literature review on diagnosis of malaria

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Malaria 2017: Update on the Clinical Literature and Management

Affiliation.

1 Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. [email protected].
PMID: 28634831
DOI: 10.1007/s11908-017-0583-8

Purpose of review: Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the diagnosis, management and prevention of malaria. This article will discuss the recent malaria epidemiologic and medical literature to review the progress, challenges, and optimal management of malaria.

Recent findings: There has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs over the last few decades. This exciting progress is tempered by continued levels of high transmission in some regions, the emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia, and the lack of a highly protective malaria vaccine. In the United States (US), the number of travelers returning with malaria infection has increased over the past few decades. Thus, US health care workers need to maintain expertise in the diagnosis and treatment of this infection. The best practices for treatment and prevention of malaria need to be continually updated based on emerging data. Here, we present an update on the recent literature on malaria epidemiology, drug resistance, severe disease, and prevention strategies.

Keywords: Drug resistance in malaria; Malaria control; Malaria epidemiology; Malaria treatment; Post-artemisinin delayed hemolysis; Severe malaria.

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Diagnosis, Treatment, and Prevention of Malaria in the US : A Review

1 Department of Medicine (Infectious Diseases), Albert Einstein College of Medicine, Bronx, New York
2 D. Samuel Gottesman Library, Albert Einstein College of Medicine, Bronx, New York
Medical News & Perspectives Vaccine Development Is Charting a New Path in Malaria Control Bridget M. Kuehn, MSJ JAMA
JAMA Patient Page Patient Information: Malaria Kristin Walter, MD, MS; Chandy C. John, MD, MS JAMA
Global Health Updated Malaria Recommendations for Children and Pregnant People Howard D. Larkin JAMA
Medical News in Brief First Ever Malaria Vaccine to Be Distributed in Africa Emily Harris JAMA

Importance Malaria is caused by protozoa parasites of the genus Plasmodium and is diagnosed in approximately 2000 people in the US each year who have returned from visiting regions with endemic malaria. The mortality rate from malaria is approximately 0.3% in the US and 0.26% worldwide.

Observations In the US, most malaria is diagnosed in people who traveled to an endemic region. More than 80% of people diagnosed with malaria in the US acquired the infection in Africa. Of the approximately 2000 people diagnosed with malaria in the US in 2017, an estimated 82.4% were adults and about 78.6% were Black or African American. Among US residents diagnosed with malaria, 71.7% had not taken malaria chemoprophylaxis during travel. In 2017 in the US, P falciparum was the species diagnosed in approximately 79% of patients, whereas P vivax was diagnosed in an estimated 11.2% of patients. In 2017 in the US, severe malaria, defined as vital organ involvement including shock, pulmonary edema, significant bleeding, seizures, impaired consciousness, and laboratory abnormalities such as kidney impairment, acidosis, anemia, or high parasitemia, occurred in approximately 14% of patients, and an estimated 0.3% of those receiving a diagnosis of malaria in the US died. P falciparum has developed resistance to chloroquine in most regions of the world, including Africa. First-line therapy for P falciparum malaria in the US is combination therapy that includes artemisinin. If P falciparum was acquired in a known chloroquine-sensitive region such as Haiti, chloroquine remains an alternative option. When artemisinin-based combination therapies are not available, atovaquone-proguanil or quinine plus clindamycin is used for chloroquine-resistant malaria. P vivax, P ovale, P malariae, and P knowlesi are typically chloroquine sensitive, and treatment with either artemisinin-based combination therapy or chloroquine for regions with chloroquine-susceptible infections for uncomplicated malaria is recommended. For severe malaria, intravenous artesunate is first-line therapy. Treatment of mild malaria due to a chloroquine-resistant parasite consists of a combination therapy that includes artemisinin or chloroquine for chloroquine-sensitive malaria. P vivax and P ovale require additional therapy with an 8-aminoquinoline to eradicate the liver stage. Several options exist for chemoprophylaxis and selection should be based on patient characteristics and preferences.

Conclusions and Relevance Approximately 2000 cases of malaria are diagnosed each year in the US, most commonly in travelers returning from visiting endemic areas. Prevention and treatment of malaria depend on the species and the drug sensitivity of parasites from the region of acquisition. Intravenous artesunate is first-line therapy for severe malaria.

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A review on automated diagnosis of malaria parasite in microscopic blood smears images

Published: 09 March 2017
Volume 77 , pages 9801–9826, ( 2018 )

Cite this article

literature review on diagnosis of malaria

Zahoor Jan 1 ,
Arshad Khan 1 ,
Muhammad Sajjad 1 ,
Khan Muhammad 1 , 2 ,
Seungmin Rho 3 &
Irfan Mehmood 4

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Malaria is a life-threatening disease caused by parasite of genus plasmodium, which is transmitted through the bite of infected Anopheles. A rapid and accurate diagnosis of malaria is demanded for proper treatment on time. Mostly, conventional microscopy is followed for diagnosis of malaria in developing countries, where pathologist visually inspects the stained slide under light microscope. However, conventional microscopy has occasionally proved inefficient since it is time consuming and results are difficult to reproduce. Alternate techniques for malaria diagnosis based on computer vision were proposed by several researchers. The aim of this paper is to review, analyze, categorize and address the recent developments in the area of computer aided diagnosis of malaria parasite. Research efforts in quantification of malaria infection include normalization of images, segmentation followed by features extraction and classification, which were reviewed in detail in this paper. At the end of review, the existent challenges as well as possible research perspectives were discussed.

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Automatic detection of Plasmodium parasites from microscopic blood images

Detection of Malaria Parasite Based on Thick and Thin Blood Smear Images Using Local Binary Pattern

Detection of Plasmodium Falciparum in Peripheral Blood Smear Images

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1A09919551).

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Digital Image Processing Laboratory, Department of Computer Science, Islamia College Peshawar, Peshawar, Pakistan

Zahoor Jan, Arshad Khan, Muhammad Sajjad & Khan Muhammad

Intelligent Media Laboratory, Digital Contents Research Institute, College of Electronics and Information Engineering, Sejong University, Seoul, Republic of Korea

Khan Muhammad

Department of Media Software, Sungkyul University, Anyang, Republic of Korea

Seungmin Rho

Department of Computer Science and Engineering, Sejong University, Seoul, Republic of Korea

Irfan Mehmood

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Jan, Z., Khan, A., Sajjad, M. et al. A review on automated diagnosis of malaria parasite in microscopic blood smears images. Multimed Tools Appl 77 , 9801–9826 (2018). https://doi.org/10.1007/s11042-017-4495-2

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Received : 13 June 2016

Revised : 15 November 2016

Accepted : 08 February 2017

Published : 09 March 2017

Issue Date : April 2018

DOI : https://doi.org/10.1007/s11042-017-4495-2

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Published: 03 February 2023

Leveraging innovation technologies to respond to malaria: a systematized literature review of emerging technologies

Moredreck Chibi 1 ,
William Wasswa 1 ,
Chipo Ngongoni 1 ,
Ebenezer Baba 2 &
Akpaka Kalu 2

Malaria Journal volume 22 , Article number: 40 ( 2023 ) Cite this article

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In 2019, an estimated 409,000 people died of malaria and most of them were young children in sub-Saharan Africa. In a bid to combat malaria epidemics, several technological innovations that have contributed significantly to malaria response have been developed across the world. This paper presents a systematized review and identifies key technological innovations that have been developed worldwide targeting different areas of the malaria response, which include surveillance, microplanning, prevention, diagnosis and management.

A systematized literature review which involved a structured search of the malaria technological innovations followed by a quantitative and narrative description and synthesis of the innovations was carried out. The malaria technological innovations were electronically retrieved from scientific databases that include PubMed, Google Scholar, Scopus, IEEE and Science Direct. Additional innovations were found across grey sources such as the Google Play Store, Apple App Store and cooperate websites. This was done using keywords pertaining to different malaria response areas combined with the words “innovation or technology” in a search query. The search was conducted between July 2021 and December 2021. Drugs, vaccines, social programmes, and apps in non-English were excluded. The quality of technological innovations included was based on reported impact and an exclusion criterion set by the authors.

Out of over 1000 malaria innovations and programmes, only 650 key malaria technological innovations were considered for further review. There were web-based innovations (34%), mobile-based applications (28%), diagnostic tools and devices (25%), and drone-based technologies (13%.

Discussion and conclusion

This study was undertaken to unveil impactful and contextually relevant malaria innovations that can be adapted in Africa. This was in response to the existing knowledge gap about the comprehensive technological landscape for malaria response. The paper provides information that countries and key malaria control stakeholders can leverage with regards to adopting some of these technologies as part of the malaria response in their respective countries.

The paper has also highlighted key drivers including infrastructural requirements to foster development and scaling up of innovations. In order to stimulate development of innovations in Africa, countries should prioritize investment in infrastructure for information and communication technologies and also drone technologies. These should be accompanied by the right policies and incentive frameworks.

In sub-Saharan Africa, malaria is the leading cause of death for children under 5. It has been reported that malaria infection during pregnancy increases the risk of maternal mortality and neonatal mortality [ 1 ]. According to the World Health Organization (WHO), there were 229 million cases of malaria in 2019 compared to 228 million cases in 2018. The estimated number of malaria deaths stood at 409,000 in 2019, compared with 411,000 deaths in 2018. Children under 5 years of age are the most vulnerable group affected by malaria and in 2019 they accounted for 67% (274,000) of all malaria deaths worldwide. The WHO African Region continues to carry a disproportionately high share of the global malaria burden. In 2019, the region was home to 94% of all malaria cases and deaths with six countries accounting for approximately half of all malaria deaths worldwide: Nigeria (23%), the Democratic Republic of the Congo (11%), United Republic of Tanzania (5%), Burkina Faso (4%), Mozambique (4%) and Niger (4%) [ 2 ].

Knowledge, learning and innovation are key to addressing, minimizing and tackling these disparities. One example of this is the knowledge hub developed by WHO called MAGICapp which aims to give living evidence and resources for tackling malaria interventions. It contains all official WHO recommendations for malaria prevention (vector control and preventive chemotherapies) and case management (diagnosis and treatment). The resources serve as a guide on the strategic use of information to drive impact, surveillance, monitoring and evaluation; operational manuals, handbooks, and frameworks; and a glossary of key terms and definitions. So, this paper aligns with identifying and adding discourse into the importance of reviews especially from a technological perspective.

To understand the advances in malaria services, various scholars have undertaken reviews across vast thematic areas of malaria interventions. In a quest to inform policy, Garner et al. [ 3 ] conducted an analysis of why Cochrane Reviews are important in malaria interventions. They noted that it is important for researchers to collaborate across regions and in understanding new preventive interventions. Their aim was to inform policymakers to understand the importance of reviews in identification of trends that are occurring in malaria interventions. Other aspects that have been looked at through reviews are the costs and cost-effectiveness aligned with malaria control interventions. White et al. [ 4 ] looked at interventions from studies published between 2000 and 2010 looking at the role of infection detection technologies for malaria elimination and eradication and the costs related to them in order to assess how accessible interventions are across regions. More recently, Conteh et al. [ 5 ] also carried on with assessing the unit cost and cost-effectiveness of malaria control during the period of January 1, 2005, and August 31, 2018. The aim was to see how resource allocation can be planned proactively according to costs, though they did highlight that care in methodological and reporting standards is required to enhance data transferability.

In a bid to combat malaria epidemic, several technological innovations have been developed all over the world that have contributed significantly to malaria response. Adeola et al. [ 6 ] reviewed the use of spatial technology for malaria epidemiology in South Africa between 1930 and 2013. The focus was on the use of statistical and mathematical models as well as geographic information science (GIS) and remote sensing (RS) technology for malaria research to create a robust malaria warning system. The mathematical modelling is also aligned with agent-based modelling which Smith et al. [ 7 ] highlighted through their analysis of 90 articles published between 1998 and May 2018 characterizing agent-based models (ABMs) relevant to malaria transmission. The aim was to provide an overview of key approaches utilized in malaria prevention. Such technologies feed into modelling sites and interventions to project various outcomes. From a platform centric perspective, Vasiman et al. [ 8 ] analysed how different mobile phone devices and handheld microscopes work as diagnostic platforms for malaria in low-resource settings. Malaria diagnostics tests and methods have also been reviewed as being key in the successful control and elimination programmes [ 9 ]. Mobile health has been found to play a key role in supporting health workers in the diagnosis and treatment of malaria in sub-Saharan Africa [ 10 ].

To add to this discourse, this paper presents a holistic systematized review of key technological innovations that have been developed worldwide targeting different areas of the malaria response, which include surveillance, microplanning, prevention, diagnosis, and management. A systematized review was utilized in this study as data sources that included unconventional grey sources was utilized and the review gravitated more towards being narrative with tabular accompaniments as compared to the systematic literature reviews that are less narrative [ 11 ]. The study was undertaken with the view to provide African countries and key stakeholders with information relating to technologies that can be adapted in their different contexts as they strengthen malaria response strategies.

Scientific databases literature search

This study adopted a systematic search strategy to identify the publications with innovations related to malaria surveillance, microplanning, prevention, diagnosis, and management from 5 scientific databases (PubMed, Google Scholar, Scopus, IEEE and Science Direct). The keywords used were malaria surveillance, microplanning, prevention, diagnosis and management combined with the words “innovations” or “technologies” in a search query. Innovations deemed not relevant to the scope of this research by the authors include drugs, vaccines, social programmes. Only papers reporting design, implementation or evaluation of malaria technological innovations were considered in this paper. The process was shown in Fig. 1 . The quality of technological innovations included was based on reported impact and judgement by the authors.

PRISMA flow chart for the malaria innovations literature search

Search through technology platforms e.g., google play store and apple app store

This study also adopted a systematic search strategy to identify the mobile apps related to malaria surveillance, microplanning, prevention, diagnosis and management available in the Google Play and Apple App stores. Keywords such as malaria surveillance, microplanning, prevention, diagnosis, and management were used in the search. The search was conducted between July 2021 and December 2021. The applications had to have a description, be in English, have 1000 + installs and reviews to be included in the analysis. The applications that did not meet these criteria were excluded. The core research question was: What mobile-based innovations are available for malaria interventions that can be adopted by the countries in the WHO Africa region for use across the continuum of the malaria response ? The resultant apps considered for this study were 260 as shown in Fig. 2 .

PRISMA flow chart for the mobile apps

Web search using a custom web-content mining algorithm

A custom web-content mining algorithm was also developed to search for malaria innovations and technologies published on different cooperate organizational websites, social media channels like twitter, and media channels like legit news websites like CNN. These technological innovations were collated between July 2021 and December 2021. The innovation name, description, Intellectual Property owner, web link to the innovation and geographical location were collated. Innovations that did not have functional and tested prototypes and were not related to addressing malaria interventions were excluded. The number of innovations surpassed 1000 however after screening, only 240 key technological innovations were selected that best fit the selection criteria.

A total of 650 malaria innovations (260 from Google play and Apple App store, 150 from scientific databases and 240 from web content mining) were considered for detailed review.

The review has identified innovations for malaria in the following technological thematic areas; web-based innovations (34%), mobile-based applications (28%), diagnostic tools and other devices (25%), and drone-based technologies (13%).

Web-based innovations

The web-based technologies include GIS systems [ 12 ]. An example is the Malaria Atlas Project (MAP), developed at the Telethon Kids Institute, Perth, Western Australia. MAP is a web platform that displays time aware raster and survey point data for malaria incidence, endemicity, and mosquito distribution. MAP has been designated as a WHO Collaborating Centre in Geospatial Disease Modelling. The impact of the Atlas Project has been validated in Sokoto Nigeria by Nakakana et al. [ 13 ]. The study concluded that the prevalence of malaria and its transmission intensity in Sokoto are similar to the Malaria Atlas Project predictions for the area and that is essential in modellings various aspects of malaria control planning purposes.

Other innovations like malariaAtlas which is an open-access R-interface on the Malaria Atlas Project, collates malariometric data, providing reproducible means of accessing such data within a freely available and commonly used statistical software environment [ 14 ]. A team from the University of Queensland developed a GIS-based spatial decision support system (SDSS) used to automatically locate and map the distribution of confirmed malaria cases, rapidly classify active transmission foci, and guide targeted responses in elimination zones. This has been implemented and evaluated in the Solomon Islands and Vanuatu in a study by Kelly et al. [ 15 ] and 82.5% of confirmed malaria cases were automatically geo-referenced and mapped at the household level, with 100% of remaining cases geo-referenced at a village level using the system. The GIS-based spatial decision support system has also been implemented in other countries like Vietnam. In Korea, the Malaria Vulnerability Map Mobile System which consists of a system database construction, malaria risk calculation function, visual expression function, and website and mobile application has been developed for use in Incheon [ 16 ]. The Malaria Decision Analysis Support Tool (MDAST) project promotes evidence-based, multi-sectoral malaria control policy-making in Kenya, Tanzania, and Uganda, serving as a pilot for such a programme in other malaria-prone countries [ 17 ].

In Zanzibar, the Malaria Case Notification (MCN) System was developed and the performance evaluation of the tool by Khandekar [ 18 ] showed that while a surveillance system can automate data collection and reporting, its performance will still rely heavily on health worker performance, community acceptance, and infrastructure within a country. A study by Mody et al. [ 19 ] showed that the use of telemedicine and e-health technologies shows promise for the remote diagnosis of malaria and hence several systems been developed. ProMED Mail (PMM) is an open and free to use, global, e-health based surveillance system from the International Society for Infectious Diseases with several use cases for malaria [ 20 , 21 ]. The Epidemic Prognosis Incorporating Disease and Environmental Monitoring for Integrated Assessment (EPIDEMIA) computer system was designed and implemented to integrate disease surveillance with environmental monitoring in support of operational malaria forecasting in the Amhara region of Ethiopia [ 22 ]. Table 1 summarizes some of the technologies.

Mobile applications-based technologies

This study has also revealed that several mobile-based malaria innovations have been developed which include smart mobile apps, Short Message Service (SMS) based apps and Unstructured Supplementary Service Data (USSD) based applications for use across the continuum of the malaria response. In India the Mobile-based Surveillance Quest using IT (MoSQuIT) is being used to automate and streamline malaria surveillance for all stakeholders involved, from health workers in rural India to medical officers and public health decision-makers. Malaria Epidemic Early Detection System (MEEDS) is a groundbreaking mHealth system used in Zanzibar by health facilities to report new malaria cases through mobile phones. Coconut Surveillance is an open-source mobile software application designed by malaria experts specifically for malaria control and elimination and it has become an essential tool for the Zanzibar Malaria Elimination Programme [ 23 ]. The SMS for Life initiative is a ‘public-private’ project that harnesses everyday technology to eliminate stock-outs and improve access to essential medicines in sub-Saharan Africa with a health focus on malaria and other vector borne diseases. This has been implemented and evaluated in Tanzania [ 24 ]. In Mozambique Community Health Workers (CHWs) use inSCALE CommCare tool for decision support, immediate feedback and multimedia audio and images to improve adherence to protocols.

Additional surveillance apps include the likes of the DHS mobile app for Malaria Indicator Surveys and Solution for Community Health-workers (SOCH) mobile app is a comprehensive mobile application tool for disease surveillance, workforce management and supply chain management for malaria elimination [ 25 ]. The National Malaria Case-Based Reporting App (MCBR) is a mobile phone application for malaria case-based reporting to advance malaria surveillance in Myanmar [ 26 ]. Mobile apps have also been used to support distribution of medicines like the Net4Schs App, an android application that is used for data capturing, processing and reporting on School Long-lasting insecticidal nets (LLINs) distribution activities. Apps have also been developed to support malaria screening and diagnosis for example the NLM Malaria Screener is a diagnostic app that assists users in the diagnosis of malaria and in the monitoring of malaria patients. This has been validated in several studies and it is reported that it makes the screening process faster, more consistent, and less dependent on human expertise [ 27 ]. Additional diagnostic apps include the Malaria System MicroApp which is a mobile device-based tool for malaria diagnosis [ 28 ], the Malaria Hero app is a web based mobile app for diagnosis of malaria, and LifeLens is a smartphone app that can detect malaria. Some key technologies are summarized in Table 2 .

Other notable mobile apps that have also been used in malaria management include CommCare’s usage in in Mozambique for integrated community case management in the remote communities. This has been reported to strengthen Community-Based Health [ 29 ]. Another app, FeverTracker, has been used for malaria surveillance and patient information management in India. There has also been a number of educational and knowledge base apps. These are the likes of Malaria Consultant, a mobile application designed to educate individuals on malaria and its prevention; the WHO Malaria toolkit App that brings together the content of the latest world malaria report and of the consolidated WHO Guidelines for malaria. This includes operational manuals for carrying out malaria interventions and other technical documents in one easy to navigate resource. Another interesting area where mobile apps have been used is in malaria prevention and such apps include those that scare away mosquitoes using high frequency sounds, and these include Anti Mosquito Repellent Sound App.

Drone-based technologies

This review has revealed that drone technologies can greatly help in malaria control programmes. The drones can be used in developing genetically-based vector control tools [ 30 ], delivering massive aerial spraying to kill mosquito larvae [ 31 ], identifying mosquito larvae sites using aerial imaging [ 32 ] and in delivering drugs and vaccines [ 33 ]. Anti-malaria drones have been widely used to spray biological insecticides in rice fields and swamps to reduce the emerging mosquito populations. This has been successful in Kenya, Tanzania, India, Rwanda and Zanzibar. In Zanzibar, the Agras MG-1S drones were used to spray 10 L of a biodegradable agent called Aquatain; a chemical that has been used to cover drinking water basins. Drones have also been used to collect data to identify mosquito breeding sites so that the larvae can be controlled, reducing the number of adult mosquitoes able to spread malaria. For example in Malawi and near Lake Victoria the DJI Phantom low-cost drones are being used to survey and find mosquito breeding grounds. A new trial using ‘gene drive’ technology is currently taking place in Burkina Faso where the trial will see the release of genetically modified mosquitoes in an attempt to wipe out the female carriers of the disease [ 34 ].

Diagnostic tools including other devices developed for malaria interventions

Devices that have been developed to respond to malaria include the SolarMal device, a solar-powered mosquito trapper being piloted in Kenya [ 35 ]. The Solar Powered Mosquito Trap (SMOT) is baited with a synthetic odor blend that mimics human odor to lure host-seeking malaria mosquitoes. Other devices such as the ThermaCell Patio Shield Mosquito Repellants developed by ThermaCell are shield lanterns that repel mosquitoes by creating a 15-foot zone of protection. Several devices have also been developed to improve malaria diagnosis and these include the Nanomal DNA analyzer a simple, rapid and affordable point-of-care (POC) handheld diagnostic nanotechnology device to confirm malaria diagnosis and detect drug resistance in malaria parasites in minutes and at the patient’s side, by analysis of mutations in malaria DNA using a range of proven nanotechnologies. Medication Events Monitoring Device (MEMS) have also been greatly used to monitor medication adherence to malaria drugs [ 36 ]. Malaria Rapid Diagnostic Tests (RDTs), sometimes called dipsticks or Malaria Rapid Diagnostic Devices (MRDDS), are simple immunochromatographic tests that identify specific antigens of malaria parasites in whole or peripheral blood. They are categorized into dipstick, cassette or hybrids. Dipstick RDTs are cheap and readily available on market [ 37 ]. An example is the OptiMAL dipstick [ 38 ]. Cassette RDTS are complex and require much time for results to be read but are much safer to use.

This research has culminated into insightful conclusions from the systematized review of the malaria technological Innovations and has been the foundation of the collated database that can be accessed via the WHO AFRO marketplace platform. This is a platform that has been developed to showcase various technologies and innovations that can be applied for different disease areas. This focused on technologies relevant for malaria response. The identified intervention technologies and focus areas provide ways of identifying key leverage points in strengthening the health systems and making tangible impact towards various mandates to fight the scourge of malaria. More importantly highlighting these trends empowers innovators and policy makers on the continent to make informed decisions on applying frugal design to develop affordable, locally manufactured, functional and sustainable innovations fit for the African continent. Furthermore, the marketplace platform provides implementation insights to African nations on the adoption of some of the technological innovations from this study.

The review has highlighted that mobile applications are a vital component of malaria response programmes and are increasingly being used along the different response areas, such as surveillance (malaria data capturing apps like Coconut Surveillance and DHS mobile app), microplanning (drug delivery and distribution management apps like Net4Schs App), prevention (mosquito repelling like Anti Mosquito Repellent Sound App), diagnosis (AI driven slide analysis apps like LifeLens and Malaria Screener), management (telehealth like the Malaria Consultant) and the provision of support for health services [decision support like the solution for Community Health-workers (SOCH) app] as outlined in Fig. 3 . Their impact has been validated in several studies [ 27 , 39 ].

Analysis of the innovations by category, application and target outcome

In 2019, 93% of the global population was covered by a mobile broadband signal. In Sub-Saharan Africa, 3G coverage expanded to 75% compared to 63% in 2017, while 4G doubled to nearly 50% compared to 2017 [ 40 ]. This implies that mobile solutions can substantially mitigate many of the health system limitations prevalent mostly in African countries where malaria is endemic. A substantial number of mobile applications have been developed for surveillance of malaria control programs in Africa such as inSCALE (Mozambique), Coconut Surveillance (Zanzibar), CommCare (Senegal) and DHIS2 (Zimbabwe, and South Africa). This shows that mobile-based apps give a larger footprint and a high level of agility to malaria response. Nevertheless, limited connectivity and erratic energy supplies have been key factors affecting the levels of adoption and some apps have been reported to have a high level of complexity. This has also been reported in other studies [ 41 , 42 ].

Moreover, it has been noted that most of these apps are independent with limited capability for interoperability. Hence there is a need to develop open standards for mobile technologies for malaria control. For example, surveillance applications should be able to have geolocation capabilities and use exiting open-source platforms like OpenStreetMap, OpenDataKit & OpenMapKit; work online and offline mode to enable usage in resource constraints areas, ease of use to enable usage with little or no training and should support different languages including local languages. This calls for more research and implementation of natural language processing frameworks for use in mobile apps in Africa, which can assist with data analytics as well. Furthermore, aligning app development with standards such as the Fast Healthcare Interoperability Resources (FHIR) which facilitate interoperability between legacy health care systems and technology is important.

Superseding technological interoperability, there needs to be platform integration and overall visibility particularly on innovations that target malaria diagnosis, surveillance and management. However, it should be noted that systemically there has been launching of different applications for different malaria interventions which may confuse the public in terms of usage. Therefore, a single application or platform integrating several services such as Coconut Surveillance and owned and managed by a reputable malaria organization or the ministries of health may benefit citizens by allowing them to access services from a single and trusted application. Misinformation and misdiagnosis from publicly available medical apps is a health threat to the public as reported by [ 43 ].

Most of the reviewed web systems depend on data or are used to collect large amounts of malaria data to support decision-making. Hence a need for national malaria control and elimination information systems that can utilize regional and global structures, prioritizing cross-border intelligence sharing information regarding disease transmission hotspots, outbreaks, and human movement. Such systems can also be very useful in responding to pandemics like COVID-19 and other infectious outbreaks. There is also a need to have malaria related data centrally stored and managed by the Ministry of Health or malaria control programmes to guide decision-making at all levels of malaria response among the different stakeholders. Hospitals and clinics have also developed standalone patient information management systems in addition to the national health information management systems like OpenMRS and DHIS2. However, there is no communication between the different patient’s information management systems hence a need for development of open data standard driven systems and APIs to enforce interoperability among health systems in Africa. An effective information system must receive data from other sources, process it and send it back to other systems being used in malaria programme, particularly at the community level.

In malaria control, larval source management is very difficult to archive in rural areas due to perceived difficulties in identifying target areas [ 44 ]. Drones can capture extremely detailed images of the landscape, opening the possibility of replacing the time-consuming hunt for mosquito larvae on the ground with identifying habitat through aerial imagery. The review has shown that this has been used in several countries for example in Malawi and near Lake Victoria using DJI Phantom; low-cost drones that survey wilderness to find mosquito breeding grounds using Geospatial technology. Geospatial technology is rapidly evolving and now can be archived using remotely sensed data [ 45 ]. In Zanzibar, drones have been used to spray rice fields with a thin, non-toxic film as a strategy to eliminate mosquitoes. The review has shown that drones are a possible solution in malaria control programmes as also indicated in other studies [ 45 , 46 ]. The review also showed that rapid diagnostics tools offer fast turnaround services while circumventing obstacles faced when using microscopy in peripheral health care settings, including cost of equipment, reagents, and the need for electricity and skilled personnel [ 47 ].

This study has reviewed key emerging technologies used in malaria control programmes. The review revealed various technological applications that have been developed in response to malaria including surveillance, microplanning, prevention, diagnosis and management. Although breakthrough innovative platforms have been made available, one key challenge remained, which is lack of integration of key end-to-end components and functionalities to facilitate effective and efficient malaria response and to reduce fragmentation.

The review has also revealed several stakeholders in malaria control hence a need for mechanisms that promote the exchange of evidence between scientific, policy, and programme management communities for analysing the potential outcomes of the different malaria control strategies and interventions. In many malaria-endemic areas in Africa, the communication gap between policy makers, health workers, and patients is a significant barrier to efficient malaria control.

Furthermore, artificial intelligence (AI) has been widely used in the reviewed technological innovations, however there is an urgent need to provide reliable datasets, develop local AI expertise among WHO African member states, implement data protection and privacy acts; and put in place health innovation clusters to bring the different stakeholders together to develop and adopt appropriate technologies to solve the intended challenges.

Limitations of this work and future prospects

The main limitation of this work was that some applications were overlapping among the response areas and hence the decision to place an innovation under a given category was based on the judgement of the authors. Another limitation is the fact that this work is not aimed at analysing the total landscape of all malaria innovations. Only those that met the inclusion criteria and deemed relevant by the authors were included hence some innovations might not have been captured but we will be subjected to continuous update on the global database for malaria innovations at https://innov.afro.who.int/emerging-technological-innovations/7-malaria-innovations . Future research can focus on reviewing the technologies that are open source dedicated to malaria, and publishing findings that can be used by medical practitioners, application developers, and governments to collaborate in the process of containing the spread of malaria.

Availability of data and materials

The data used in this report is available to readers.

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Moredreck Chibi, William Wasswa & Chipo Ngongoni

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MC lead the conceptualization and designing of the study, and writing of the manuscript. WW contributed with data mining, analytics and writing the manuscript. CN contributed with systematized literature review and reviewing the manuscript. EB contributed to conceptualizing the study and reviewing of the draft manuscript. AK contributed to reviewing the draft manuscript and providing expert oversight. All authors read and approved the final manuscript.

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Published: 04 June 2024

What are medical students taught about persistent physical symptoms? A scoping review of the literature

Catie Nagel 1 ,
Chloe Queenan 1 &
Chris Burton 1

BMC Medical Education volume 24 , Article number: 618 ( 2024 ) Cite this article

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Persistent Physical Symptoms (PPS) include symptoms such as chronic pain, and syndromes such as chronic fatigue. They are common, but are often inadequately managed, causing distress and higher costs for health care systems. A lack of teaching about PPS has been recognised as a contributing factor to poor management.

The authors conducted a scoping review of the literature, including all studies published before 31 March 2023. Systematic methods were used to determine what teaching on PPS was taking place for medical undergraduates. Studies were restricted to publications in English and needed to include undergraduate medical students. Teaching about cancer pain was excluded. After descriptive data was extracted, a narrative synthesis was undertaken to analyse qualitative findings.

A total of 1116 studies were found, after exclusion, from 3 databases. A further 28 studies were found by searching the grey literature and by citation analysis. After screening for relevance, a total of 57 studies were included in the review. The most commonly taught condition was chronic non-cancer pain, but overall, there was a widespread lack of teaching and learning on PPS. Several factors contributed to this lack including: educators and learners viewing the topic as awkward, learners feeling that there was no science behind the symptoms, and the topic being overlooked in the taught curriculum. The gap between the taught curriculum and learners’ experiences in practice was addressed through informal sources and this risked stigmatising attitudes towards sufferers of PPS.

Faculties need to find ways to integrate more teaching on PPS and address the barriers outlined above. Teaching on chronic non-cancer pain, which is built on a science of symptoms, can be used as an exemplar for teaching on PPS more widely. Any future teaching interventions should be robustly evaluated to ensure improvements for learners and patients.

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Persistent Physical Symptoms (PPS) are symptoms which are disproportionate to currently recognised pathology and are common in all fields of medicine. The term encompasses single symptoms such as pain, dizziness or fatigue, and established syndromes including fibromyalgia and irritable bowel syndrome. It is increasingly understood that PPS arise from complex interactions between the brain and body [ 1 , 2 ]. While historically terms such as “medically unexplained symptoms” have been in common use, most symptoms can actually be explained [ 3 ] and PPS is a more acceptable term to patients [ 4 ].

PPS are common and present to nearly every medical specialty. They represent the primary reason for presentation in around 45% of general practice consultations and between 30 and 70% of presentations to neurology, gynaecology, and rheumatology outpatient clinics [ 5 ]. People with PPS suffer unduly in a medical system that is predisposed to ‘body part medicine,’ [ 6 ] resulting in what Balint referred to as the “collusion of anonymity.” [ 7 ] In other words, patients who pass from specialist to specialist, without any doctor taking full responsibility for holistic care. Patients with PPS consult more frequently [ 8 ] and tend to have a higher rate of referral to secondary care [ 9 ]. This is costly, both in financial terms and in terms of the emotional work for patients and clinicians [ 10 , 11 ]. Patients with PPS often have a poor experience of the health system and can be left feeling marginalised and even stigmatised [ 12 ].

Doctors find it difficult to consult and manage patients with persistent physical symptoms [ 8 ]. The absence of a common language of explanation to reconcile patients’ lived experience with doctors’ biomedical models, is particularly problematic [ 13 ]. It is plausible that difficulties may arise, or be perpetuated by, issues in each of the three domains of learning: cognitive (knowledge), psychomotor (skills) and affective (attitudes) [ 14 ].

The shifting perspectives, particularly around “medically unexplained symptoms” may account for historical uncertainty, however recent adoption of more consistent language and underlying models of symptoms mean that a common curriculum should be possible [ 15 ]. It is the authors’ experience that little teaching and learning at the undergraduate level has previously taken place on this topic. We wanted to find out if this was still the case, by reviewing the current medical education literature.

We carried out a scoping review with narrative synthesis following the approach of Arksey & O’Malley [ 16 ]. The PRISMA-ScR guidelines were used to structure reporting [ 17 ].

Research questions

The aim of the review was to explore the published literature regarding undergraduate medical teaching and learning on persistent physical symptoms. The specific research questions were:

What teaching and learning on persistent physical symptoms has been described for medical undergraduates?

What teaching methods have been used and how have these been evaluated?

Search strategy

We used a Population, Concept, and Context (PCC) framework to structure a systematic search. The population was undergraduate medical students, the concept was persistent physical symptoms, and the context was teaching and learning. A variety of synonyms were used in order to be inclusive, given the constant evolution of terms for persistent physical symptoms. We used adjacency searching and truncation methods in order to broaden the search as widely as possible and to account for different spellings of words or use of phrases across the international context. Search concepts were then combined using Boolean operators. No date range was used, so all studies before 31 March 2023 were included. Inclusion criteria were: studies relating to the teaching and learning of Persistent Physical Symptoms; medical students included in the population; available in the English language. Exclusion criteria were: studies about cancer or terminal pain without the inclusion of other forms of chronic or persistent pain; population not including medical students; letters to the editor, and papers which were not available in the English language. See Table 1 for the full search strategy.

Sources of evidence

Two authors searched for published literature in MEDLINE, PsycINFO, and Web of Science. Additionally, we searched Google and Google Scholar in order to include any grey literature or sources that had not been picked up by the previous search method. We employed citation analysis, by following backward citations from included papers and analysed the citations of any existing literature reviews.

Study selection

We used a two-stage screening process to identify eligible papers: first at title and abstract level and then at full text. This method was undertaken separately by two reviewers.

Literature reviews were excluded to avoid duplicated representation of primary data, but citations in these reviews were analysed to ensure consistent inclusion of studies and to check for any additional sources.

Charting the data: summary and synthesis

Summary findings for each full text article were charted to determine the most relevant items for extraction. This was an iterative process given the high degree of heterogeneity between the studies. Charting was conducted by two reviewers independently. Discrepancies in charting and data extraction were discussed in review meetings and a consensus was reached regarding which data to include for analysis.

Reviewers extracted descriptive data including: country of origin, whether the study was experimental or observational, the characteristics of the study participants, and whether any teaching intervention was evaluated. Other study characteristics were noted, such as the symptom or syndrome represented, as well as the type of study or intervention.

The expectation was that there would be a lack of teaching and learning on the subject of persistent physical symptoms. For this reason, the scoping review aimed to capture the greatest breadth of studies, rather than exclude studies based on quality criteria. If a teaching intervention was used, we did look at whether this was evaluated using a validated tool.

Following the extraction of descriptive data, a narrative synthesis was undertaken to identify other key findings. An inductive, iterative approach was taken in order to identify themes relating back to the research question. Manual coding was undertaken by two authors independently, followed by a discussion with all authors to arrive at an interpretation of the findings.

Search strategy, study selection, and data extraction

Searches identified 1390 unique titles. Studies were limited to English language and human participants, leading to 274 being excluded. First stage screening excluded a further 1080 studies. It was not possible to retrieve one study and six were excluded on full text. Ten further records were identified through a grey literature search using Google and Google Scholar and 18 were found through citation searching, three of which were from a previous literature review [ 15 ]. This resulted in 57 publications for inclusion in the review. See the PRISMA flow diagram in Fig. 1 for a summary of these findings.

PRISMA Diagram

Adapted from Page MJ, et al. [ 17 ]

Descriptive analysis

Study types.

The studies included for review were highly heterogeneous in their nature. 15/57 (26%) studies employed a teaching intervention, with the remaining either being observational or qualitative. 8/57 (14%) studies described or evaluated the teaching curriculum, 13/57 (22%), included an assessment of the current level of learner knowledge. 9/57 (16%) used qualitative methods with learners and 6/57 (11%) with medical educators. One literature review on assessing knowledge, perceptions and attitudes to pain was found [ 15 ]. The citations of this review were checked and the three new sources [ 18 , 19 , 20 ] were included for review. Sources within this literature review that did not meet the eligibility criteria were excluded. The findings of the review itself were noted for congruity, but not formally analysed.

Study characteristics

23/57(40%) of studies took place in USA and 13/57 (23%) in the UK. Six studies took place in Scandinavia and four in Canada, four in Australia and one in New Zealand, India, and Nigeria respectively. Some studies were based in more than one country e.g. Australia and New Zealand [ 21 ]. Publication dates ranged from 1992 to 2022. See Table 2 for a summary of the descriptive data.

Teaching and learning methods

A wide range of teaching and learning methods were discussed in the literature. These are fully described in Table 3 , but included lectures, workshops, reflective practice, and forum theatre.

Evaluation of teaching studies

Four studies used validated tools to assess learner attitudes towards patients with PPS, but only one used such a tool to evaluate a teaching intervention [ 22 ]. Morris, Rankin, and Briggs used the HC-PAIRS attitudinal questionnaire to assess learner attitudes towards patients with chronic low back pain [ 18 , 23 , 24 ]. Whereas Friedberg et al. [ 22 ] used the Chronic Fatigue Syndrome Attitudes Test (CFSAT) and paired t-test to analyse learner attitudes before and after a teaching intervention. The remaining educational interventions either did not use a validated tool for evaluation or were not formally evaluated. See Table 3 for more details.

Thematic synthesis

All studies identified a lack of teaching about persistent physical symptoms (PPS) at undergraduate level. The narrative synthesis identified four themes: An awkward problem, an absence of science, being easily overlooked, and a hidden curriculum.

An awkward problem

PPS was consistently viewed as an awkward problem. Medical educators and learners found it difficult to understand, particularly when referring to the symptoms as ‘unexplained.’ Some educators described PPS as too complex or too confusing, even ‘dangerous’ to introduce at an undergraduate level and stated the need to focus on the easily ‘explainable.’ [ 25 ] Chronic non-cancer pain was the dominant condition represented in the literature, but despite theoretical concepts of chronic pain being more established, learners found the subject challenging, even ‘unpleasant.’ [ 26 , 27 ].

The absence of science

Four studies highlighted that learners infer patients with PPS have ‘no science’ behind their symptoms. In the study by Vasanthy [ 28 ], clinical role models in Kerala were found to have a ‘nihilistic’ attitude towards people with fibromyalgia and regarded the condition as benign and unimportant. This finding was echoed by UK studies [ 29 , 30 , 31 ] where the impact of a lack of teaching and negative role modelling was evident:

“You can’t really train someone for it because there is no science behind it” [ 30 ].

One final year medical student stated that fibromyalgia was “not a medical issue” intimating that it had no place in the taught curriculum [ 29 ]. Learners understood the need to be supportive and for good communication, but only as a way of achieving relational congruence, not epistemic congruence [ 8 ]. Terminology may be important and in one study learners’ attitudes towards PPS varied depending on the diagnostic label [ 32 ]. As an example, learners thought that people with myalgic encephalopathy were less likely to recover than those with chronic fatigue syndrome [ 32 ].

Easily overlooked

Even without the overt attitudinal barriers described in some studies, PPS as a topic is overlooked in undergraduate medical education. The most common barrier was an already overloaded teaching curriculum [ 25 , 33 ]. PPS was not deemed a priority area by educational leaders and [ 33 ] even when they recognised its importance, they cited a lack of ownership of the topic and a lack of coordination between teaching specialties as a barrier to implementing teaching. This was in contrast to chronic non-cancer pain teaching which usually did have clear ownership by pain specialists and established interdisciplinary relationships [ 34 ]. The experience of learners in the clinical setting was that they were shielded from patients with PPS or directed towards patients with other more easily defined clinical problems [ 28 ].

Stigma and the hidden curriculum

Given the vacuum of formal teaching, learners were taking on stigmatised messages about sufferers of PPS, frequently from role models in the clinical placement setting. Stenhoff and colleagues described a cycle of negativity created by the lack of teaching on the subject of chronic fatigue, which resulted in negative behaviour by clinical role models, in turn perpetuating negative attitudes in the next generation of learners [ 31 ]. Whilst learners recognised the problematic nature of the attitudes towards people with PPS, they lacked the tools to challenge negative stereotypes [ 29 , 30 , 35 ]. Learners experienced a mismatch between formal teaching on the topic and their experience on placement, where these conditions were frequently encountered. They addressed the gap by seeking information about PPS from informal sources, such as their own or their families’ experiences or from the internet [ 36 ]. This lack of explicit teaching and the influence of informal sources has been termed by some authors as the ‘hidden curriculum’ [ 29 , 30 , 31 , 36 ] and this has had a significant impact on learners’ attitudes towards people suffering with PPS.

Suggestions for improvement: relationship to domains of learning

The findings of the narrative synthesis map onto Bloom’s revised three domains of learning [ 14 ].

Knowledge (cognitive)

A number of studies demonstrate success in teaching on the topic of chronic non-cancer pain. Teaching interventions tended to include a foundation of knowledge such as teaching on pain mechanisms, pharmacology, and pain management [ 37 , 38 ]. Such theory-driven interventions led to improved scores on assessment [ 39 ]. Methods of teaching should be considered in the explicitly taught curriculum. Authors recommended an integrated approach [ 40 , 41 ] and one which drew on the skills and knowledge from a variety of disciplines [ 37 , 42 ]. Curriculum mapping was recommended by Howman et al. [ 33 ] in order to identify ways in which this integration could be implemented. The need for an holistic approach which emphasises the importance of empathy [ 41 ] and the biopsychosocial was also widely recognised [ 43 , 44 , 45 , 46 ]. Learners cited a lack of assessment as an indicator that PPS was either unimportant or uncommon [ 29 , 33 ] and therefore any teaching intervention should include assessment in order to drive learning and engagement.

Skills (psychomotor)

Learners valued the addition of skills-based teaching and engaged best with teaching that was experiential [ 47 ] and included either patients with PPS or simulated patients [ 45 , 48 , 49 ]. In one study the focus of the teaching was on interactive, practical teaching for emotionally demanding consultations and the skills taught in such a programme could be transferable to the PPS context [ 49 ]. Approaches to help learners find a common language of explanation [ 13 ] will not only bridge the epistemic gap between clinicians and patients [ 8 ], but should give learners greater confidence and satisfaction in consultations where PPS are the focus.

Attitudes (affective) and the role of reflection

Reflection is a key transferable skill that graduates should acquire as part of their undergraduate training [ 50 ]. Both learners and educators voiced a great deal of anxiety regarding teaching and managing patients with PPS. Some authors utilised reflective logs and visual art as a way of teaching about chronic pain [ 51 ] and learners valued the deep insights provided by this method. Skills in reflection might help to ameliorate the negative emotions felt by learners, especially if combined with a taught framework that helps them understand concepts such as internal bias and cognitive dissonance [ 52 ].

Summary of main findings

This review found that teaching on persistent physical symptoms in undergraduate medical education is inconsistent and incomplete. We identified four important themes: an awkward problem, the absence of science, easily overlooked, and the hidden curriculum. Mapping these to teaching and learning domains provides a coherent framework for undergraduate teaching of these common conditions. Where teaching does take place, this is more frequently on the topic of chronic non-cancer pain. A number of studies have demonstrated improved knowledge [ 39 ], skills [ 49 ], and attitudes [ 51 ] as a result of this teaching [ 34 , 47 ], but high quality evaluation of such teaching and learning is lacking.

Strengths and limitations

This scoping review has addressed a gap in the literature. By undertaking a search of three databases, the grey literature, and citation analysis, a wide range of sources were included for initial screening. Two researchers independently undertook the search strategy before comparing findings which has helped to ensure a robust and systematic approach. Narrative synthesis was undertaken by three researchers, one with expertise in the field of persistent physical symptoms.

The majority of the studies identified were from the USA and UK. Papers that were not accessible in English were excluded, which may explain this finding. Where teaching and learning evaluations had taken place, this was on a small scale usually within one institution. Only one study [ 22 ] used a validated tool to evaluate the efficacy of the teaching intervention.

Implications for practice, policy, and research

There is a lack of teaching on PPS in undergraduate medical education. As a result, medical graduates are ill-equipped to recognise, consult for, and manage this group of conditions. Given the prevalence of PPS across medical specialties this is a priority area that needs to be addressed, whilst acknowledging the barriers that exist to implementation.

The solutions offered up in the literature include the need to consider whole-person care, in order to avoid fragmentation and the “collusion of anonymity” [ 7 ] described above. For this reason, teaching on PPS should be integrated into the core curriculum and draw on a variety of disciplines.

A better understanding of the science behind PPS [ 1 , 2 ] is needed for both educators and learners. There is also a need to move learners beyond reductionist models of communication skills towards more theory-driven approaches of person-centredness, as identified by Bansal [ 53 ]. We need to convey to learners that skilled communication is not about platitudes, but can make a difference to recovery and addresses the current epistemic gap between clinicians and their patients [ 8 , 13 ].

Future educational research should focus on the most effective methods to improve the knowledge base of both educators and students and how best to evaluate the success of future teaching interventions. Skills in person-centred communication and explanation [ 3 ] need to be taught, alongside those in reflection and challenging prejudice.

We identified four important themes which underpin the challenges of teaching medical undergraduates about persistent physical symptoms. Educational faculties need to find ways to integrate teaching into current programmes and work around the existing barriers to successful implementation and evaluation of teaching about these common and limiting conditions. Examples of successful teaching on chronic non-cancer pain were found in the literature. These tended to articulate the science behind symptoms and often included experiential elements. Such examples should be used to inform an approach for teaching about other forms of PPS. Importantly, robust evaluation that accounts for the complexity of the taught environment is needed to ensure our teaching is making a difference, both for our learners and the patients they will go on to encounter.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Functional connectivity changes in the brain of adolescents with internet addiction: A systematic literature review of imaging studies

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

Affiliation Child and Adolescent Mental Health, Department of Brain Sciences, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Roles Conceptualization, Supervision, Validation, Writing – review & editing

* E-mail: [email protected]

Affiliation Behavioural Brain Sciences Unit, Population Policy Practice Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Max L. Y. Chang,
Irene O. Lee

Published: June 4, 2024
https://doi.org/10.1371/journal.pmen.0000022
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Internet usage has seen a stark global rise over the last few decades, particularly among adolescents and young people, who have also been diagnosed increasingly with internet addiction (IA). IA impacts several neural networks that influence an adolescent’s behaviour and development. This article issued a literature review on the resting-state and task-based functional magnetic resonance imaging (fMRI) studies to inspect the consequences of IA on the functional connectivity (FC) in the adolescent brain and its subsequent effects on their behaviour and development. A systematic search was conducted from two databases, PubMed and PsycINFO, to select eligible articles according to the inclusion and exclusion criteria. Eligibility criteria was especially stringent regarding the adolescent age range (10–19) and formal diagnosis of IA. Bias and quality of individual studies were evaluated. The fMRI results from 12 articles demonstrated that the effects of IA were seen throughout multiple neural networks: a mix of increases/decreases in FC in the default mode network; an overall decrease in FC in the executive control network; and no clear increase or decrease in FC within the salience network and reward pathway. The FC changes led to addictive behaviour and tendencies in adolescents. The subsequent behavioural changes are associated with the mechanisms relating to the areas of cognitive control, reward valuation, motor coordination, and the developing adolescent brain. Our results presented the FC alterations in numerous brain regions of adolescents with IA leading to the behavioural and developmental changes. Research on this topic had a low frequency with adolescent samples and were primarily produced in Asian countries. Future research studies of comparing results from Western adolescent samples provide more insight on therapeutic intervention.

Citation: Chang MLY, Lee IO (2024) Functional connectivity changes in the brain of adolescents with internet addiction: A systematic literature review of imaging studies. PLOS Ment Health 1(1): e0000022. https://doi.org/10.1371/journal.pmen.0000022

Editor: Kizito Omona, Uganda Martyrs University, UGANDA

Received: December 29, 2023; Accepted: March 18, 2024; Published: June 4, 2024

Copyright: © 2024 Chang, Lee. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The behavioural addiction brought on by excessive internet use has become a rising source of concern [ 1 ] since the last decade. According to clinical studies, individuals with Internet Addiction (IA) or Internet Gaming Disorder (IGD) may have a range of biopsychosocial effects and is classified as an impulse-control disorder owing to its resemblance to pathological gambling and substance addiction [ 2 , 3 ]. IA has been defined by researchers as a person’s inability to resist the urge to use the internet, which has negative effects on their psychological well-being as well as their social, academic, and professional lives [ 4 ]. The symptoms can have serious physical and interpersonal repercussions and are linked to mood modification, salience, tolerance, impulsivity, and conflict [ 5 ]. In severe circumstances, people may experience severe pain in their bodies or health issues like carpal tunnel syndrome, dry eyes, irregular eating and disrupted sleep [ 6 ]. Additionally, IA is significantly linked to comorbidities with other psychiatric disorders [ 7 ].

Stevens et al (2021) reviewed 53 studies including 17 countries and reported the global prevalence of IA was 3.05% [ 8 ]. Asian countries had a higher prevalence (5.1%) than European countries (2.7%) [ 8 ]. Strikingly, adolescents and young adults had a global IGD prevalence rate of 9.9% which matches previous literature that reported historically higher prevalence among adolescent populations compared to adults [ 8 , 9 ]. Over 80% of adolescent population in the UK, the USA, and Asia have direct access to the internet [ 10 ]. Children and adolescents frequently spend more time on media (possibly 7 hours and 22 minutes per day) than at school or sleeping [ 11 ]. Developing nations have also shown a sharp rise in teenage internet usage despite having lower internet penetration rates [ 10 ]. Concerns regarding the possible harms that overt internet use could do to adolescents and their development have arisen because of this surge, especially the significant impacts by the COVID-19 pandemic [ 12 ]. The growing prevalence and neurocognitive consequences of IA among adolescents makes this population a vital area of study [ 13 ].

Adolescence is a crucial developmental stage during which people go through significant changes in their biology, cognition, and personalities [ 14 ]. Adolescents’ emotional-behavioural functioning is hyperactivated, which creates risk of psychopathological vulnerability [ 15 ]. In accordance with clinical study results [ 16 ], this emotional hyperactivity is supported by a high level of neuronal plasticity. This plasticity enables teenagers to adapt to the numerous physical and emotional changes that occur during puberty as well as develop communication techniques and gain independence [ 16 ]. However, the strong neuronal plasticity is also associated with risk-taking and sensation seeking [ 17 ] which may lead to IA.

Despite the fact that the precise neuronal mechanisms underlying IA are still largely unclear, functional magnetic resonance imaging (fMRI) method has been used by scientists as an important framework to examine the neuropathological changes occurring in IA, particularly in the form of functional connectivity (FC) [ 18 ]. fMRI research study has shown that IA alters both the functional and structural makeup of the brain [ 3 ].

We hypothesise that IA has widespread neurological alteration effects rather than being limited to a few specific brain regions. Further hypothesis holds that according to these alterations of FC between the brain regions or certain neural networks, adolescents with IA would experience behavioural changes. An investigation of these domains could be useful for creating better procedures and standards as well as minimising the negative effects of overt internet use. This literature review aims to summarise and analyse the evidence of various imaging studies that have investigated the effects of IA on the FC in adolescents. This will be addressed through two research questions:

How does internet addiction affect the functional connectivity in the adolescent brain?
How is adolescent behaviour and development impacted by functional connectivity changes due to internet addiction?

The review protocol was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (see S1 Checklist ).

Search strategy and selection process

A systematic search was conducted up until April 2023 from two sources of database, PubMed and PsycINFO, using a range of terms relevant to the title and research questions (see full list of search terms in S1 Appendix ). All the searched articles can be accessed in the S1 Data . The eligible articles were selected according to the inclusion and exclusion criteria. Inclusion criteria used for the present review were: (i) participants in the studies with clinical diagnosis of IA; (ii) participants between the ages of 10 and 19; (iii) imaging research investigations; (iv) works published between January 2013 and April 2023; (v) written in English language; (vi) peer-reviewed papers and (vii) full text. The numbers of articles excluded due to not meeting the inclusion criteria are shown in Fig 1 . Each study’s title and abstract were screened for eligibility.

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https://doi.org/10.1371/journal.pmen.0000022.g001

Quality appraisal

Full texts of all potentially relevant studies were then retrieved and further appraised for eligibility. Furthermore, articles were critically appraised based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework to evaluate the individual study for both quality and bias. The subsequent quality levels were then appraised to each article and listed as either low, moderate, or high.

Data collection process

Data that satisfied the inclusion requirements was entered into an excel sheet for data extraction and further selection. An article’s author, publication year, country, age range, participant sample size, sex, area of interest, measures, outcome and article quality were all included in the data extraction spreadsheet. Studies looking at FC, for instance, were grouped, while studies looking at FC in specific area were further divided into sub-groups.

Data synthesis and analysis

Articles were classified according to their location in the brain as well as the network or pathway they were a part of to create a coherent narrative between the selected studies. Conclusions concerning various research trends relevant to particular groupings were drawn from these groupings and subgroupings. To maintain the offered information in a prominent manner, these assertions were entered into the data extraction excel spreadsheet.

With the search performed on the selected databases, 238 articles in total were identified (see Fig 1 ). 15 duplicated articles were eliminated, and another 6 items were removed for various other reasons. Title and abstract screening eliminated 184 articles because they were not in English (number of article, n, = 7), did not include imaging components (n = 47), had adult participants (n = 53), did not have a clinical diagnosis of IA (n = 19), did not address FC in the brain (n = 20), and were published outside the desired timeframe (n = 38). A further 21 papers were eliminated for failing to meet inclusion requirements after the remaining 33 articles underwent full-text eligibility screening. A total of 12 papers were deemed eligible for this review analysis.

Characteristics of the included studies, as depicted in the data extraction sheet in Table 1 provide information of the author(s), publication year, sample size, study location, age range, gender, area of interest, outcome, measures used and quality appraisal. Most of the studies in this review utilised resting state functional magnetic resonance imaging techniques (n = 7), with several studies demonstrating task-based fMRI procedures (n = 3), and the remaining studies utilising whole-brain imaging measures (n = 2). The studies were all conducted in Asiatic countries, specifically coming from China (8), Korea (3), and Indonesia (1). Sample sizes ranged from 12 to 31 participants with most of the imaging studies having comparable sample sizes. Majority of the studies included a mix of male and female participants (n = 8) with several studies having a male only participant pool (n = 3). All except one of the mixed gender studies had a majority male participant pool. One study did not disclose their data on the gender demographics of their experiment. Study years ranged from 2013–2022, with 2 studies in 2013, 3 studies in 2014, 3 studies in 2015, 1 study in 2017, 1 study in 2020, 1 study in 2021, and 1 study in 2022.

https://doi.org/10.1371/journal.pmen.0000022.t001

(1) How does internet addiction affect the functional connectivity in the adolescent brain?

The included studies were organised according to the brain region or network that they were observing. The specific networks affected by IA were the default mode network, executive control system, salience network and reward pathway. These networks are vital components of adolescent behaviour and development [ 31 ]. The studies in each section were then grouped into subsections according to their specific brain regions within their network.

Default mode network (DMN)/reward network.

Out of the 12 studies, 3 have specifically studied the default mode network (DMN), and 3 observed whole-brain FC that partially included components of the DMN. The effect of IA on the various centres of the DMN was not unilaterally the same. The findings illustrate a complex mix of increases and decreases in FC depending on the specific region in the DMN (see Table 2 and Fig 2 ). The alteration of FC in posterior cingulate cortex (PCC) in the DMN was the most frequently reported area in adolescents with IA, which involved in attentional processes [ 32 ], but Lee et al. (2020) additionally found alterations of FC in other brain regions, such as anterior insula cortex, a node in the DMN that controls the integration of motivational and cognitive processes [ 20 ].

https://doi.org/10.1371/journal.pmen.0000022.g002

The overall changes of functional connectivity in the brain network including default mode network (DMN), executive control network (ECN), salience network (SN) and reward network. IA = Internet Addiction, FC = Functional Connectivity.

https://doi.org/10.1371/journal.pmen.0000022.t002

Ding et al. (2013) revealed altered FC in the cerebellum, the middle temporal gyrus, and the medial prefrontal cortex (mPFC) [ 22 ]. They found that the bilateral inferior parietal lobule, left superior parietal lobule, and right inferior temporal gyrus had decreased FC, while the bilateral posterior lobe of the cerebellum and the medial temporal gyrus had increased FC [ 22 ]. The right middle temporal gyrus was found to have 111 cluster voxels (t = 3.52, p<0.05) and the right inferior parietal lobule was found to have 324 cluster voxels (t = -4.07, p<0.05) with an extent threshold of 54 voxels (figures above this threshold are deemed significant) [ 22 ]. Additionally, there was a negative correlation, with 95 cluster voxels (p<0.05) between the FC of the left superior parietal lobule and the PCC with the Chen Internet Addiction Scores (CIAS) which are used to determine the severity of IA [ 22 ]. On the other hand, in regions of the reward system, connection with the PCC was positively connected with CIAS scores [ 22 ]. The most significant was the right praecuneus with 219 cluster voxels (p<0.05) [ 22 ]. Wang et al. (2017) also discovered that adolescents with IA had 33% less FC in the left inferior parietal lobule and 20% less FC in the dorsal mPFC [ 24 ]. A potential connection between the effects of substance use and overt internet use is revealed by the generally decreased FC in these areas of the DMN of teenagers with drug addiction and IA [ 35 ].

The putamen was one of the main regions of reduced FC in adolescents with IA [ 19 ]. The putamen and the insula-operculum demonstrated significant group differences regarding functional connectivity with a cluster size of 251 and an extent threshold of 250 (Z = 3.40, p<0.05) [ 19 ]. The molecular mechanisms behind addiction disorders have been intimately connected to decreased striatal dopaminergic function [ 19 ], making this function crucial.

Executive Control Network (ECN).

5 studies out of 12 have specifically viewed parts of the executive control network (ECN) and 3 studies observed whole-brain FC. The effects of IA on the ECN’s constituent parts were consistent across all the studies examined for this analysis (see Table 2 and Fig 3 ). The results showed a notable decline in all the ECN’s major centres. Li et al. (2014) used fMRI imaging and a behavioural task to study response inhibition in adolescents with IA [ 25 ] and found decreased activation at the striatum and frontal gyrus, particularly a reduction in FC at inferior frontal gyrus, in the IA group compared to controls [ 25 ]. The inferior frontal gyrus showed a reduction in FC in comparison to the controls with a cluster size of 71 (t = 4.18, p<0.05) [ 25 ]. In addition, the frontal-basal ganglia pathways in the adolescents with IA showed little effective connection between areas and increased degrees of response inhibition [ 25 ].

https://doi.org/10.1371/journal.pmen.0000022.g003

Lin et al. (2015) found that adolescents with IA demonstrated disrupted corticostriatal FC compared to controls [ 33 ]. The corticostriatal circuitry experienced decreased connectivity with the caudate, bilateral anterior cingulate cortex (ACC), as well as the striatum and frontal gyrus [ 33 ]. The inferior ventral striatum showed significantly reduced FC with the subcallosal ACC and caudate head with cluster size of 101 (t = -4.64, p<0.05) [ 33 ]. Decreased FC in the caudate implies dysfunction of the corticostriatal-limbic circuitry involved in cognitive and emotional control [ 36 ]. The decrease in FC in both the striatum and frontal gyrus is related to inhibitory control, a common deficit seen with disruptions with the ECN [ 33 ].

The dorsolateral prefrontal cortex (DLPFC), ACC, and right supplementary motor area (SMA) of the prefrontal cortex were all found to have significantly decreased grey matter volume [ 29 ]. In addition, the DLPFC, insula, temporal cortices, as well as significant subcortical regions like the striatum and thalamus, showed decreased FC [ 29 ]. According to Tremblay (2009), the striatum plays a significant role in the processing of rewards, decision-making, and motivation [ 37 ]. Chen et al. (2020) reported that the IA group demonstrated increased impulsivity as well as decreased reaction inhibition using a Stroop colour-word task [ 26 ]. Furthermore, Chen et al. (2020) observed that the left DLPFC and dorsal striatum experienced a negative connection efficiency value, specifically demonstrating that the dorsal striatum activity suppressed the left DLPFC [ 27 ].

Salience network (SN).

Out of the 12 chosen studies, 3 studies specifically looked at the salience network (SN) and 3 studies have observed whole-brain FC. Relative to the DMN and ECN, the findings on the SN were slightly sparser. Despite this, adolescents with IA demonstrated a moderate decrease in FC, as well as other measures like fibre connectivity and cognitive control, when compared to healthy control (see Table 2 and Fig 4 ).

https://doi.org/10.1371/journal.pmen.0000022.g004

Xing et al. (2014) used both dorsal anterior cingulate cortex (dACC) and insula to test FC changes in the SN of adolescents with IA and found decreased structural connectivity in the SN as well as decreased fractional anisotropy (FA) that correlated to behaviour performance in the Stroop colour word-task [ 21 ]. They examined the dACC and insula to determine whether the SN’s disrupted connectivity may be linked to the SN’s disruption of regulation, which would explain the impaired cognitive control seen in adolescents with IA. However, researchers did not find significant FC differences in the SN when compared to the controls [ 21 ]. These results provided evidence for the structural changes in the interconnectivity within SN in adolescents with IA.

Wang et al. (2017) investigated network interactions between the DMN, ECN, SN and reward pathway in IA subjects [ 24 ] (see Fig 5 ), and found 40% reduction of FC between the DMN and specific regions of the SN, such as the insula, in comparison to the controls (p = 0.008) [ 24 ]. The anterior insula and dACC are two areas that are impacted by this altered FC [ 24 ]. This finding supports the idea that IA has similar neurobiological abnormalities with other addictive illnesses, which is in line with a study that discovered disruptive changes in the SN and DMN’s interaction in cocaine addiction [ 38 ]. The insula has also been linked to the intensity of symptoms and has been implicated in the development of IA [ 39 ].

“+” indicates an increase in behaivour; “-”indicates a decrease in behaviour; solid arrows indicate a direct network interaction; and the dotted arrows indicates a reduction in network interaction. This diagram depicts network interactions juxtaposed with engaging in internet related behaviours. Through the neural interactions, the diagram illustrates how the networks inhibit or amplify internet usage and vice versa. Furthermore, it demonstrates how the SN mediates both the DMN and ECN.

https://doi.org/10.1371/journal.pmen.0000022.g005

(2) How is adolescent behaviour and development impacted by functional connectivity changes due to internet addiction?

The findings that IA individuals demonstrate an overall decrease in FC in the DMN is supported by numerous research [ 24 ]. Drug addict populations also exhibited similar decline in FC in the DMN [ 40 ]. The disruption of attentional orientation and self-referential processing for both substance and behavioural addiction was then hypothesised to be caused by DMN anomalies in FC [ 41 ].

In adolescents with IA, decline of FC in the parietal lobule affects visuospatial task-related behaviour [ 22 ], short-term memory [ 42 ], and the ability of controlling attention or restraining motor responses during response inhibition tests [ 42 ]. Cue-induced gaming cravings are influenced by the DMN [ 43 ]. A visual processing area called the praecuneus links gaming cues to internal information [ 22 ]. A meta-analysis found that the posterior cingulate cortex activity of individuals with IA during cue-reactivity tasks was connected with their gaming time [ 44 ], suggesting that excessive gaming may impair DMN function and that individuals with IA exert more cognitive effort to control it. Findings for the behavioural consequences of FC changes in the DMN illustrate its underlying role in regulating impulsivity, self-monitoring, and cognitive control.

Furthermore, Ding et al. (2013) reported an activation of components of the reward pathway, including areas like the nucleus accumbens, praecuneus, SMA, caudate, and thalamus, in connection to the DMN [ 22 ]. The increased FC of the limbic and reward networks have been confirmed to be a major biomarker for IA [ 45 , 46 ]. The increased reinforcement in these networks increases the strength of reward stimuli and makes it more difficult for other networks, namely the ECN, to down-regulate the increased attention [ 29 ] (See Fig 5 ).

Executive control network (ECN).

The numerous IA-affected components in the ECN have a role in a variety of behaviours that are connected to both response inhibition and emotional regulation [ 47 ]. For instance, brain regions like the striatum, which are linked to impulsivity and the reward system, are heavily involved in the act of playing online games [ 47 ]. Online game play activates the striatum, which suppresses the left DLPFC in ECN [ 48 ]. As a result, people with IA may find it difficult to control their want to play online games [ 48 ]. This system thus causes impulsive and protracted gaming conduct, lack of inhibitory control leading to the continued use of internet in an overt manner despite a variety of negative effects, personal distress, and signs of psychological dependence [ 33 ] (See Fig 5 ).

Wang et al. (2017) report that disruptions in cognitive control networks within the ECN are frequently linked to characteristics of substance addiction [ 24 ]. With samples that were addicted to heroin and cocaine, previous studies discovered abnormal FC in the ECN and the PFC [ 49 ]. Electronic gaming is known to promote striatal dopamine release, similar to drug addiction [ 50 ]. According to Drgonova and Walther (2016), it is hypothesised that dopamine could stimulate the reward system of the striatum in the brain, leading to a loss of impulse control and a failure of prefrontal lobe executive inhibitory control [ 51 ]. In the end, IA’s resemblance to drug use disorders may point to vital biomarkers or underlying mechanisms that explain how cognitive control and impulsive behaviour are related.

A task-related fMRI study found that the decrease in FC between the left DLPFC and dorsal striatum was congruent with an increase in impulsivity in adolescents with IA [ 26 ]. The lack of response inhibition from the ECN results in a loss of control over internet usage and a reduced capacity to display goal-directed behaviour [ 33 ]. Previous studies have linked the alteration of the ECN in IA with higher cue reactivity and impaired ability to self-regulate internet specific stimuli [ 52 ].

Salience network (SN)/ other networks.

Xing et al. (2014) investigated the significance of the SN regarding cognitive control in teenagers with IA [ 21 ]. The SN, which is composed of the ACC and insula, has been demonstrated to control dynamic changes in other networks to modify cognitive performance [ 21 ]. The ACC is engaged in conflict monitoring and cognitive control, according to previous neuroimaging research [ 53 ]. The insula is a region that integrates interoceptive states into conscious feelings [ 54 ]. The results from Xing et al. (2014) showed declines in the SN regarding its structural connectivity and fractional anisotropy, even though they did not observe any appreciable change in FC in the IA participants [ 21 ]. Due to the small sample size, the results may have indicated that FC methods are not sensitive enough to detect the significant functional changes [ 21 ]. However, task performance behaviours associated with impaired cognitive control in adolescents with IA were correlated with these findings [ 21 ]. Our comprehension of the SN’s broader function in IA can be enhanced by this relationship.

Research study supports the idea that different psychological issues are caused by the functional reorganisation of expansive brain networks, such that strong association between SN and DMN may provide neurological underpinnings at the system level for the uncontrollable character of internet-using behaviours [ 24 ]. In the study by Wang et al. (2017), the decreased interconnectivity between the SN and DMN, comprising regions such the DLPFC and the insula, suggests that adolescents with IA may struggle to effectively inhibit DMN activity during internally focused processing, leading to poorly managed desires or preoccupations to use the internet [ 24 ] (See Fig 5 ). Subsequently, this may cause a failure to inhibit DMN activity as well as a restriction of ECN functionality [ 55 ]. As a result, the adolescent experiences an increased salience and sensitivity towards internet addicting cues making it difficult to avoid these triggers [ 56 ].

The primary aim of this review was to present a summary of how internet addiction impacts on the functional connectivity of adolescent brain. Subsequently, the influence of IA on the adolescent brain was compartmentalised into three sections: alterations of FC at various brain regions, specific FC relationships, and behavioural/developmental changes. Overall, the specific effects of IA on the adolescent brain were not completely clear, given the variety of FC changes. However, there were overarching behavioural, network and developmental trends that were supported that provided insight on adolescent development.

The first hypothesis that was held about this question was that IA was widespread and would be regionally similar to substance-use and gambling addiction. After conducting a review of the information in the chosen articles, the hypothesis was predictably supported. The regions of the brain affected by IA are widespread and influence multiple networks, mainly DMN, ECN, SN and reward pathway. In the DMN, there was a complex mix of increases and decreases within the network. However, in the ECN, the alterations of FC were more unilaterally decreased, but the findings of SN and reward pathway were not quite clear. Overall, the FC changes within adolescents with IA are very much network specific and lay a solid foundation from which to understand the subsequent behaviour changes that arise from the disorder.

The second hypothesis placed emphasis on the importance of between network interactions and within network interactions in the continuation of IA and the development of its behavioural symptoms. The results from the findings involving the networks, DMN, SN, ECN and reward system, support this hypothesis (see Fig 5 ). Studies confirm the influence of all these neural networks on reward valuation, impulsivity, salience to stimuli, cue reactivity and other changes that alter behaviour towards the internet use. Many of these changes are connected to the inherent nature of the adolescent brain.

There are multiple explanations that underlie the vulnerability of the adolescent brain towards IA related urges. Several of them have to do with the inherent nature and underlying mechanisms of the adolescent brain. Children’s emotional, social, and cognitive capacities grow exponentially during childhood and adolescence [ 57 ]. Early teenagers go through a process called “social reorientation” that is characterised by heightened sensitivity to social cues and peer connections [ 58 ]. Adolescents’ improvements in their social skills coincide with changes in their brains’ anatomical and functional organisation [ 59 ]. Functional hubs exhibit growing connectivity strength [ 60 ], suggesting increased functional integration during development. During this time, the brain’s functional networks change from an anatomically dominant structure to a scattered architecture [ 60 ].

The adolescent brain is very responsive to synaptic reorganisation and experience cues [ 61 ]. As a result, one of the distinguishing traits of the maturation of adolescent brains is the variation in neural network trajectory [ 62 ]. Important weaknesses of the adolescent brain that may explain the neurobiological change brought on by external stimuli are illustrated by features like the functional gaps between networks and the inadequate segregation of networks [ 62 ].

The implications of these findings towards adolescent behaviour are significant. Although the exact changes and mechanisms are not fully clear, the observed changes in functional connectivity have the capacity of influencing several aspects of adolescent development. For example, functional connectivity has been utilised to investigate attachment styles in adolescents [ 63 ]. It was observed that adolescent attachment styles were negatively associated with caudate-prefrontal connectivity, but positively with the putamen-visual area connectivity [ 63 ]. Both named areas were also influenced by the onset of internet addiction, possibly providing a connection between the two. Another study associated neighbourhood/socioeconomic disadvantage with functional connectivity alterations in the DMN and dorsal attention network [ 64 ]. The study also found multivariate brain behaviour relationships between the altered/disadvantaged functional connectivity and mental health and cognition [ 64 ]. This conclusion supports the notion that the functional connectivity alterations observed in IA are associated with specific adolescent behaviours as well as the fact that functional connectivity can be utilised as a platform onto which to compare various neurologic conditions.

Limitations/strengths

There were several limitations that were related to the conduction of the review as well as the data extracted from the articles. Firstly, the study followed a systematic literature review design when analysing the fMRI studies. The data pulled from these imaging studies were namely qualitative and were subject to bias contrasting the quantitative nature of statistical analysis. Components of the study, such as sample sizes, effect sizes, and demographics were not weighted or controlled. The second limitation brought up by a similar review was the lack of a universal consensus of terminology given IA [ 47 ]. Globally, authors writing about this topic use an array of terminology including online gaming addiction, internet addiction, internet gaming disorder, and problematic internet use. Often, authors use multiple terms interchangeably which makes it difficult to depict the subtle similarities and differences between the terms.

Reviewing the explicit limitations in each of the included studies, two major limitations were brought up in many of the articles. One was relating to the cross-sectional nature of the included studies. Due to the inherent qualities of a cross-sectional study, the studies did not provide clear evidence that IA played a causal role towards the development of the adolescent brain. While several biopsychosocial factors mediate these interactions, task-based measures that combine executive functions with imaging results reinforce the assumed connection between the two that is utilised by the papers studying IA. Another limitation regarded the small sample size of the included studies, which averaged to around 20 participants. The small sample size can influence the generalisation of the results as well as the effectiveness of statistical analyses. Ultimately, both included study specific limitations illustrate the need for future studies to clarify the causal relationship between the alterations of FC and the development of IA.

Another vital limitation was the limited number of studies applying imaging techniques for investigations on IA in adolescents were a uniformly Far East collection of studies. The reason for this was because the studies included in this review were the only fMRI studies that were found that adhered to the strict adolescent age restriction. The adolescent age range given by the WHO (10–19 years old) [ 65 ] was strictly followed. It is important to note that a multitude of studies found in the initial search utilised an older adolescent demographic that was slightly higher than the WHO age range and had a mean age that was outside of the limitations. As a result, the results of this review are biased and based on the 12 studies that met the inclusion and exclusion criteria.

Regarding the global nature of the research, although the journals that the studies were published in were all established western journals, the collection of studies were found to all originate from Asian countries, namely China and Korea. Subsequently, it pulls into question if the results and measures from these studies are generalisable towards a western population. As stated previously, Asian countries have a higher prevalence of IA, which may be the reasoning to why the majority of studies are from there [ 8 ]. However, in an additional search including other age groups, it was found that a high majority of all FC studies on IA were done in Asian countries. Interestingly, western papers studying fMRI FC were primarily focused on gambling and substance-use addiction disorders. The western papers on IA were less focused on fMRI FC but more on other components of IA such as sleep, game-genre, and other non-imaging related factors. This demonstrated an overall lack of western fMRI studies on IA. It is important to note that both western and eastern fMRI studies on IA presented an overall lack on children and adolescents in general.

Despite the several limitations, this review provided a clear reflection on the state of the data. The strengths of the review include the strict inclusion/exclusion criteria that filtered through studies and only included ones that contained a purely adolescent sample. As a result, the information presented in this review was specific to the review’s aims. Given the sparse nature of adolescent specific fMRI studies on the FC changes in IA, this review successfully provided a much-needed niche representation of adolescent specific results. Furthermore, the review provided a thorough functional explanation of the DMN, ECN, SN and reward pathway making it accessible to readers new to the topic.

Future directions and implications

Through the search process of the review, there were more imaging studies focused on older adolescence and adulthood. Furthermore, finding a review that covered a strictly adolescent population, focused on FC changes, and was specifically depicting IA, was proven difficult. Many related reviews, such as Tereshchenko and Kasparov (2019), looked at risk factors related to the biopsychosocial model, but did not tackle specific alterations in specific structural or functional changes in the brain [ 66 ]. Weinstein (2017) found similar structural and functional results as well as the role IA has in altering response inhibition and reward valuation in adolescents with IA [ 47 ]. Overall, the accumulated findings only paint an emerging pattern which aligns with similar substance-use and gambling disorders. Future studies require more specificity in depicting the interactions between neural networks, as well as more literature on adolescent and comorbid populations. One future field of interest is the incorporation of more task-based fMRI data. Advances in resting-state fMRI methods have yet to be reflected or confirmed in task-based fMRI methods [ 62 ]. Due to the fact that network connectivity is shaped by different tasks, it is critical to confirm that the findings of the resting state fMRI studies also apply to the task based ones [ 62 ]. Subsequently, work in this area will confirm if intrinsic connectivity networks function in resting state will function similarly during goal directed behaviour [ 62 ]. An elevated focus on adolescent populations as well as task-based fMRI methodology will help uncover to what extent adolescent network connectivity maturation facilitates behavioural and cognitive development [ 62 ].

A treatment implication is the potential usage of bupropion for the treatment of IA. Bupropion has been previously used to treat patients with gambling disorder and has been effective in decreasing overall gambling behaviour as well as money spent while gambling [ 67 ]. Bae et al. (2018) found a decrease in clinical symptoms of IA in line with a 12-week bupropion treatment [ 31 ]. The study found that bupropion altered the FC of both the DMN and ECN which in turn decreased impulsivity and attentional deficits for the individuals with IA [ 31 ]. Interventions like bupropion illustrate the importance of understanding the fundamental mechanisms that underlie disorders like IA.

The goal for this review was to summarise the current literature on functional connectivity changes in adolescents with internet addiction. The findings answered the primary research questions that were directed at FC alterations within several networks of the adolescent brain and how that influenced their behaviour and development. Overall, the research demonstrated several wide-ranging effects that influenced the DMN, SN, ECN, and reward centres. Additionally, the findings gave ground to important details such as the maturation of the adolescent brain, the high prevalence of Asian originated studies, and the importance of task-based studies in this field. The process of making this review allowed for a thorough understanding IA and adolescent brain interactions.

Given the influx of technology and media in the lives and education of children and adolescents, an increase in prevalence and focus on internet related behavioural changes is imperative towards future children/adolescent mental health. Events such as COVID-19 act to expose the consequences of extended internet usage on the development and lifestyle of specifically young people. While it is important for parents and older generations to be wary of these changes, it is important for them to develop a base understanding of the issue and not dismiss it as an all-bad or all-good scenario. Future research on IA will aim to better understand the causal relationship between IA and psychological symptoms that coincide with it. The current literature regarding functional connectivity changes in adolescents is limited and requires future studies to test with larger sample sizes, comorbid populations, and populations outside Far East Asia.

This review aimed to demonstrate the inner workings of how IA alters the connection between the primary behavioural networks in the adolescent brain. Predictably, the present answers merely paint an unfinished picture that does not necessarily depict internet usage as overwhelmingly positive or negative. Alternatively, the research points towards emerging patterns that can direct individuals on the consequences of certain variables or risk factors. A clearer depiction of the mechanisms of IA would allow physicians to screen and treat the onset of IA more effectively. Clinically, this could be in the form of more streamlined and accurate sessions of CBT or family therapy, targeting key symptoms of IA. Alternatively clinicians could potentially prescribe treatment such as bupropion to target FC in certain regions of the brain. Furthermore, parental education on IA is another possible avenue of prevention from a public health standpoint. Parents who are aware of the early signs and onset of IA will more effectively handle screen time, impulsivity, and minimize the risk factors surrounding IA.

Additionally, an increased attention towards internet related fMRI research is needed in the West, as mentioned previously. Despite cultural differences, Western countries may hold similarities to the eastern countries with a high prevalence of IA, like China and Korea, regarding the implications of the internet and IA. The increasing influence of the internet on the world may contribute to an overall increase in the global prevalence of IA. Nonetheless, the high saturation of eastern studies in this field should be replicated with a Western sample to determine if the same FC alterations occur. A growing interest in internet related research and education within the West will hopefully lead to the knowledge of healthier internet habits and coping strategies among parents with children and adolescents. Furthermore, IA research has the potential to become a crucial proxy for which to study adolescent brain maturation and development.

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Acknowledgments

The authors thank https://www.stockio.com/free-clipart/brain-01 (with attribution to Stockio.com); and https://www.rawpixel.com/image/6442258/png-sticker-vintage for the free images used to create Figs 2 – 4 .

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Case report
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Published: 25 May 2024

Wandering spleen presenting in the form of right sided pelvic mass and pain in a patient with AD-PCKD: a case report and review of the literature

Yitagesu aberra shibiru ORCID: orcid.org/0000-0003-3645-9115 1 ,
Sahlu wondimu 1 &
Wassie almaw 1

Journal of Medical Case Reports volume 18 , Article number: 259 ( 2024 ) Cite this article

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Wandering spleen is a rare clinical entity in which the spleen is hypermobile and migrate from its normal left hypochondriac position to any other abdominal or pelvic position as a result of absent or abnormal laxity of the suspensory ligaments (Puranik in Gastroenterol Rep 5:241, 2015, Evangelos in Am J Case Rep. 21, 2020) which in turn is due to either congenital laxity or precipitated by trauma, pregnancy, or connective tissue disorder (Puranik in Gastroenterol Rep 5:241, 2015, Jawad in Cureus 15, 2023). It may be asymptomatic and accidentally discovered for imaging done for other reasons or cause symptoms as a result of torsion of its pedicle and infarction or compression on adjacent viscera on its new position. It needs to be surgically treated upon discovery either by splenopexy or splectomy based on whether the spleen is mobile or not.

Case presentation

We present a case of 39 years old female Ethiopian patient who presented to us complaining constant lower abdominal pain especially on the right side associated with swelling of one year which got worse over the preceding few months of her presentation to our facility. She is primiparous with delivery by C/section and a known case of HIV infection on HAART. Physical examination revealed a right lower quadrant well defined, fairly mobile and slightly tender swelling. Hematologic investigations are unremarkable. Imaging with abdominopelvic U/S and CT-scan showed a predominantly cystic, hypo attenuating right sided pelvic mass with narrow elongated attachment to pancreatic tail and absent spleen in its normal position. CT also showed multiple different sized purely cystic lesions all over both kidneys and the pancreas compatible with AD polycystic kidney and pancreatic disease.

With a diagnosis of wandering possibly infarcted spleen, she underwent laparotomy, the finding being a fully infarcted spleen located on the right half of the upper pelvis with twisted pedicle and dense adhesions to the adjacent distal ileum and colon. Release of adhesions and splenectomy was done. Her post-operative course was uneventful.

Wandering spleen is a rare clinical condition that needs to be included in the list of differential diagnosis in patients presenting with lower abdominal and pelvic masses. As we have learnt from our case, a high index of suspicion is required to detect it early and intervene by doing splenopexy and thereby avoiding splenectomy and its related complications.

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Introduction

Wandering spleen is a rare clinical entity characterized by hypermobility of the spleen as a result of absence or abnormal laxity of its suspensory ligaments which in turn can be congenital or precipitated by a number of risk factors like repeated pregnancy, trauma, surgery or connective tissue disorder. The spleen therefore migrates from its normal left hypochondriac position, to other parts of the peritoneal cavity especially the pelvis [ 3 ]. Since the first case report in 1667, there have been less than 600 cases reported in the literature so far [ 1 , 3 ].

Wandering spleen can have different clinical presentations ranging from asymptomatic incidental finding on imaging to features of acute abdomen as a result of complete torsion of the pedicle and total infarction of the spleen or complete obstruction of adjacent hollow viscus due to pressure effect. Less dramatic presentation includes chronic lower abdominal pain, swelling and symptoms of partial obstruction of bowel especially of the colon [ 3 , 4 , 5 , 6 ].

Diagnosis is confirmed by imaging usually abdominal ultrasound or CT which reveals that the spleen is absent from its normal anatomical position but seen somewhere else in the new location within the peritoneal cavity [ 3 , 9 , 10 ]. Once diagnosed, surgical intervention is required either by splenopexy or splenectomy depending on the viability of the organ [ 3 , 5 ] and can be done laparoscopically or by laparotomy.

Owing to its rarity, a high index of suspicion is required and this condition should always be considered as a possible differential diagnosis in patients presenting with lower abdominal swelling and pain. We present this case to share our experience in diagnosing and managing such a rare pathology and once again bring it to the attention of fellow clinicians handling this sort of abdominal conditions.

Case summary

Our patient is a 39 years old female Primi-para Ethiopian, who presented with lower abdominal dull aching pain of one-year duration which got worse over the last few months associated with right lower abdominal swelling, easy fatigability, LGIF, loss of appetite and weight. She is a known case of RVI on HAART for the past 18yrs and hypertensive for the last 8 years for which she was taking enalapril and atenolol. Her only child was delivered by C/section 10 years ago.

On examination , she looked chronically sick with her vitals in the normal range. The abdomen was flat with a lower midline surgical scar and a visible round mass on the right paraumblical and lower quadrant areas. The mass was well defined, smooth surfaced, slightly tender and mobile (Fig. 1 —black arrow).

Black arrow shows the splenic mass, red arrow shows the stomach, cyan arrow shows previous CS scar

Her hematologic tests revealed WBC of 8.7 × 103, Hgb of 12.3 and PLT count of 544 × 10 3 . Serum electrolyte and liver function tests were all in the normal range. Creatinine was 1.4 mg/dl.

Abdominal ultrasound

Multiple bilateral renal, liver and pancreatic cysts. An ehcocomplex mainly hypoechoic, 13 cmx8cm well defined right sided abdomino-pelvic mass, with absent color Doppler flow. Spleen was not visualized in its normal anatomic site.

Contrast enhanced abdomino-pelvic CT

Described the mass as a hypoattenuating, well circumscribed lesion with no contrast enhancement located at right abdomino pelvic cavity (Fig. 2 ). Its long torsed pedicle could be traced to the region of the tail of the pancreas and the spleen was missing from its normal location. (Fig. 3 ) Majority of the renal parenchyma is almost replaced with different sized cystic lesions with imperceptible wall causing bilateral renal enlargement. (Fig. 3 ) The liver and the pancreas too is filled with similar cysts. The portal vein were not visualized and replaced by periportal enlarged collateral vessels. (Figs. 3 , 4 ).

Infarcted spleen

Absent spleen in the splenic fossa

Spleen seen in the abdomino-pelvic cavity

With a diagnosis of wandering spleen located in the right abdomino pelvic region with torsion of the pedicle and infarction, she was admitted and underwent laparotomy. Intraoperatively, dense adhesion encountered between the anterior abdominal wall, omentum, the wandering spleen and small bowel. The spleen was whitish, distended and grossly infarcted with its long stalk torsed > 360°. (Fig. 5 ) Adhesions were gently released and splenectomy done. The splenic mass was sent for biopsy.

The intra-op picture of our patient upon exploration

She was discharged on the 3rd postoperative day and her post-operative course was uneventful. She was seen after a month on follow up clinic with no report of complication. Her biopsy result showed splenic tissue. She got her pentavelant vaccine on the third week.

Wandering spleen is a rare clinical entity characterized by splenic hypermobility from its left hypochondriac position to any other abdominal or pelvic position caused by absent or abnormal laxity of the suspensory ligaments [ 1 , 2 ].

The first case of wandering spleen was reported by Von Horne in 1667. So far less than 600 cases are reported world wide [ 1 , 3 ].

Anatomically a normal spleen is found in the left hypochondriac region suspended by ligaments to the stomach, kidney, pancreas, colon and left hemi-diaphram by the gastrosplenic, splenorenal, pancreaticosplenic, splenocolic, splenophreni ligaments and presplenic folds [ 1 ]. Our patient presented with RLQ palpable abdominal mass which is against the commonest presentation being in the LLQ of the abdomen (Fig. 1 ).

It could result from either a developmental failure of the embryonic septum transversum to fuse properly with the posterior abdominal wall which results in absent/lax ligaments [ 4 ] or from acquired conditions that result in lax suspensory ligaments as in pregnancy or connective tissue disorders [ 3 ]. The spleen is found in any quadrant of the abdomen or the pelvis though mostly in the left quadrants attached only by a long and loose vascular pedicle. Our patient presented with RLQ mass.

It is mostly seen in multiparous women [ 4 ] though the incidence is found to be nearly equal in both sexes in the prepubertal age group [ 3 ]. Our patient was a Para 1 mother and presented with 01 year history of abdominal pain which got worse in the past 06 months. Otherwise she had no any other pressure symptoms. She had visible umbilical area mass which was mobile up on examination

Wandering spleen can have different presentation ranging from asymptomatic incidental finding on imaging or upon surgical exploration for other surgical conditions to a presentation that mimics acute abdomen [ 3 , 5 ]. Mostly it presents as an on and of type acute/ subacute non-specific abdominal pain due to torsion and spontaneous de-torsion of the loose splenic pedicle [ 3 , 4 ]. This chronic torsion results in congestion and splenomegaly [ 3 , 5 ]. Hence patients could have palpable mobile mass [ 6 ] which is the typical presentation of this patient. The other presentations are usually related to the mass effect of the enlarged spleen and patients could present with GOO, bowel obstruction, pancreatitis and urinary symptoms [ 3 , 6 ].

In some cases it is reported to be associated with some other disorders like gastric volvulus [ 7 ] and distal pancreatic volvulus [ 8 ].

Ultrasound is one of the imaging modalities to investigate patients whom we suspect had wandering spleen. It usually shows absent spleen in the splenic fossa and a comma shaped spleen in the abdomen or pelvis [ 9 ]. Doppler study might help us see the vascular condition and ads up to a better preoperative plan. CT scan shows absence of the spleen in the left upper quadrant, ovoid or comma-shaped abdominal mass, enlarged spleen, a whirled appearance of non-enhancing splenic vessels and signs of splenic hypo-perfusion: homogenous or heterogeneous decreased enhancement depending on the degree of infarction [ 3 , 9 , 10 ].

Our patient was scanned with US and showed 13*8 cm large midline abdomino-pelvic well defined oval mass which was predominantly solid with areas of cystic component with absent color Doppler flow. Otherwise the spleen was not visualized in the splenic fossa. Bilateral kidney and liver has multiple different sized cystic lesions. With this image Abdomino-pelvic CT was done and shows spleen is located in the lower abdomen and appears to have torsed vascular pedicle and the whole splenic parenchyma is hypodense and no enhancement seen. Majority of the renal parenchyma is almost replaced with different sized cystic lesions with imperceptible wall causing bilateral renal enlargement. The whole liver is filled with cystic lesions with imperceptible wall. The portal veins were not visualized and replaced by periportal enlarged collateral vessels (Figs. 6 , 7 ).

Usually surgical management is the rule once a patient is diagnosed with wandering spleen [ 3 , 5 ]. Most patients; 65% as reported in some studies will have torsion of the vascular pedicle at some point of their life [ 5 , 6 ]. Hence splenopexy or splenectomy shall be considered when a wandering spleen is found incidentally up on surgical exploration for some other purposes [ 6 ]. Complicated wandering spleen like infarcted, signs of hypersplenism, huge in size and splenic vein thrombosis needs splenectomy while others can be managed with splenopexy [ 3 , 5 , 6 ]. Nowadays though laparoscopic technique is the gold standard, open technique can be used for splenopexy and splenectomy [ 3 , 5 ].

Partial infraction of a wandering spleen might necessitate partial splenectomy and splenopexy or splenectomy and splenic implantation [ 6 , 11 ].

The spleen might get fixed by different methods [ 8 , 9 ].

Simple splenic fixation involves simple tacking the splenic capsule to the peritoneum

Retroperitoneal pouch splenopexy- Tissue [ 11 , 12 ]/Mesh splenopexy (sandwich technique) [ 13 ].

Omental and peritoneal pouch splenic fixation [ 14 ].

In our case, Spleen was absent from the normal anatomic splenic fossa and the spleen in the abdomino-pelvic area looks infarcted. Hence she was managed with splenectomy and the patient was extubated on table and having a stable postoperative course .

Wandering spleen is a rare form of splenic pathology. Such a rare pathology presents commonly as an acute torsion with infarction. Spleen in the RLQ with chronic torsion and infarction is a very rare presentation for wandering spleen. In addition there is no report of such a presentation in a patient with AD-PCKD.

Recommendation

We recommend Clinicians to consider wandering spleen in their differential diagnosis in a patient presenting with RLQ abdominal mass and chronic abdominal pain.

Availability of supporting data

Data related with this case report is available at Addis ababa university, Tikur Ambesa Tertiary Hospital.

Abbreviations

Autosomal dominant polycystic kidney disease

Blood pressure

Low grade intermittent fever

High active anti-retroviral therapy

Right lower quadrant

Retro viral infection

Hypertension

White blood cell count

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Acknowledgements

We would like to thank the managing team of this patient including all the ward staffs who played a great role in the peri-operative management of this patient. We also appreciate the support of our consultants, residents and member of the department of surgery and HPB unit. Our kind gratitude goes to the family of this patient for their unreserved support in post-operative period that helped for the fast recovery of this patient

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Yitagesu aberra shibiru, Sahlu wondimu & Wassie almaw

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Dr. Yitagesu Aberra, Main author of this case report, is an HPB surgery fellow in the department of surgery, college of health science, Addis Ababa University who was the leading surgeon in the management of this patient. Dr. Sahlu Wendimu is an HPB surgery subspecialist and Assistant professor of General Surgery who was the consultant in duty during the management of this patient. Dr.Wassie Almaw is a 2nd year pediatric surgery resident attaching at HPB surgery unit who took part in the management of this patient.

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shibiru, Y.a., wondimu, S. & almaw, W. Wandering spleen presenting in the form of right sided pelvic mass and pain in a patient with AD-PCKD: a case report and review of the literature. J Med Case Reports 18 , 259 (2024). https://doi.org/10.1186/s13256-024-04580-6

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Case Report
Open access
Published: 03 June 2024

Cytological diagnosis of patients with embryonal rhabdomyosarcoma of the cervix: case report and literature review

Xiaoxia Wei 1 , 2 &
Lei Li 1 , 2

Diagnostic Pathology volume 19 , Article number: 73 ( 2024 ) Cite this article

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Cervical embryonal rhabdomyosarcoma(ERMS) is a rare malignancy. To date, no cases of ERMS diagnosed by cervical cytology have been reported. In this study, we report a case of cervical ERMS identified by a liquid-based cytology test and cell blocks in a 46-year-old postmenopausal woman. We describe the cytological features of ERMS, with the aim of helping cytopathologists recognize this rare cervical tumor.

Rhabdomyosarcoma (RMS) is the most common malignant solid tumor in children [ 1 ], but RMS of the cervix is a rare disease in adults [ 2 ]. RMS can occur in any tissue in the body [ 3 ]. RMS occurs most frequently in the genitourinary tract and the head and neck [ 4 ]. Embryonal RMS (ERMS) displays the most common histology and can be further classified into the classic subtype, botryoid subtype, and spindle cell subtype [ 5 ]. The cytological characteristics of ERMS are not well-defined, and there are very few reports in the literature on the cytology of ERMS. We report the case of a 46-year-old perimenopausal woman diagnosed with ERMS by liquid-based cytology testing, cell block examination and immunohistochemistry. We describe the cytological features of ERMS as well as the cell-block and immunohistochemical findings and demonstrate that a definite diagnosis of ERMS can be made based on cytologic examination alone.

Case presentation

This 46-year-old female patient presented to a local hospital four months earlier with “intermenstrual bleeding,” and a physical examination revealed a cervical neoplasm. Cervical polypectomy and laser treatment were performed at the local hospital one month later, and the postoperative pathology revealed a polyp (no reports). There were a few recent bloody vaginal secretions, but no other discomfort occurred. The patient reached menarche at age 13. The patient had a total of 9 gestations, including 5 productions and 4 miscarriages. Gynecological physical examination revealed a 4 × 4 cm cervical neoplasm as well as blood and papilla of the cervical canal. Subsequently, cervical cytology and HPV typing were performed.

Then, a cervical smear was performed. Microscopically, we observed some small sheets of cells, small clusters of cells, and scattered small blue cells admixed with the normal squamous epithelium (Fig. 1 A). Most of the neoplastic cells had round to oval nuclei with high nuclear to cytoplasmic ratio, scant cytoplasm and indistinct cell border. The surfaces were layered with epithelial cells, and there were dark-stained small blue cells below. Most cells were small and blue, with little cytoplasm and irregular nuclei, and individual cells were somewhat tadpole- or ribbon-shaped. The nuclei were round to oval with evenly distributed coarse chromatin and inconspicuous nucleoli, and the cell size was slightly larger than that of normal lymphocytes (Fig. 1 B-D). The initial diagnosis was atypical cells that were considered to constitute a malignant tumor. Then, we made cell blocks from the remaining specimens, and the morphology revealed in the cell blocks was consistent with the cytopathological features of the cervical smear. The cell blocks showed polypoid tissue with mucus and inflammatory exudates under low magnification (Fig. 2 A). Examination under high magnification revealed that the tissue surface was covered with mucous gland epithelium, and dense small blue cells were distributed in a band-like manner under the epithelium. A cambium layer was observed, comprising a subepithelial condensation of undifferentiated cells. The cells were small and spindle-shaped, and the strap cells were interspersed (Fig. 2 B). On immunohistochemistry (IHC), the small blue cells were focally positive for desmin, MyoD1 (Fig. 2 C&D) and myogenin and negative for CK-P, ER and caldesmon. The final diagnosis from cervical cytology was malignant tumor cells predisposed to embryonal rhabdomyosarcoma.

Cervical smear showing small sheets of cells, small clusters of cells, and scattered small blue cells admixed with the normal squamous epithelium under low-power microscopy ( A , Papanicolaou stain, ×100). Most of the neoplastic cells had round to oval nuclei with high nuclear to cytoplasmic ratio, scant cytoplasm and indistinct cell border. The surface was layered with epithelial cells, and there were dark-stained small blue cells below. ( B , Papanicolaou stain, ×1000). Most cells were small and blue, with little cytoplasm and irregular nuclei, and individual cells were somewhat tadpole- or ribbon-shaped. The nuclei were round to oval with evenly distributed coarse chromatin and inconspicuous nucleoli, and the cell size was slightly larger than that of normal lymphocytes. ( C&D , Papanicolaou stain, ×1000)

The cell block of the cervical smear showing the examination of polypoid tissue for mucus and inflammatory exudates under low magnification ( A , H&E, ×100). High magnification revealed that the tissue surface was covered with mucous gland epithelium, and dense small blue cells were distributed band-like under the epithelium. A cambium layer composed of subepithelial condensates of undifferentiated cells was observed. The cells were small and spindle-shaped, and interspersed strap cells were observed ( B , H&E, ×400). IHC demonstrated that the small blue cells were focally positive for desmin ( C , ×400 ) and MyoD1 ( D , ×400)

CT revealed an abnormal nodular soft tissue shadow at the cervical canal and outer cervical opening with a long diameter of approximately 3 cm and uneven enhancement (Fig. 3 A). A cervical lobated neoplasm measuring 4 × 4 cm in size was observed via colposcopy. The neoplasm had a grape-like appearance (Fig. 3 B).

CT revealing an abnormal soft tissue nodule shadow in the cervical canal and an outer cervical opening with a long diameter of approximately 3 cm and uneven enhancement after enhancement ( A ). A cervical lobated neoplasm (4 × 4 cm) was observed via colposcopy. The neoplasm was grape-like in appearance ( B )

Considering the lack of parametrical and lymph node involvement, a decision was made to proceed with single-port laparoscopic-modified extensive total hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection and abdominal aortic fat lymph node sampling. A polyp-like mass measuring 2.7 × 0.6 × 0.5 cm in size was observed in the inner mouth of the cervical canal with a wide base. The mass section was grayish-white and soft. The root of the tumor seemed to invade the surrounding tissue (Fig. 4 A). The tumor was composed of mainly hypocellular areas with rhabdoid changes and myxoid stroma (Fig. 4 B & C). Pathologic examination revealed invasion of the cervical stromal connective tissue. These findings confirmed embryonal rhabdomyosarcoma of the uterine cervix with local invasion into the superficial interstitial layer of the cervical canal. No lymph node invasion was observed. Repeat immunohistochemistry revealed strongly and diffusely positive staining for desmin; focal positive staining for myogenin, MyoD1, myoglobin, CD10 and cyclin D1; and negative staining for CK-P, ER, PR and S-100. The percentage of Ki67-positive cells was approximately 80%. The findings were consistent with a diagnosis of embryonal rhabdomyosarcoma of the cervix. The patient’s disease was classified as FIGO stage IB3 (T1b, N0, M0). Based on the Intergroup Rhabdomyosarcoma Study Group (IRSG) classification, the patient’s case was categorized as IA.

A polyp-like mass measuring 2.7 × 0.6 × 0.5 cm in size observed in the inner mouth of the cervical canal with a wide base ( A ). The tumor was composed of mainly hypocellular areas with rhabdoid changes and myxoid stroma ( B&C , H&E, ×100&400)

The patient’s postoperative course was unremarkable. The patient subsequently received adjuvant chemotherapy consisting of vincristine, actinomycin-D and cyclophosphamide administered over a 6-month period. Computed tomography (CT) of the abdomen and pelvis after two cycles of chemotherapy did not show any evidence of disease.

Embryonal rhabdomyosarcoma (ERMS) of the cervix is a very rare malignancy, accounting for 0.4-1.0% of all cervical malignancies [ 4 ]. The literature reports that up to 90% of cases of ERMS occur in women less than 25 years old, and approximately 60–70% of cases occur in children less than 10 years of age. Occurrence in perimenopausal women is very rare, but the prognosis in this age category is generally poor [ 6 ]. Clinical symptoms of ERMS that occur in the female reproductive system often include vaginal bleeding and an exophytic or polypoid mass [ 5 ]. The tumor often resembles a grape-like cluster with an average size of 5.75 cm [ 7 ]. Among the reported cases, tumors as large as 14 cm have been observed, and the smallest tumor is approximately 1.5 cm in size [ 7 , 8 ]. The incidence of small round cell tumors such as rhabdomyosarcoma in the cervix is much lower than that of epithelium-derived tumors. In cervical cytology, the morphology overlaps with that of other tumors, so the diagnosis of rhabdomyosarcoma with cervical cytology is very difficult. To date, no cases of cervical ERMS diagnosed by cervical cytology have been reported. Our case was the first reported case involving a diagnosis via liquid-based cytology testing.

The cytopathologic features observed in this patient were as follows: mostly round or oval tumor cells, with high nucleoplasmic ratios, scarce cytoplasm, and indistinct borders. Some of the cells had “naked nuclei” in shape, and some had small clusters or scattered cells that were slightly rich in cytoplasm and had a “drag tail”. The nuclei were round to oval, and a small number of cells were irregular in shape, had deep nuclear staining, were slightly larger than those of normal lymphocytes, had fine chromatin, and had no nucleoli or nuclear divisions. By combining these findings with information from cell block examination and IHC, we finally diagnosed the patient with ERMS.

The appearance of small blue round cells and rhabdomyoblast-like cells on cervical cytology requires consideration of the possibility of small blue round cell tumors such as rhabdomyosarcoma. It is very difficult to make a diagnosis by solely relying on cell morphology, so the diagnosis can be made by incorporating the results of immunohistochemical testing of the cell blocks. Because the biological behavior of small, blue, round cell tumors often appears to be highly malignant, and their treatment and prognosis are different, accurate and differential diagnoses are very important [ 8 ]. The differential diagnoses by cytology included the following (Table 1 ): (1) Nonkeratinized squamous cell carcinoma (NSCC): Cells occur singly or in syncytial aggregates with poorly defined cell borders. Cells may be somewhat smaller than those of many HSIL, but display most of the features of HSIL. Nuclei demonstrate markedly irregular distribution of coarsely clumped chromatin with chromatin clearing. Nucleoli may be prominent. A tumor diathesis is often present. (2) Adenocarcinoma in situ of the cervix (AIS): Cells occur in sheets, clusters, pseudostratifi ed strips, and rosettes with nuclear crowding and overlap and loss of a well-defi ned honeycomb pattern. Single abnormal cells may be present but are uncommon. Cell clusters have a palisading nuclear arrangement with nuclei and cytoplasmic tags protruding from the periphery (“feathering”). Nuclei are enlarged, variably sized, and oval or elongated. Nuclear hyperchromasia with evenly dispersed, coarsely granular chromatin. Nucleoli are usually small or inconspicuous. Mitoses and apoptotic bodies are common. Background is typically clean (no tumor diathesis). (3) Adenocarcinoma of cervix: Cytologic criteria overlap those outlined for AIS, but may show additional features indicative of invasion. Abundant abnormal cells, typically with columnar configuration. Single cells, two-dimensional sheets or three-dimensional clusters, and syncytial aggregates. Enlarged, pleomorphic nuclei demonstrate irregular chromatin distribution, chromatin clearing, and nuclear membrane irregularities.The nucleoli are large, and cytoplasm is usually finely vacuolated. Necrotic tumor diathesis is common. (4) Small cell neuroendocrine carcinoma (SCNC): Small cell carcinoma is composed of relatively uniform small, cells with scant cyanophilic cytoplasm. The nuclei are angulated, hyperchromatic with granular or stippled chromatin and inconspicuous nucleoli. Background necrosis and mitotic figures are common. Currently, there is no consensus regarding the optimum management protocol for patients with cervical ERMS. Therefore, clinicians often follow the treatment guidelines for genitourinary primary ERMS. However, multimodal treatment appears to improve patient outcomes. This approach consists of a combination of surgical intervention, systemic chemotherapy, and/or radiotherapy for local control [ 7 ]. Since patients with ERMS are younger and often require fertility preservation, this is a major factor in treatment selection. When the lesion is localized to the cervix, the best treatment for preserving fertility is polypectomy and simple or radical trachelectomy combined with adjuvant chemotherapy [ 9 , 10 ]. After resection, these patients should undergo adjuvant chemotherapy with vincristine, adriamycin D, and cyclophosphamide (VAC); these agents comprise the gold standard chemotherapeutic regimen [ 11 , 12 ]. Our patient underwent adjuvant chemotherapy with vincristine, actinomycin-D and cyclophosphamide after receiving single-port laparoscopic-modified extensive total hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection and abdominal aortic fat lymph node sampling. The patient’s computed tomography (CT) scan of the abdomen and pelvis after two cycles of chemotherapy did not show any evidence of disease.

Cervical smears are an important means of cervical cancer screening. In addition to screening for cancer, screening for other rare tumors is possible with such a modality. Although ERMS is uncommon in older adults, the disease must be considered in the differential diagnosis when there is vaginal bleeding or a protruding mass. In cervical cytology, the morphology overlaps with that of other tumors, so the differentiation of rhabdomyosarcoma from cervical cytological examination is very difficult. The pathologist should be familiar with these cytological features and characteristic findings from cell block examination and IHC, allowing early and accurate diagnosis of ERMS for timely treatment and avoidance of unnecessary surgical biopsy.

Data availability

All data generated or analyzed during this case are included within the article.

Abbreviations

Cervical embryonal rhabdomyosarcoma

Immunohistochemistry

Nonkeratinized squamous cell carcinoma

High-grade squamous intraepithelial lesion

Adenocarcinoma in situ of the cervix

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Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China

Xiaoxia Wei & Lei Li

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Xiaoxia Wei drafted the manuscript and assisted with the clinical data collection and interpretation. Lei Li participated in revising the manuscript and contributed to pathological examination and diagnoses. All the authors read and approved the final manuscript.

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Wei, X., Li, L. Cytological diagnosis of patients with embryonal rhabdomyosarcoma of the cervix: case report and literature review. Diagn Pathol 19 , 73 (2024). https://doi.org/10.1186/s13000-024-01497-y

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Plasmodium falciparum malaria.

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Continuing Education Activity

Malaria is a global infectious disease that remains a leading cause of morbidity and mortality in the developing world. Severe and fatal malaria is predominantly caused by Plasmodium falciparum. Its management and prognosis depend on the awareness of a possible diagnosis in travelers returning from endemic areas, early recognition, and timely effective treatment. This activity reviews the evaluation and management of patients with falciparum malaria and explains the role of the interprofessional team in evaluating and treating patients with this condition.

Identify the pathophysiology of P. falciparum infection.
Summarize the findings seen in a patient with P. falciparum malaria.
Describe common complications for patients with severe P. falciparum malaria.
Outline the importance of communication and collaboration among the interdisciplinary team to enhance the delivery of care and improve outcomes for patients affected by P. falciparum malaria.
Introduction

Malaria is a mosquito-borne disease caused by five protozoa: Plasmodium falciparum , P. vivax , P. malariae , P. ovale, and most recently implicated P.knowlesi . Infection with P. falciparum is being accounted for more than 90% of the world’s malaria mortality and therefore remains an important threat to public health on a global scale. [1] [2] The World Health Organization (WHO) World Malaria report 2019 estimates 228 million cases of malaria worldwide, causing 405 000 deaths in the year 2018, many under the age of 5. Malaria is endemic in more than 90 countries, affecting approximately 40% of the world’s population. [2] There is a significant number of cases of imported malaria and local transmission following importation occurring in non-malarial countries, including North America and Europe. [3] Malaria is associated with travelers to the endemic areas, and increasing numbers of imported malaria necessitate an understanding of frequently non-specific symptoms, difficulties related to the malarial diagnosis, and treatment possibilities. [2]

Five species of genus Plasmodium are known to cause malaria in humans. The vector for Plasmodium spp. is a female A nopheles mosquito that inoculates sporozoites contained in her salivary glands into the puncture wound when feeding. [3] Sporozoites enter peripheral bloodstream and are uptaken by hepatocytes, where they undergo an asexual pre-erythrocytic liver-stage as liver schizonts lasting up to 2 weeks before the onset of the blood stage. [3] [4] As they replicate within hepatocytes, they form motile merozoites that are subsequently released into the bloodstream, where they invade red blood cells (RBC). The process continues through serial cycles of asexual replication of merozoites that go through ring, trophozoite, and schizont stages before forming and releasing new invasive daughter merozoites that consequently infect new RBC, therefore causing a rise in parasite numbers. [3] [5] P. falciparum produces high levels of blood-stage parasites and is known to modify the surface of the infected RBC, creating an adhesive phenotype, e.g. (sticky cell) causing RBC sequestration inside small and middle-sized vessels, removing the parasite from the circulation for nearly half of the asexual cycle. [6] Sequestration leads to splenic parasite clearance avoidance, host cell endothelial damage, and microvascular obstruction. [5] [6] A small fraction of intra-erythrocytic parasites switch to sexual development, producing morphologically distinct male and female gametocytes that reach the host's dermis and are ingested by a mosquito, rendering it infectious to humans. [3] [4] [5] After ingestion by a female A nopheles mosquito, the male micro-gametocytes go through a process of ex-flagellation in the mosquito's midgut, fusing with female macro-gametes to form a zygote. The zygote then reaches the stage of ookinete that migrates through a thin wall, matures into oocyst, producing and upon rupturing, releasing numerous sporozoites that are dispersed throughout mosquitos body, including salivary glands, therefore completing the lifecycle. Gametocytes are hence of vital importance to the transmission cycle of malaria. [2] [4] [7] The clinical symptoms are, however, predominantly a result of the asexual stages of parasite replication in human blood. [5]

Epidemiology

Worldwide

WHO World Malaria Report 2019 states that an estimated 228 million cases of malaria occurred worldwide in 2018, and reports steadily decreasing the number of cases since 2010. In 2018, nineteen sub-Saharan African countries and India carried approximately 85% of the global malaria burden. The most prevalent and pathogenic malaria parasite, most commonly associated with severe illness and death, especially in the WHO African region, accounting for 99.7% malaria cases, is P. falciparum. [8] P. falciparum is also highly prevalent in South-East Asia, Eastern Mediterranean, and Western Pacific regions. The most vulnerable groups affected by malaria in high-transmission areas are children younger than 5 years old, their deaths accounting for 67% of global malaria deaths, and primigravidae. In low transmission areas, all ages are at risk due to low immunity. [2]

The United States

Most malaria cases diagnosed in the United States of America are imported from endemic countries. [9] The risk of infection depends on the length of exposure and the intensity of malaria transmission in the geographical region. [10] During 2015 CDC received 1517 reports of confirmed malaria in the United States of America, one of the cases was classified as congenital, 1485 were imported from endemic countries, and 31 reports had an incomplete travel history. The 12.1% decrease of imported malaria in 2015 correlates with the decrease in the number of cases imported from West Africa, possibly due to altered travel because of the Ebola epidemic. However, the overall trend shows that, on average additional 29 cases of malaria are reported every year since 1973, coinciding with an increasing number of international travel. Among the cases with species determination, the majority were P. falciparum , accounting for 86.6% cases from Africa, 70.9% from Central America, 20.8% from South America, and 4.8% from Asia . [8]

Based on present predictions for climate change, researchers predict an increase in the geographical distribution of malaria and an increasingly suitable climate for malaria transmission in tropical regions. [11] However, several other determinates factor in the epidemiology of malaria other than global warming: such as politics, economic development, urbanization, and population growth, migration changes, etc. [3] [11] Additionally, there is an impending threat of artemisinin- and multidrug-resistant P. falciparum , particularly prevalent in Greater Mekong Subregion (GMS), causing high failure rates of artemisinin-combination therapies. [12] [3]

General Epidemiology and Risk Groups

Severe malaria occurs in patients with no or little effective immunity. In parts of the world with the stable and intense transmission of P. falciparum , severe malaria is mostly a disease of the pediatric population younger than 5 years, as specific acquired immunity develops with age (due to repeated infections), providing increased, although incomplete, protection in older children and adults. Severe malaria can, however, occur at any age in areas with low or/and unstable transmission rates and individuals with no-immunity (e.g., travelers to the endemic areas). [13] Susceptibility to malarial infections increases during pregnancy. [14] Pregnant women in the second trimester are at the greatest risk of infection, although the risk is somewhat affected by age and gravidity, with young primigravidae being at the highest risk at high transmission areas. [15] Women living in areas with unstable and low malaria transmission rates are infected infrequently and therefore lack the immunity, which often causes a rapid progression to severe malaria and death. [14]

Pathophysiology

The rupture of the first liver schizont and the release of motile merozoites into peripheral circulation to invade red blood cells marks the start of a possible symptomatic infection. The first rupture and invasion are usually silent in most infected patients, but as the asexual cycle repeats itself in the next 24 to 48 hours, parasitemia rises, and immune response increases accordingly. It is usually associated with an increase of TNF alpha and other inflammatory markers in the cascade, including interleukin 10 (IL-10) and interferon-gamma (IFN-gamma). [6] Higher parasitemias are generally associated with a more severe clinical picture, but the relationship is very variable. [16]

The most important virulence determinant in P. falciparum infection is the parasite´s ability to modify the surface of the infected red blood cell, thus creating an adhesive phenotype. The cytoadhesion is mediated through the P. falciparum erythrocyte membrane protein 1(PfEMP1) family, which is the product of var gene transcription. There is immense diversity in var genes in the parasite population, which has recently been a focus of research, due to its suggested association between increased transcription of specific var genes and the development of severe malaria. [6] [17] The cytoadherence of mature-staged infected RBC to the endothelium, platelets, and uninfected red blood cells causes sequestration in the microvasculature of various organs, resulting in microcirculation obstruction, impaired tissues perfusion, lactic acidosis and consequently, end-organ damage. [18] [19] [20] Prominent sequestration occurs in the placenta during pregnancy, causing low birth weight, anemia, miscarriage, and congenital malaria. [6] [19]

In essence, the key features that render a fatal disease are the sequestration of P. falciparum in tissues, in conjunction with the up-regulation of cytokines and other toxic substances and an absence or an untimely provision of effective antimalarial therapy. [6]

History and Physical

Malaria is a complex disease with a spectrum of clinical effects that not only differ between children and adults but can range from practically none in patients with asymptomatic parasitemia, to uncomplicated malaria, through to severe and possibly lethal malaria. [20] The mean incubation period for P. falciparum is 12 days, with most patients presenting in the first or second month after exposure in endemic areas. [21] [22] It is key to take a detailed travel history in any patient with fever or history of fever, as malaria is a crucial diagnosis to consider in any individual who has traveled to a malaria-endemic area. [22] [21]

Uncomplicated P. falciparum Malaria

Malaria can be separated into two disease presentations: uncomplicated and severe. [4] The WHO defines the presence of symptoms without clinical or laboratory signs to indicate severity or vital organ dysfunction as uncomplicated malaria. [6] Symptoms are generally non-specific, including fever, chills, myalgia, headache, anorexia, and cough, making clinical diagnosis unreliable. [4] [21] Patients occasionally present with gastrointestinal symptoms, respiratory symptoms, and jaundice. [22] The classical malarial paroxysms with spiking fever, chills, and rigors occurring at specific intervals are relatively uncommon, but if present, indicate an infection with P. ovale or P. vivax . [3] Progression to severe or ultimately fatal disease is largely confined to P. falciparum infections, although only a small percentage, approximately 1% to 2% of infections, lead to severe malaria. [20] [13] Features of a severe disease usually appear after 3 to 7 days of the abovementioned non-specific symptoms, although there are some reports of rapid deterioration, failure to recover consciousness after a grand-mal seizure, and non-immune patients dying within 24 hours of their first symptom. [13]

Severe P. falciparum Malaria

The patient presenting with at least one of the clinical or laboratory features listed below, with asexual P. falciparum parasitemia (either detected in the peripheral blood smear or confirmed with rapid diagnostic test) and no other confirmed cause of his symptoms, classifies as suffering from severe malaria. [13] [23] Although P. falciparum is responsible for the majority of the cases of severe malaria, it is also, albeit rarely, observed with P. vivax and P. knowlesi infections. [18] [13]

A shortened list of danger signs is used for rapid clinical assessment, which includes prostration, respiratory distress (acidotic breathing), and impaired consciousness. [4] Other clinical manifestations of severe malaria include multiple convulsions, radiologically confirmed pulmonary edema (respiratory failure due to acute lung injury progressing to acute respiratory distress syndrome), abnormal bleeding (disseminated intravascular coagulation), acute kidney injury, jaundice, shock, and coma. [4] [21] [13] Laboratory features in severe malaria can show severe anemia, hypoglycemia, acidosis, hyperlactatemia, renal impairment, and hyperparasitemia . [13] A comprehensive list of diagnostic criteria for falciparum malaria is shown in Table 1 - Diagnostic criteria for severe P. falciparum malaria. [13] [18]

Physical Examination

Physical examination is usually unremarkable, especially of patients with uncomplicated malaria. They frequently present with irregular and erratic fever, reaching up to 41°C, sometimes accompanied by agitation or confusion. [3] [13] Mild spontaneously resolving jaundice can sometimes be seen in patients with otherwise-uncomplicated falciparum malaria. [3] [22] Other physical signs can include anemia and postural hypotension. [13] In some cases, patients can present with tender hepatosplenomegaly after some days. However, a palpable spleen is particularly common in otherwise healthy populations in endemic areas, reflecting repeated infections. [3] The comprehensive list of clinical features associated with severe malaria is shown in Table 1 - Diagnostic criteria for severe P. falciparum malaria. [13] [18]

Children are more likely to present with non-specific and gastrointestinal symptoms such as fever, lethargy, malaise, nausea, vomiting, abdominal cramps, and somnolence. [22] They are more likely to develop hepatomegaly, splenomegaly, and severe anemia without major organ dysfunction than adults. In a case of severe malaria, they present with more frequent seizures (in 60% to 80%), hypoglycemia, and concomitant sepsis but are less likely to develop pulmonary edema and renal failure than adults. [3] [22]

Pregnant Women

The clinical features of infection in pregnancy vary from asymptomatic to severe, depending on the degree of (incomplete) immunity that a woman had acquired by the time she got pregnant. In semi-immune pregnant women, only a few infections result in fever or other symptoms. [15] Malaria in pregnancy has a devastating effect not only on maternal health but has been associated with increased infant mortality due to low birth weight caused by either intrauterine growth restriction or preterm labor or both. [15] P. falciparum infections are proven to be associated with complications such as maternal anemia, low birth weight, miscarriage, stillbirths, and congenital malaria. [6] [15] It is more likely for a pregnant woman in the second or third trimester to develop severe malaria with complications such as hypoglycemia and pulmonary edema, compared to non-pregnant adults. [18]

Once malaria is considered a possible diagnosis, it is important to facilitate immediate laboratory testing. [4] It is essential to distinguish between non-falciparum and falciparum malaria. [24] As per the Centers for Disease Control and Prevention (CDC) guidelines, malaria should be routinely suspected in any febrile patient that has a recent history of travel to the endemic areas. The clinical features of either uncomplicated or severe malaria are non-specific, therefore requiring diagnosis by microscopy or rapid diagnostic test (RDT). [18] The results should be communicated back to the requesting doctor as soon as possible, ideally within a few hours. [24]

A full blood count, urea, creatinine and electrolytes, blood glucose level, and liver function tests should be routinely performed. Thrombocytopenia suggests both non-falciparum and falciparum malaria infections in non-immune adults and children. In severely ill patients, additional studies such as blood gases, blood culture, lactate, and clotting studies are appropriate. In patients with fever and impaired consciousness, one should consider a lumbar puncture to exclude meningitis. [24]

The golden standard for diagnosis is a microscopic analysis of thick and thin blood smears. Thick smears allow for a sensitive parasitemia quantification, as parasitemias as low as 30-50/microL can be detected, while thin smears enable a determination of the Plasmodium species, prognostic assessment based on the staging of parasite development and estimation of the proportion of neutrophils containing malaria pigment. [13] [18] Three sets of thick and thin blood films spaced 12 to 24 hours apart should be performed by experienced laboratory personnel before a clinician can confidently rule out malaria. [8]

Perceived peripheral blood parasitemia varies greatly in patients with severe malaria, due to the sequestration of the infected red blood cells in tissues. [13] [18] Although severe malaria can present with low parasite count, high counts are associated with increased risk of deterioration and subsequent treatment failure even without signs or symptoms of severity. [13] More than 2% of parasitized RBC suggests an increased chance of developing severe disease, and parasitemia over 10% is considered as one of the diagnostic criteria for severe disease and is associated with increased mortality. [24] Furthermore, in severe falciparum malaria, poor outcomes can be predicted by the presence of late-stage parasites in RBC and more than 5% of the neutrophils containing pigment. [18]

Rapid diagnostic tests are commonly used in addition to blood slides and are useful alternatives in settings where a microscopic diagnosis is non-reliable or infeasible. [24] [9] It is, however, recommended that all the RDTs should be followed by microscopy for confirmation and, if positive, quantification of parasitemia. [9] They are immune-chromatographic tests that most commonly identify either malaria antigens (e.g., P. falciparum histidine-rich-protein 2 (PfHRP2)) or enzyme called Plasmodium lactate dehydrogenase (pLDH). Tests have several downfalls as they cannot provide quantitative results, can stay positive months after infection with P. falciparum, or are, if testing for pLDH, positive only while there are living parasites in the blood. [13]

Polymerase chain reaction (PCR) is one of the possible diagnostic modalities but is, even if promptly available, too timely to use for initial diagnosis and prompt treatment of acute malaria. It should, however, be used for research and epidemiologic purposes in any malaria infection in the USA, to determine and confirm the infecting species. [8] All cases should also be evaluated for evidence of drug resistance, as per CDC guidelines. [9]

Treatment / Management

CDC recommends that the treatment of malaria should not be initiated until the diagnosis has been confirmed by laboratory testing. Treatment should be initiated immediately after the confirmation of malaria infection. Empirical treatment is, however, reserved only for extreme cases where there is a strong clinical suspicion with convincing exposure history, presence of severe disease, or an inability to diagnose malaria due to inadequate laboratory facilities.

The treatment should be guided by three main factors: the infecting Plasmodium species, the clinical status of the patient, and drug susceptibility of infecting Plasmodium , determined by the geographic region where the infection was acquired. Chloroquine sensitivity can be expected if the infection was acquired in Central America west of Panama Canal, Haiti, and the Dominican Republic. In a case when the diagnosis is strongly suspected, and it cannot be confirmed, or when there is no species determination possible, given the global spread of P. falciparum resistant to chloroquine, the clinician should opt for a treatment option effective against chloroquine-resistant P. falciparum . CDC recommends making additional blood smears in infections with P. falciparum after initiating the treatment, to confirm adequate parasitological response (decrease in density) to treatment.

Extended, evidence-based, and comprehensive guidelines for malaria management and optimal dosing of antimalarial medications can be found in the third edition of WHOs Guidelines for the treatment of malaria. Treatment and management algorithms for malaria in the USA are available on the CDC´s official website.

Uncomplicated Falciparum Malaria

Uncomplicated falciparum malaria should be treated with one of the artemisinin-based combination therapies (ACT). Artemisinin-based combination therapy (ACT) is highly effective due to its effect on a broader range of parasite life cycles, causing faster parasite clearance and is therefore considered a drug of choice for uncomplicated malaria. [24] The duration of ACT treatment is 3 days. ACTs are also recommended for pregnant women in the second and third trimester but should be used during the first trimester only if other treatment options are not available. During the first trimester, a combination of quinine and clindamycin should be prescribed. In low transmission areas, gametocytocidal therapy (e.g., primaquine) is added to ACTs to reduce transmission potential (except pregnant women, infants younger than 6 months and women breastfeeding infants younger than 6 months). [18]

There are some other treatment options, although not as effective as ACTs, such as atovaquone-proguanil, quinine sulfate plus doxycycline, tetracycline, or clindamycin, and mefloquine. For chloroquine-sensitive P. falciparum infections (including

pregnant women), the drug of choice is chloroquine. However, any of the drug choices listed above for chloroquine-resistant strains can be used. Treatment options are the same for the pediatric population, with doses adjusted by the patient’s weight.

Severe Falciparum Malaria

All patients diagnosed or with a strong suspicion with signs and symptoms of severe malaria should be promptly treated with parenteral antimalarial therapy. Effective, urgent, and appropriate treatment has the greatest impact on prognosis. [24]

Intravenous or intramuscular artesunate is the first-line treatment in all patients (including children, lactating women, and pregnant women in all trimesters) worldwide and should be used for at least 24 hours and until the oral medication is tolerated. [18] Children should receive a higher dose (3 mg/kg BW per dose) of the artesunate to ensure the equivalent drug effect. The dose for larger children and adults is 2.4 mg/kg BW per dose. Three doses of intravenous artesunate should be given: one immediately, followed by a dose at 12 hours and 24 hours.

If artesunate is not available, the recommended drug is artemether in preference to quinine. After the complete course of a 24 hour intravenous artesunate, a regimen of a follow-up drug should be completed. A full 3-day regimen of ACT is recommended. In returning traveler, the follow-on antimalarial medication needs to be other than the antimalarial medication taken for prophylaxis. [18]

Intravenous artesunate is currently not approved by the Food and Drug Administration (FDA) or commercially available in the U.S. but is available from CDC under an expanded-access investigational drug (IND) protocol. It is prepositioned at distribution sites throughout the USA and readily available after contacting CDC. Since severe malaria can progress rapidly, CDC offers guidance on oral treatment that can be used while waiting for IV artesunate to be delivered. They recommend interim treatment with oral artemether-lumefantrine (preferably), atovaquone-proguanil, quinine sulfate, or mefloquine. If a patient can not tolerate oral medications, administration after an antiemetic or via nasogastric tube should be considered.

Patients with falciparum malaria should be admitted to the hospital due to the possibility of deterioration even after the effective treatment was initiated. If patients are determined to have uncomplicated malaria, they can be treated as outpatients after confirming that they can tolerate oral therapy, and the parasitemia has declined. [13] Ideally, a patient with severe malaria should be admitted to an intensive-care unit or high dependency unit with close monitoring of clinical status, vital signs, consciousness level, and laboratory values. [13] [24]

It is important to provide supportive therapy, such as glucose to maintain euglycemia and acetaminophen for fever control, careful, individualized fluid management as patients present with variable degrees of hypovolemia, acidosis, and acute kidney failure. Blood transfusion is sometimes indicated in severe anemias; benzodiazepines should be used for seizure control. However, prophylactic antiepileptic medications are not recommended, and empiric antibiotics should be used in children with severe malaria and adults with concurrent shock. [4] [22] [18]

Differential Diagnosis

Other travel-related infections such as typhoid, viral hemorrhagic fevers (such as Ebola, Lassa fever, etc.), hepatitis, dengue, and other arboviruses, enteric fever, avian influenza, tuberculosis, MERS-CoV infections, HIV, meningitis, and encephalitis can resemble malaria. Non-tropical infections such as bacterial pneumonia, septicemia, and influenza should be excluded. [24] [25]

Cerebral malaria can mimic bacterial meningitis, measles, (locally prevalent) viral encephalitis, toxic syndromes, and intracranial vascular or mechanical events. [13]

Patients with uncomplicated malaria, especially with timely diagnosis, treatment, and proper compliance, usually recover from malaria without consequences. The mortality rate for uncomplicated malaria is low, around 0.1%. [3] [6] The mortality rate rises steeply once the patient develops signs and symptoms of severe falciparum malaria. Adults have higher mortality rates and more frequent multisystem involvement than children, with mortality rates being 18.5% and 9.7%, respectively. [20] The two main determinants reflecting the outcome for both adults and children were found to be the level of consciousness assessed by coma scales and the degree of metabolic acidosis, assessed clinically by breathing pattern or more precisely with measurement of bicarbonate, base deficit, and plasma lactate. [13] While the general mortality of treated severe malaria is between 10% to 20%, the mortality in pregnant women reaches approximately 50%. [18]

Complications

A distinct complication of P. falciparum malaria is cerebral malaria (CM), a diffuse and symmetrical encephalopathy. [16] It is a clinical syndrome defined as an impaired consciousness (clinically determined as stated in Table 1) that cannot be attributed to other causes such as convulsions, hypoglycemia, sedative drugs, or other non-malarial causes and is associated with an unequivocal diagnosis of malarial infection. Due to several other possible causes of altered consciousness, the presence of retinopathy has been used in an attempt to increase the specificity of diagnosis of CM and improve the classification of severe malaria. [13]

Other possible complications, predominantly caused by P. falciparum , include:

Acute kidney injury complicates up to 40% of P. falciparum malaria. [18]
Non-cardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS), and hypoxia [13]
Electrolyte and fluid abnormalities [13]
Acid-base disturbances – mostly acidosis and hyperlactatemia [13]
Hypoglycemia, often exacerbated by quinine therapy [4]
Anemia, with the reduction in hemoglobin levels being proportional to disease severity and duration of illness before treatment [13] [16]
Other hematological complications (delayed hemolytic anemia following artemisinin treatment, hyper-reactive malarial splenomegaly (HMS), and splenic rupture) [4]
Blackwater fever and hemoglobinuria due to intravascular hemolysis in patients with severe clinical manifestations of falciparum malaria [13]
Profound thrombocytopenia is often associated with P. falciparum infection, however, bleeding and disseminated intravascular coagulation (DIC) are rare. [13]
Hepatic dysfunction [13]
Shock and associated infections (such as Salmonella bacteriemia, aspiration pneumonia, nosocomial infections, etc.) [3] [13]
Neurological sequelae (epilepsy, permanent focal deficits, etc.) [4]

The three most common complications occurring in children are cerebral malaria, severe anemia, and acidosis, either isolated or overlapping. [20]

Deterrence and Patient Education

Although no intervention for preventing the infection is 100% effective, there are several different approaches available that can be used alone or in combination. Personal protective measures reduce the risk of exposure to infective mosquitoes, and chemoprophylaxis can aid in reducing the risk of a poor outcome if infected. [26] A common approach usually applied is an “ABCD” of malaria – A standing for awareness of the risk, B for bite avoidance, C for compliance with chemoprophylaxis, and D for diagnosis in case of fever. It is essential to consider traveler´s health (especially pregnancy, age, immunosuppression) when assessing the risk for developing severe malaria and choosing an appropriate antimalarial drug. [10]

It is necessary to emphasize the importance of personal protective measures such as barrier clothing, insecticide-impregnated bed nets, application of effective mosquito repellent (higher percentage of active ingredient provides longer protection), and spraying the residence with insecticide. Products that contain 20%-40% of DEET (N, N-Diethyl-meta-toluamide), picaridin, oil of lemon eucalyptus or PMD (p-menthane-3,8-diol) and IR3535 are recommended. Behaviors to minimize exposure to mosquitos are also encouraged – for instance, staying indoors from dusk till dawn, choosing screened accommodations. [9] [26] Indoor residual spraying and long-lasting insecticidal nets remain to be the most effective tools for malaria control and elimination, despite the emergence of insecticide-resistant Anopheles mosquitos. [27] [28]

A standard recommendation for all travelers to endemic areas is strict compliance with the antimalarial drug. There are several different drug choices, prescribed after assessing individual´s risk (level of local transmission, duration of exposure, rural vs. urban travel, type of travel and season), travelers health status, present contraindications, level of parasite drug resistance (mostly chloroquine and mefloquine resistance) and traveler’s preference based on schedule, cost and nature of possible side effects . There is an increasing problem with counterfeit and substandard medications being sold in several Sub-Saharan countries, and travelers should be advised to buy the needed medications before departure. [29] [10] A complete list of recommendations for drug choice can be found on the CDCs website – Malaria Information by Country.

As pregnant women are at increased risk for severe malaria, the WHO and other organizations recommend not traveling to the endemic areas. [10]

Travelers to the endemic areas, former residents of malaria-endemic areas and people diagnosed with malaria should be informed, as per Food and Drug Administration (FDA) recommendations, that they may not donate blood for 1 year after travel or 3 years after departing or revisiting the country or for 3 years after treatment, respectively. [9]

Travelers should be informed that malaria can be fatal with delayed treatment, and one should, therefore, seek medical attention while abroad if symptoms of malaria develop and not fly back for treatment, as medical treatment may not be readily available on transit . [9]

Pearls and Other Issues

Malaria vaccine would be an ideal tool to control, prevent, eliminate, and ultimately eradicate the disease. The complexity of P. falciparum infection has hindered several attempts at developing an effective vaccine, yet the acquisition of partial immunity and successful treatment of malaria with purified immunoglobulins from semi-immune adults showed that the development of a vaccine is attainable. Researchers have identified several potential targets in the parasite´s infectious cycle. Currently, 20 vaccine candidates are undergoing clinical trials. [27] The most promising and most advanced vaccine to be developed so far is a licensed RTS, S subunit vaccine (RTS, S/ASO1), targeting the pre-erythrocytic stage of infection, thus preventing hepatocyte infection and parasite development, consequently limiting RBC invasion. It consists of a recombinant protein of the P. falciparum circumsporozoite protein (CSP) conjugated to the hepatitis B surface antigen. [27] RTS, S/ASO1, the first malaria vaccine which has received regulatory approval for human use, was used to start the first routine malaria vaccination program in Africa – a pilot study in Malawi in April 2019, which has since expanded to Kenya and Ghana. The pilot study is planned to last about 50 months and to enroll 720 000 children in vaccination and control clusters, however several safety concerns, that are now being investigated in the pilot study, have already been identified in phase III trials: higher risk of meningitis, cerebral malaria and doubled female mortality. If no serious safety concern is determined in the first 24 months of trial, the pilot study will run its full course before any decision will be made about its broader use in endemic countries. [30]

There has been an emergence of a (widely used) pyrethroid insecticide-resistant malaria vector population, causing extensive research with their first results suggesting a better effect of long-lasting insecticidal nets treated with PBO (piperonyl butoxide) instead of pyrethroid laced nets. [28]

Enhancing Healthcare Team Outcomes

Most cases of malaria in the U.S. are imported and could, therefore, be avoided with appropriate personal protective measures and compliance with prescribed chemoprophylaxis. Health care providers on all levels must be educated not only on the diagnosis and treatment of malaria but especially on the importance of prevention. They should be able to provide enough information to travelers at risk. Travelers to the endemic areas should obtain appropriate clothing, insecticides, and other protective gear based on the information offered by health care providers and CDC. Collaboratively, a physician and a pharmacist, should decide on, recommend and prescribe appropriate chemoprophylaxis, considering traveler's personal preferences, time of travel, current health status, risk factors, drug-drug interactions, and possible contraindications, while emphasizing the importance of compliance with the drug-taking regimen.

The crucial issue in the diagnosis and treatment of malaria is the consideration of the possibility of diagnosis. Expert advice from an infectious disease or travel medicine specialist should be sought once malaria is a suspected diagnosis, especially in the setting of severe disease. [24] The execution of a microscopic analysis of a stained blood smear often depends on several factors such as laboratory equipment, quality of reagents, and laboratorian expertise. Laboratorians should, therefore, be trained in the preparation and analysis of blood-smears to diagnose a malarial infection correctly. The results need to be communicated back to the physician as soon as possible. All laboratory-confirmed cases of malaria should be reported to CDC to help with their surveillance efforts. Healthcare providers that are a part of the interprofessional team (nurses, respiratory therapists, physicians, etc.) managing patients with severe malaria in critical or intensive care units, should be educated on early recognition of complications.

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Life Cycle of the Malaria Parasite Contributed by Wikimedia Commons, National Institutes of Health (NIH) (Public Domain)

Mosquito-Borne Diseases. Mosquitoes are carriers of various diseases, including Zika, dengue fever, West Nile fever, chikungunya, yellow fever, and malaria. National Institute of Allergy and Infectious Diseases, National Institutes of Health

Blood smear malaria Image courtesy S Bhimji MD

Diagnostic criteria for severe P. falciparum malaria Contributed by Lara Zekar, MD

Rings of P. falciparum in a thin blood smear. Contributed by the Center for Disease Control and Prevention (CDC)

Disclosure: Lara Zekar declares no relevant financial relationships with ineligible companies.

Disclosure: Tariq Sharman declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Zekar L, Sharman T. Plasmodium falciparum Malaria. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Leveraging innovation technologies to respond to malaria: a systematized literature review of emerging technologies

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Scientific databases literature search

Search through technology platforms e.g., google play store and apple app store

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Malaria Journal

What are medical students taught about persistent physical symptoms? A scoping review of the literature

Research questions

Search strategy

Sources of evidence

Study selection

Charting the data: summary and synthesis

Search strategy, study selection, and data extraction

Descriptive analysis

Study characteristics

Teaching and learning methods

Evaluation of teaching studies

Thematic synthesis

An awkward problem

The absence of science

Easily overlooked

Stigma and the hidden curriculum

Suggestions for improvement: relationship to domains of learning

Knowledge (cognitive)

Skills (psychomotor)

Attitudes (affective) and the role of reflection

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