanding of the pathogenic mechanisms and to the risk group staging. Prognostic factors and staging into risk group of transformation to AL are elements under permanent change. Therapeutic strategy in myelodysplastic syndromes depends on the risk group staging. By bringing on the same page the data in the literature, it is recommendable to elaborate a “risk model” for evolution into AL or death, that focuses on the predictability degree of certain parameters such as: World Health Organization classification, degree of cytopenias, serum ferritin level and transfusion requirement, percentage of blasts, myelofibrosis, as well as cytogenetic and molecular abnormalities [2,3,4,5].

THERAPEUTICAL PRACTICE


Diagnosis and risk group staging Myelodysplastic syndromes constitute a

heterogeneous group of conditions that are difficult to diagnose, often underdiagnosed or misdiagnosed or caught in the transition phase to AL. In the case of an MDS suspicion the primary objective is to establish correctly the diagnosis and the risk group staging.

An analysis of recently presented data during the 4th International Conference on Myleodysplastic Syndromes (Estoril, Portugal, 15-17 May 2014) revealed an establishment of the main diagnostic and staging in the risk group criteria, that prove to be real challenges to the medical community. Professor Luca Malcovati (Pavia) presented new data on the risk factors analysis, emphasising the impact of the new revised IPSS risk model (Revised - International Prognostic Scoring System) on the clinical practice.

The “Genetics and epigenetics of MDS” session constituted an opening for the discussions and papers presented at the 19th Congress of the European Haematology Association (Milan, 12-15 June 2014). Thus, mutations and deletions identified in MDS patients have been classified as follows: epigenetic modifications (including TET2 and DNMT3A), RNA alterations (“RNA splicing”, including SF3B1 and U2AF1) and translocation involved in protein synthesis, including RPS14. For patients with MDS, applying these molecular investigations in the clinical practice will improve the diagnosis, risk group classification, prognostic estimates, as well as the treatment response prediction.

In myelodysplastic syndromes (MDS), a proper risk group staging constitutes the basis for the future therapeutic attitude. The review of the prognostic models in the literature highlights that prognostic in MDS patients relies upon different risk models, some being disease related: French-American-British system (FAB), World Health Organization classification, International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), MD Anderson Scoring System (MDACC), while others being patient and comorbidities related: MDS-specific Comorbidity Index (MDS-CI) [6,7,8,9]. FAB and WHO classifications do not take into consideration the cytogenetic modifications. The International Prognostic Scoring System (IPSS) is the instrument the most frequently used for staging of MDS cases at the moment of diagnosis, but it underestimates the role of transfusion dependency and of cytogenetic markers. The WHO Prognostic Scoring System (WPSS) can be used throughout the disease evolution but it fails to take into account chromosomal modifications. Finally, the MD Anderson Cancer Center (MDACC) system can be applied in secondary MDSs, while MDS Comorbidities Index (MDS-CI) system assesses the role of co-morbidities. In 2012, Peter L. Greenberg and collaborators published in Blood a material on The Revised International Scoring System (R-IPSS) that included MDS patients in five risk groups, based on cytogenetic changes [10]. In an effort to estimate the global survival rate and time to AL evolution, the authors’ group, led by Maria Teresa Voso validated the R-IPSS system as a significant predictor. [11]

Figure 1. November 2009, May-Grünwald Giemsa stain, bone marrow aspirate: hypercellularity (80%), dyserythropoiesis, dysgranulopoiesis, giant megakariocytes


Material and methods

By bringing together data in literature, a risk group classification was applied in the case of a 65 years old male patient, based on several of the above mentioned models. The patient was diagnosed with MDS in 2009 - refractory cytopenia with multilineage dysplasia and ringed sideroblasts (WHO 2008) in the Haematology Clinic of “Colentina” Hospital, Bucharest.

In November 2009 the patient was admitted in our clinic with severe anaemia and neutropenia, normal platelets count (Hb 7 g/dL with MCV 100.8 fL and reticulocytes 1%, WBC 2000/µL with 679 neutrophils/µL). The patient denies any significant history, no comorbidities and no exposure to chemical substances. Performance status at admission: ECOG scoring 1 based on the anaemic syndrome. B12 and folate serum

Figure 2. November 2009, Pearls stain, bone marrow aspirate: 20% ringed sideroblasts

levels were within normal range, serum ferritin: 680 µg/L (N:16.4–293.9) and a slight increase in serum erythropoietin 300 mU/mL (N: 2.4–33.0). Other laboratory tests presented no significant changes. The morphological examination of the peripheral blood and bone marrow (biopsy and aspirate) with immunohistochemistry and sideroblasts special coloration established the diagnosis of refractory cytopenia with multilineage dysplasia and ringed sideroblasts (about 20%), based on WHO classification (Figures 1 and 2). Cytogenetic examination revealed no modifications.

Results

Based on the scoring systems previously described, at diagnosis the patient was classified as follows: intermediate-1 (IPSS-1), intermediate (WPSS) and low risk (MDACC and MDS-CI) (Fig. 3, 4, 5, 6).

Figure 3. International Prognostic Scoring System (IPSS): the patient enters the group risk intermediate-1 1 (IPSS Int-1 risk)


Figure 4. WHO Prognostic Scoring System: the patient enters the intermediate risk group (WPSS Intermediate)

Figure 5. MD Anderson Scoring System (MDACC): the patient enters the low risk group (MDACC Low risk)

Figure 6. MDS-specific Comorbidity Index (MDS-CI): the patient enters the low risk group (MDS-CI Low risk) [12]

The patient was initiated on red blood cells transfusions and erythropoietin. Shortly after, the patient became transfusion dependent, with an average of 3-4 erythrocytes units transfused per month.

One year after the diagnosis, the ferritin level increased to >1000 µg/L which led to introduction of iron chelation therapy with Deferasirox, at an initial dosage of 20 mg/kg/day, subsequently increased to 30 mg/kg/day (Fig. 7).

In September 2012 the bone marrow aspirate displayed: multilineage dysplasia with 25% ringed sideroblasts and erythroblastopenia, without residual thymic tissue at CT chest examination. Consecutively, we introduced Cyclosporine therapy at a dose of 5

mg/kg, and subsequent increase to 8 mg/kg, without haematological response. The transfusion demand increased to 6 units/month, and multiple hospital admissions. Progressively he developed left-ventricular dysfunction, secondary to severe anaemia and recurrent transfusions.

After approximately four years, in May 2013, the patient was still staged in an intermediate risk group (WPSS staging) but associated comorbidities (transfusion dependence and heart failure) included him in an increased risk group, based on MDS Comorbidities Index (MDS-CI Int - High risk), with low chances of survival. The bone marrow aspirate performed in May 2013 showed similar results as the previous one, respectively multilineage dysplasia and the presence of 20% ringed sideroblasts (Fig. 8).


Figure 7. The patient’s evolution under Deferasirox therapy

Figure 8. May 2013, May-Grünwald Giemsa stain, bone marrow aspirate: dyserythropoiesis, dysgranulopoiesis

Immunosuppression, severe anaemia with transfusion dependency and repeated hospital admissions had a significant impact on the prognosis.

In June 2013, the patient was diagnosed with staphylococcal endocarditis that led to his death, but no signs of leukemic transformation at that moment.

Figure 9. Posterior mitral valve vegetation revealed during the cardiac ultrasound examination


Discussions

The patient’s new staging into an increased risk group, according to MDS

Comorbidities Index (MDS-CI Int - High risk) with low survival chances was confirmed by his death due to staphylococcal endocarditis, with no leukemic transformation. Thus it becomes clearer that in MDS patients staged in low or intermediary risk groups co-morbidities represent an independent risk factor that requires a reassessment of the current prognostic systems.

Conclusions

The diagnosis and staging of MDS patients in the correct risk groups help the medical staff to choose the appropriate therapy. However, for low risk MDS cases the evolution is heterogeneous and quite often influenced by comorbidities and not by leukemic transformation. In this context, various working groups in the world are trying to establish new risk models.Aknowledgements This paper is supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/159/1.5/S/137390/.The present article has been elaborated and written by Daniela Georgescu, MD and PhD student, since 2011, at UMF Carol Davila, Bucharest, under the coordination of Prof. Dr. Anca Lupu, MD PhD - Haematology Department.

References

1. Ayalew Tefferi, M.D., and James W. Vardiman, M.D. Myelodysplastic Syndromes, N Engl J Med 2009; 361:1872-85.

2. Platzbecker U., Ades L. Clinical management of patients with myeolodisplastic syndromes, Hematology Education 2014; 8:243-250.

3. Cazzola M. Prognostic biomarkers in myelodyspalstic syndromes Hematology Education 2014; 8:237-242.

4. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients” Blood 2007; 110:4385-4395.

5. Gattermann N, Rachmilewitz EA. Independent impact of iron overload and transfusion dependency on survival in patients with MDS Ann Hematol 2011; 90:1-10.

6. Germing U, et al., WHO Clasiffication 2008, Ann Hematol 2008; 87:691-699.

7. Greenberg P, et al. International Prognostic Scoring System (IPSS)”Blood. 1997; 89:2079-2088.

8. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes J Clin Oncol 2007; 25:3503-3510.

9. Kantarjian H, O’Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System, Cancer 2008; 113:1351-1361.

10. Peter L.Greenberg et al, Revised International Prognostic Scoring System for Myelodysplastic Syndromes, BLOOD, 20 September 2012, Volume 120, Number 12: 2454-2464.

11. Maria Teresa Voso et al Revised International Prognostic Scoring System (IPSS), Predicts Survival and Leukemic Evolution of Myelodysplastic Syndromes Significantly Better Than IPSS and WHO Prognostic Scoring System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database J Clin Oncol, 2013; 21:2671-2677.

12. Della Porta MG, et al. Haematologica. [Epub ahead of print 2010 Dec 6].


Florin Săvulescu Central Military Hospital, Second Surgical DepartmentStr. Mircea Vulcănescu, nr. 88, Sector 1, 010825, Bucharest, Romaniae-mail: [email protected]

Abstract. Even if they have a low incidence (0.1-3% of gastrointestinal tumours), the stromal tumours located in the digestive tract raise important issues in predicting the risk of recurrence. Their diagnosis and treatment have evolved over the last 20 years, particularly in etiopathogenic terms, due to the arsenal of laboratory investigations like imunohistochemistry and mutational analysis techniques. The main factors that determine the risk of recurrence, initially evaluated by Mietinen (2006) and subsequently clarified by Joensuu (2008, 2011) are the size, the number of mitoses, the tumour location and the intrusion capsule.The main pillars of treatment are surgery and therapy with Imatinib. Three representative cases for the factors described and well coded as diagnosis, treatment and postoperative monitoring are presented in this article: a bulky gastric tumour and one giant gastric intestinal (resected by laparotomy) and cecal gastrointestinal stromal tumour (GIST) (rarerly concerning the location) incidentally discovered during an appendectomy, laparoscopically resolved.The review of literature in this field combined with the clinical experience highlight the characteristics of these tumours, and, ultimately, guide the therapeutic approach in similar situations. Keywords: GIST, recurrence risk, mitotic index, tumour intrusion.

1. Central Military Emergency University Hospital Second Surgical Department, Bucharest, Romania2. Central Military Emergency University Hospital Dermatology Department, Bucharest, Romania

Săvulescu F.1, Duțu C.1, Trifu V.2, Dărmănescu Monica2, Surdeanu D.1, Merticariu B.1, Cirlan C.1

GASTROINTESTINAL STROMAL TUMOUR: PREDICTING THE RISK OF RECURRENCE OF PRIMARY TUMOURS


History

The smooth muscle tumour, found in 1960, was introduced (1983) by Mazur and Clark, with

the proto-oncogene mutation c-kit receptor tyrosine kinase transmembrane substrate (Hirota, 1998). GIST (gastrointestinal stromal tumour) is the most common mesenchymal tumour of the digestive system, developed from the Cajal interstitial cells [1], with the function of gastrointestinal motility pacemaker.

GIST epidemiology shows that they represent 0.1-3% of gastro intestinal neoplasms and 80% of gastrointestinal mesenchymal neoplasms during the IV-VII decades of life, with a slight predominance (54%) in men [2], the incidence of GIST [3, 4] having the following values:

• USA: 10 to 20 cases / 1,000,000 • Europe: 6-14 cases / 1,000,000 • Romania: 5 cases / 1,000,000The GIST classification can be based on: a) Histology [2]:

1. With spindle cells (70%) - arranged in short fascicles

2. With epithelioid cells (20%) - with nested architectural aspect

3. With mixed cells (10%) - form containing both types of cells

b) Location [5] 1. Stomach (60%) 2. Small intestine (30%) 3. Colon (<5%) - below check 1%! 4. Esophagus (<1%) 5. Rectum (<1%) 6. Extra-digestive (mesentery, omentum,

retroperitoneum ) <1%Paraclinical diagnosis

• Ultrasound• Barium • CT / PET CT • EDS / EDI - with ultrasound • Ultrasound-guided fine needle puncture • Laparoscopic Biopsy / exploratory laparotomy

(assessed resectability)

Histopathologic diagnosis: spindle cell / round / polygonal / mixed.Immunohistochemical diagnosis may reveal markers like [2]:At these markers the protein Ki-67 is added (particularly present in tumours> 5 cm). When c-KIT is negative (5-10%) a mutational analysis is necessary, which may reveal c-KIT/PGFRA/GIST "wild" mutations.

CASE REPORT


/ secondary resistant tumors at Imatinib. • Subsequent surgery (a hepatic embolization / RF

ablation for liver metastases)Principles of surgery in primary GIST tumours [7,8]: • R0 resection of the involved digestive segment

with intact pseudocapsule. • "Wide" resection brings no benefits • Thorough surgical exploration to locate and to

execute excision of the peritoneal tumour nodule is important.

• If the original resection is found to be R1, re-excision may be an option if it is not providing significant sequelae.

The risk of recurrence of GIST is estimated mainly by [10]: • The size of the tumour (high risk> 10 cm) • Mitotic rate (> 5/50 HPF) • Location (non gastric - high risk) • Tumour rupture (high risk)

The differential diagnosis is carried out mainly in affections as gastric ulcer disease, ectopic pancreas, adenocarcinoma, lymphoma or gastric carcinoid.

Principles of treatment A. "Mini GIST" - submucosal nodules, incidental :

• > 2cm (histologically GIST) - resection; • < 2cm / (histopathological non GIST) - monitoring.

B. Clinical GIST • Macroscopic R0 resection (negative margins);• Extended resections when the size of the tumour

requires; • Regional lymphadenectomy is not required.

C. Metastatic disease • Initial medication (t unresectable / metastatic) • Imatinib 400/800 mg / day, 3 years, transmembrane

tyrosine kinase inhibitor or Sunitinib for primary

Figure 1. Immunohistochemical markers used in the diagnosis of GIST

Figure 2. Scheme of treatment for primary GIST


Risk Category Tumour size(cm)

Mitotic/50 HPFS Index

Location

Very low <2 <5 AnyLow<10% 2-5 <5 AnyIntermediate 10-30% 2-5 >5 Gastric

<5 6-10 Any5-10 <5 Gastric

High >30% Any Any Tumour rupture>10 Any AnyAny >10 Any>5 >5 Any2-5 >5 Nongastric

5-10 <5 Nongastric

Figure 3. Classification of the recurrence risk of primary GIST (according to Joensuu 2011)

We will present three illustrative cases of primary GIST from the perspective of diagnosis, treatment and postoperative evolution, operated in the Secondary Surgery Department of the Central Military Emergency Hospital, highlighting the factors that determine the risk of recurrence, according to Joensuu (2011 criteria) :

CASE NO 1 - GIST stomach, lesser curvature• 60 years old, M

• Clinical: palpable tumour, heartburn • Location: small curvature • Macroscopic: exofitic tumour, diameter of 20 cm • Adjacent Invasion: omentum • Metastases: NO• Immunohistochemistry: c-KIT positive • Mitosis: 10/50 • HIGH recurrence risk > 30%

Figure 4. Gastric GIST, CT scan, a cross-sectional front sagittal section

Figure 5. Gastric GIST, intraoperative and resection piece images


CASE 2 - bowel GIST• 60 years old, M • Clinical: palpable tumour, abdominal pain. • Location: small intestine at 1.2 m from the Treitz

angle • Macroscopic: encapsulated tumour, 25 cm

diameter

Figure 8. Small intestine GIST - Intraoperative and resection piece view

• Adjacent Invasion: omentum • Metastases: NO• Immunohistochemistry: c-KIT positive / vimentin

+ / actin + / Ki67 • Mitosis: 10/50• HIGH recurrence risk, > 30%

Figure 6. Small intestine GIST: Urography Exam, MR and CT

Figure 7. Small intestine GIST - c-kit mutational analysis in exon 11

CASE 3 – CEC GIST• 34 years old, F • Clinical: colicky pain in the FID • Location of lesion: cec - the medial face• Macroscopic: encapsulated tumour, 4 cm in

diameter

• Adjacent Invasion: NO• Metastases: NO• Immunohistochemistry: c-kit positive (!) • Mitosis: 2/50 • LOW recurrence risk <10%

Figure 9. Cecal GIST intraoperatively diagnosed: Laparoscopic appendectomy and tumorectomie

Postoperatively, all 3 cases received imatinib 400 mg, patients were periodically evaluated, clinical and

laboratory examinations, none showed signs of relapse at 3, 2 and 2.5 years after surgery.


Conclusions

GIST is currently an underdiagnosed pathology, given that within the EU incidence in relation with the Romanian population, it should result in 300 cases discovered annually, while in Romania the actual incidence is 100 cases. This highlights the importance of the quintet: gastroenterologist – surgeon – radiologist – pathologist – oncologist.

The characteristics of gastrointestinal tumours are: relatively low incidence, difficulty regarding preoperative diagnostic and variable malignant potential.

Patient prognosis depends on rapid diagnosis and intervention, the presence of possible complications and the degree of malignancy.

Surgery is the main curative treatment in the localized disease and resectable, followed by treatment with Imatinib.

In the metastatic disease, Imatinib plays a neoadjuvant role, followed by elective surgery.

The risk of recurrence of GIST depends mainly on: the tumour size, the mitotic rate, the tumour intrusion and localization.

References

1. Nilsson et al. Cancer. 2005; 103:821-829.2. Miettinen M et al. Arch Pathol Lab Med. 2006;

130:1466-14783. Fletcher CDM et al. Hum Pathol. 2002; 33:459-

465. 4. Goettsch WG et al. Eur J Cancer. 2005; 41:2868-

28725. Corless CL et al. Annu Rev Pathol. 2008; 3:557-

5866. Nowain et al. J Gastro Hepatol. 2005; 20:818-8247. Demetri GD et al. J Natl Compr Conc Netw.

2007; 5(suppl 2):S1-S29.8. Casali P et al. Ann Oncol. 2009; 20 (suppl

4):64-67.9. NCCN. Clinical Practice Guidelines; Soft Tissue

Sarcoma. V.2.2009.10. Joensuu. Human Pathology, Vol. 39, No. 10.

(October 2008), pp. 1411-1419.


Oana Patrinoiu19-21 Stefan cel Mare Street, Bucharest, RomaniaPhone: +40724511036e-mail: [email protected]

Abstract. Tyrosine kinase inhibitors based therapy has completely changed the prognosis for patients with chronic myeloid leukaemia in the sense that most of them have a life expectancy almost similar with the healthy population. The best responses occur in patients diagnosed while in chronic phase of the disease, with a 60-65% probability to maintain a complete cytogenetic response up to five years. For the cases whose illness begins already in an advanced phase (accelerated or blastic) and who present new unfavourable cytogenetic or molecular prognosis factors, complete cytogenetic response under therapy with tyrosine kinase inhibitors (TKIs) is obtained rather late or it is not obtained at all, making allotransplant a curative therapy. The current paper describes the case of a female patient, diagnosed with accelerated phase chronic myeloid leukaemia, high risk group, who lost the complete cytogenetic response with first generation TKIs therapy and presented trisomy 8, clonal cytogenetic abnormality and unfavourable prognosis marker in Ph + cells. Despite this evolution our patient has been under oral therapy with Dasatinib for six years (IInd generation TKIs) and for the past four years in complete molecular remission, in other words the disease is currently undetectable. Keywords: chronic myeloid leukemia- advanced phase; tyrosine kinase inhibitors; complete molecular response; complete cytogenetic response; clonal chromosome abnormality, trisomy 8

1 Colentina Clinical Hospital, Bucharest, Romania

Patrinoiu Oana¹, Georgescu Daniela¹

THERAPEUTIC SUCCESS IN CHRONIC MYELOID LEUKAEMIA- ACCELERATED PHASE AT ONSET


Introduction

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of the pluripotent

hematopoietic stem cell that generates proliferation of the myeloid elements in all growth stages. The symptoms follow unspecific patterns while the most frequent clinical sign is splenomegaly. The disease presents 3 stages: chronic, accelerated and blastic, but in most cases patients are diagnosed in the chronic stage [1].

This condition represents the very first for which the term leukaemia was used and also the first malignant illness associated with a chromosomal anomaly (Philadelphia chromosome) which is the result of the ABL gene translocation, between chromosomes 9 and 22, t[(9;22)(q34;q11)]. At molecular level this translates into the emergence of a new hybrid fusion gene (BCR-ABL) that encodes for an oncoprotein (p210, and more rarely p190 or p230) with tyrosine-kinase activity. [2,9]

If during the 1990s Interferon alfa treatment

was considered a top choice, in the early 2000s a tyrosine-kinase inhibitor molecule was discovered, based on the essential role of BCR-ABL molecule in CML. This is a 2-phenylamidopyrimidine named STI571, Imatinib mesylate or Imatinib that occupies the BCR-ALB kynase site, thus blocking ATP access and preventing phsophorylation in any substratum. Consequently, in a relatively short amount of time tyrosine-kinase inhibitors therapy (TKIs) became the gold standard for patients diagnosed with CML, given the promising results released by clinical studies on first generation TKIs (Imatinib) and second generation TKIs (Dasatinib, Nilotinib) [3,4,5,6].

Given the evolution in CML’s treatment, this condition is no longer considered incurable or fatal, the rate of prevalence being quite high due to a substantial expansion of the survival rate.

Oral therapy with Imatinib (the first TKI used for first line regimens during the chronic, accelerated or blastic phase) continues to be the basic option throughout the world, while obtaining a complete cytogenetic response and complete molecular response is the main target of CML therapy. Assessment of the hematologic, cytogenetic and molecular responses is performed every three months and obtaining them represents the most important prognostic factor for the patient’s follow up, as ESMO and ELN Guidelines recommend. [7,8,9,10]

CASE REPORT


Optimal Warning FailureBaseline NA High risk

Or CCA/Ph+, major route

NA

3 mo BCR-ABL1 ≤10% and/or Ph+ ≤35%

BCR-ABL1 >10% and/or Ph + 36-95%

Non-CHR and/or Ph+ >95%

6 mo BCR-ABL1 <1% and/or Ph+ 0 (CCyR)

BCR-ABL1 1-10% and/or Ph+ 1-35%

BCR-ABL1 >10% and/or Ph+>35%

12 mo BCR-ABL1 ≤0.1% (MMR)

BCR-ABL1 >0.1-1% BCR-ABL1 >1% and/or Ph+ >0

Then, and at any time BCR-ABL1 ≤0.1% CCA/Ph– (–7, or 7q–) Loss of CHR Loss of CCyR Confirmed loss of MMR Mutations CCA/Ph+

Table I. Definition of the response to TKIs (any TKI) as first-line treatment (ELN criteria, 2013)

Other considerable prognostic factors are: Sokal scores [11], Euro [12] or more recently EUTOS [13] (during the debut phase), certain chromosome abnormalities as trisomy 8, trisomy Ph (der(22)t(9;22)(q34;q11)), isochromosome 17 (i(17)(q10)), trisomy 19 and ider(22)(q10)t(9;22)(q34;q11) as well as BCR-ABL 1 kinase domain mutations, whose discovery at the time of diagnosis or during the clinical course of the disease raise big concerns [3].

An optimal answer usually associates with a life expectancy similar to the one measured in the general population; therapeutic failure entails switching to second generation TKIs therapy in order to limit the risk of disease progression to accelerated or blastic phases.

Case presentation

Given the general presentation above, we aim to discuss the case of a female patient who in 2006, at the age of 34 was diagnosed with chronic myeloid leukaemia: Ph (+), accelerated phase, high risk group, Ph (+) in 100% of assessed metaphases, Sokal score= 3.33 (increased score >1.2). The bone marrow biopsy was showing granulocyte hyperplasia with left shift and 10% myeloblasts, 16% eosonophiles and 10% basophiles. (Figure 1)

Figure 1. Diagnostic bone marrow biopsy

We initiated cytoreductive therapy with Hydroxyurea, Purinethol (initially WBC count was 367x10³/µL and CBC count 770x10³/µL) associated with chemotherapy (2 courses of Cytarabine), under which WBC and haemoglobin level decreased significantly. In March 2007, three months after the first diagnostic and following haematology rebalancing, we introduced single dose 400mg/day Imatinib therapy that enabled our patient to obtain hematologic remission (CHR), based on ELN guidelines, while bone marrow biopsy displayed chronic CML with 4% myeloblasts. (figure 2)

Blasts in blood or marrow 10-19%Basophils in blood >20%Persistent thrombocytopenia (<100x109/L) unrelated to therapy CCA/Ph+ on treatmentThrombocytosis (>1000x109/L) unresponsive to therapyIncreasing spleen size and increasing white blood cell count unresponsive to therapy

Table II. Definition of the accelerated phase of CML according to WHO criteria

Figure 2. Bone marrow biopsy at 4 months after starting therapy with Imatinib


The patient continued therapy with Imatinib but adjusted the doses (300-400 mg/day) and, temporarily, she even discontinued therapy due to treatment induced anaemia and leukopenia, with hepatic cytolytic syndrome. Considering that after six months of therapy our patient presented minor cytogenetic response (44,44% Ph+ marrow cell metaphases) that was no longer present at the nine months assessment (100% Ph+ metaphases), we decided to introduce second generation TKIs : primarily Dasatinib 140 mg/day, at a later phase 100 mg/day. The loss of cytogenetic response to first generation TKIs in a young patient made us look for a match donor, in view of a possible allotransplant.

Dasatinib is known to have a 325 higher inhibitor activity on tyrosine kinase than Imatinib and is also very active in all Imatinib resistance mutations, except for BCR-ABL T 315I kinase domain [5,7].

In December 2008, at six months after the new therapy initiation, our patient presented complete cytogenetic response (0 Ph+ metaphases) and obtained major molecular response (0.019% BCR-ABL1 transcripts level) after one year of second generation TKI therapy. The cytogenetic assessment performed in 2010 revealed the occurrence of a major route clonal abnormality with significant prognostic value: trisomy 8 present in 23% of assessed metaphases and no Ph+ metaphases. (figure 3)

The absence of Ph+ metaphases was confirmed through cytogenetic assessment by fluorescence in situ hybridization of interphase nuclei (I-FISH) : no identification of BCR-ALB+ nuclei. (figura 4)

Figure 3. Cytogenetic assessment by chromosome banding technique (CBA) of bone marrow cell : no

Ph+ metaphases, trisomy 8 present

Figure 4. Interphase FISH patterns of BCR/ABL ˉ nuclei

Subsequent molecular assessments confirmed major molecular remission (MMR) until April 2012 when our patient was declared in complete molecular remission (undetectable BCR-ABL translocation).

Discussions

We opted to present this case due to its particularities in terms of disease onset and evolution under TKIs therapy.

First, our patient was very young at the time of diagnosis, a rare situation considering that chronic myeloid leukaemia often occurs in persons over 60 years of age. Another atypical aspect is the disease onset directly in an accelerated phase, with no sign of splenomegaly but with a high WBC count.

Poor evolution under Imatinib therapy was due either to adverse effects that generated a decrease and even discontinuation of therapeutic doses or due to suboptimal dosage for the accelerated debut phase. [14,15,16].

Second generation tyrosine-kinase inhibitor therapy obtained rapidly a CCR (complete cytogenetic response) and maintained it, despite the occurrence of a major route clonal cytogenic abnormality (CCA) with unfavourable prognosis. Clonal cytogenetic abnormalities in Ph– cells (CCA/Ph–) occur in a small number of patients (5% to 10% ) and almost all of them, in the absence of dysplasia, do not seem to adversely affect outcome. The identification of trisomy 8 under therapy determined us to examine more frequently the peripheral blood morphology for cytopenia or dysplastic elements but the patient maintained haematological and cytogenetic responses and, even more, obtained molecular remission [16,17,21]

Data in literature suggest that shifting to a different TKI as well as using chemotherapy or investigational therapies offer limited possibilities during an accelerated or blastic phase of disease.

Allotransplant remains the best option for these patients, provided it is performed prior to progression to the blastic phase. Should our patient loose the complete cytogenetic response and the disease advances again to the accelerated phase we will also opt for it [18].

From another standpoint, TKI therapy can be administered for an indefinite period, but currently there are data that suggest Imatinib can be safely discontinued in patients with undetectable illness by molecular assessment for minimum two years. This contributes to the increase in the patients’ quality of life and will probably represent the endpoint for future studies [19,20]

Taking into account her disease history, it is hard to predict whether our patient will continue being in remission so that she qualifies for a future study on Dasatinib discontinuation.

Conclusions

TKI therapy demonstrated its efficacy in a case with multiple unfavourable factors, identified both at onset and throughout the therapeutic course, despite the fact


that treatment for advanced or blastic stages is rather an unconquered territory.

Aknowledgements: This paper is supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romania Government under the contract number POSDRU/159/1.5/S/137390/".The present article has been elaborated and written by Oana Patrinoiu, MD and third year PhD student since 2011, at UMF Carol Davila Bucharest, under the coordination of Prof. Dr. Anca Lupu, MD PhD- Hematology Department.

References

1. Vardiman JW, Melo JV, Baccarani M., Thiele J. Chronic myeloid leukemia BCR-ABL 1 positive.In: Swerdlow SH. et al ,eds. WHO Classification of tumours of Hematopoietic and lymphoid tissues. Lyon: IARC. 2008: 32-37

2. Deininger W.M ,Goldman JM, Melo JV et al. The molecular biology of chronic myeloid leukemia. Blood 2000; 96:3343-3354

3. O’Brien SG, Guilhot F, Larson RA, et al; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348(11):994-1004.

4. Hochhaus A, O’ Brien SG ET AL. Six-year follow-up of patients receiving imatinib for the first -line treatment of chronic myeloid leukemia. Leukemia 2009; 23:1054-11061

5. Saglio G, Kantarjian HM, Shah N, et al. Early response (molecular and cytogenetic), 3-year data and long-term outcomes in newly diagnosed chronic myeloid leukemia in chronic phase: exploratory analysis of DASISION 3-year data. Blood. 2012; 120(21). [Abstract 1675]

6 . Hochhaus A, Hughes TP, Saglio G, et al. Outcome of patients with chronic myeloid leukemia in chronic phase based on early molecular response and factors associated with early response: 4-year follow-up of data from ENESTnd (evaluating nilotinib efficacy and safety in clinical trials newly diagnosed patients). [abstract] Blood. 2012; 120(21). [Abstract 167]

7. Baccarani M, Deininger W.M, Rosti G. et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872-884

8. Baccarani M, Cortes J, Pane F, et al; European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. Clin Oncol. 2009; 27(35):6041-6051.

9. Quintas-Cardama A, Cortes J. Molecular biology of bcr-abl 1- positive chronic myeloid leukemia. Blood 2009; 113:1619-1630

10. Baccarani M, Pane F, Saglio G. Monitoring treatment of chronic myeloid leukemia.Haematologica 2008; 93:161-169

11. Sokal JE, Cox EB, Baccarani M et al. Prognostic discrimination in good-risk chronic granulocytic leukemia. Blood 1984; 63:789-799

12. Hasford J, Pfirrmann M, Hehlmann R et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998; 90:850-858

13. Hasford J, Baccarani M, Hoffman V et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on Imatinib treatment: the EUTOS score. Blood 2011; 118:686-692

14. Baccarani M, Rosti G, castagnetti F et al. Comparison of Imatinib 400mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood 2009; 113:4497-4504

15. Apperley JF Part I: mechanisms of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol 2007; 8:1018-1029

16. Apperley JF Part II: management of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol 2007; 8:1116-1128

17. Hochhaus A, Kartajian HM, Baccarani M et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303-2309

18. Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117:755-763

19. Mahon Fx, Rea D, Guilhot J et al. Discontinuation of Imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial; Lancet Oncol 2010; 118:1208-1215

20. Efficace F, Baccarani M, Breccia M et al Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with Imatinib compared with the general population. Blood 2011; 118:4554-4560

21. Deininger MWN, Cortes J, Paquette R, et al.The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells. Cancer. 2007; 110(7):1509-1519.


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ABSTRACT: a brief summary of the research; include a brief introduction, a description of the tested hypothesis, the approach used to test the hypothesis, the recorded result and the conclusion. No abbreviations allowed, cited.

KEYWORDS: 5-6 specific word, not repeating the title of the manuscript.

TEXT: the text of the original research manuscript should be arranged in the following sections – introduction, materials and methods, results, discussion, conclusions. Introduction: description of the research area, relevant background information, and the hypotheses tested in the study should be included. Materials and methods: materials and subjects utilized in the study as well as the procedures undertaken to complete the work. The methods should be described in sufficient detail if they could be repeated by a competent researcher. Mentioning of the statistical tool used for analysis of the results. All procedures involving experimental animals or human subjects must be accompanied with a statement on the necessary ethical approval from an appropriate ethics committee. Results: should describe the reason for each experiment, the obtained result and its significance. Discussion: relate the results’ section to the current understanding of the scientific problem being investigated; discuss the significance of your result. Avoid the use of footnotes in the text. Use the metric system, SI units to express weight and measures. Clearly indicate the place where the table or figure is to be inserted.

TABLES AND FIGURES: insert title above the table with initial capitals, extra space but no punctuation. They should be numbered in the order of their mentioning in the text. Use Roman numerals for tables and Arabic numerals for figures. Table should be in MS Word. Figures: most figures are in black-and-white, without gridlines. Save as .tiff, .jpeg. The minimal accepted resolution – 300 dpi. Do not place a box or ruled frame around a finished table. Place figures and tables separately, at the end of manuscript, one per page. Any table or figure must have a legend. For graphs Excel graphs are acceptable. Present 2D data and avoid 3D plots.

ACKNOWLEDGEMENTS: can mention people who have helped make your manuscript possible. Mention all applicable grants and other funding that supported your work.

REFERENCES: number consecutively in the order that are cited in the text not in alphabetical order. The list must contain the first six authors (if there are least six) or the first three authors (if more than six) and et all. Articles: authors should be presented: last name, initial of first name. Indicate title of article, name of journal, year of publication, volume and issue number, start-end page. Journal name abbreviation should conform to those used in Index Medicus. If journal is not included in Index Medicus use the entire title of the journal. For articles published in online journals also add the URL and the date when the article was accessed. Books: author of the chapter, title of the chapter, editor, title of book, edition, city and country, publisher, year, specific pages. For web contents list: author, title of the page or content, name or owner of the web site, URL, publication, update, access date. It is the responsibility of the author to verify the accuracy of all references.

ABBREVIATION, ACRONYMS AND SYMBOLS: use only standard abbreviations. Abbreviations must be defined on their first use in the paper – the full term should be spelled out first, followed by the abbreviated term in parentheses.

The article should be submitted to Therapeutics, Pharmacology and Clinical Toxicology

Editorial Office: Dr. Cristina Negulescu, INBI „Prof. dr. Matei Bals”, Pavilion IV, Etaj IVStr. Dr. Calistrat Grozovici nr. 1, Sector 2, București, CP 021105 or by e-mail at the address: [email protected]


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CASE REPORTterapeutica.ro/img/rev/pdf/26/2014-2_.pdf · Negulescu Cristina, Drăgănescu Anca,...

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