The Accident and Emergency department at Queen’s Medical Centre has received a visit from a 22-year-old male who has recently returned from a trip to Nigeria and is presenting symptoms of cerebral malaria (CM). A full blood count (FBC) was taken and presented various results for haemoglobin, platelets and white blood cell count which shall be discussed further along with why the cause of this case is likely to be CM.
This decision has been made is due to the symptoms being similar to those presented in this type of malaria targeting the brain and not as severe in adults unless it is not treated and develops gradually over 2 to 3 days (Hunt and Grau, 2003). The patient was visiting friends meaning that during his stay it is unlikely that he stayed in a hotel which would have mosquito nets and other preventative procedures to keep mosquitos and insects away, so he would be more exposed to mosquitos in a house. Nigeria is in sub-Saharan Africa and countries in this region have CM transmitted by Plasmodium falciparum. Sequestration of this in red blood cells is the main reason CM occurs (Storm and Craig, 2014).
Figure 1: The worldwide endemic spatial distribution of P.falciparum (Hay et al. 2009). The light grey areas show areas with no risk of transmission of the pathogen and the dark areas show very little risk of transmission. As the colour develops from yellow to red this shows an increase in the mean distribution of P.falciparum. the areas with the greatest distribution is sub-Saharan Africa. Brazil and South Asia have similar distributions around 20-30. Nigeria has a large distribution of the pathogen approximately at 70 and is surrounded by countries also with a high distribution.
The patient presents symptoms relating to CM specifically which develops over a few days suggesting that he possibly experienced them a few days before he landed in the UK. Flu like symptoms are common including body aches, headaches and a fever which are frequent in normal cases of malaria. The reason for these symptoms being specific to CM is because the parasite binds to the red blood cells affecting the cerebral blood-brain barrier and this has an influence on cerebral epithelium cells (Moore et al.,2016). The sequestration causing blood flow to be disorientated and destroyed and this can lead to hypoxia which is the reduction of blood flow to a tissue or organ, and when this occurs with the brain it is called cerebral anoxia. When this is long term it can lead to neuronal cell death by apoptosis (Idro et al., 2010). The P. falciparum erythrocyte membrane protein 1 (PfEMP1) is encoded by a variant gene and has a large role with the sequestration process and can be considered as a parasite antigen.
Parasitic proteins mediate adhesion of P. falciparum by binding specifically to numerous endothelial cell receptors such as CD36. This leads to sequestration of infected erythrocytes being widespread causing greater pro-inflammatory procoagulant responses resulting in cerebral swelling (Bernabeu et al., 2016). Cerebral malaria is specific to the brain and expression of the PfEMP1 variant protein is promoted by by containing either DC13 or DC8 and controls binding of infected erythrocytes to the endothelial protein C receptor found on the brain’s surface epithelium. Sometimes DC4 can be present to strengthen binding to endothelial cells due to the involvement of ICAM-1, a protein-coding gene (Aird et al., 2013).
The symptoms the patient present are specific to cerebral malaria, however many of these overlap with other types of malaria such as fevers making it non-specific. Fever and the feeling of being cold is cause by the erythrocyte-stage also known as blood-stage schizonts rupturing through apoptosis. It is normally present for 1 to 4 days and then frequently leads to a coma afterward if left untreated (Crutcher and Hoffman, 1996). Fever caused by P. falciparum malaria occurs every 3rd day in cycles but is not always obvious to detect the cause due to being exposed to numerous parasites (Misra et al., 2011). The erythrocyte cycle is responsible for causing these symptoms as erythrocytes need to be present for the Plasmodium species to infect a human and the parasite modifies the erythrocyte’s morphology forming knobs on the erythrocyte membrane (Moore et al.,2016), and cell surface proteins are presented here, leading to further sequestration (Gerald et al., 2011).
An unrousable coma is one of the more severe neurological symptoms and complications that can occur. The cause of this is due to parasitized RBCs (pRBCs) in cerebral micro circulation being isolated and obstruction of brain microvasculature also occurs resulting in sequestration of pRBCs. This is associated with an induction of microvascular congestion by erythrocytes. (Ponsford et al., 2011). As comas associated with cerebral malaria are multifactorial they can also occur due to microvascular congestion in found in cerebral vessels. This goes against the idea that malarial toxin is released and can stimulate the release of cytokines from macrophages which results in the induction of Nitric Oxide being released uncontrollably in the brain which is another possible explanation for why a coma can occur. However, combined together sequestration and endothelial damage can both contribute to rupturing of vessels leading to a coma as less oxygen is able to reach the brain (Hearn et al., 2000). Therefore a loss of consciousness is one of the most severe symptoms the patient could experience if treatment is not provided and is sometimes accompanied by seizures, another clinical feature.
Seizures and loss of consciousness are clinical features associated with CM which tend to occur once the basic symptoms have worsened and frequently lead to death. This is manifested by the cerebral hemisphere not functioning appropriately. Due to there being a lack of oxygen and glucose and an increased demand for this during a seizure, there is a significant risk for the patients experiencing neural injury and the patient’s metabolism cannot keep up. The consequences of this would increase also if the patient is hypoglycaemic meaning that a Glucose Tolerance Test should be taken into consideration (Aminoff et al., 2013).
Full Blood Count results of 22-year-old patient compared to reference ranges
Test Result Normal Range Units
WBC 7.0 3.6-11.0 x109/L
Platelet 90.0 140.0-400.0 x109/L
Hb 98.0 130.0-180.0 (Male) g/L
Figure 2: Comparison of patient’s results from FBC to reference values (Gloshospitals.nhs.uk, 2015). From the normal range values only the White blood cell count is within the normal range. The Platelet count falls 50 x109/L below the range and the Haemoglobin level falls 228 g/L below the normal range too.
A full blood count (FBC) was undertaken to confirm the presence of malaria. The WBC count is the only variable within the reference ranges, in this case the range is 3.6-11.0 x109/L, however this does not mean that the WBCs are normal (Moore, 2016). As it is not greater than the range, this suggests that it is not a severe malarial infection. This occurs because the immune response is not triggered. The platelet count is significantly low by around 50×109/L which is normally expected in cerebral malaria (Gloshospitals.nhs.uk, 2015). This results in reduced clumping of P.falciparum-parasitized red blood cells which can affect laminar flow meaning that they are linked to red blood cells as platelet erythrocyte aggregates can form and red blood cells clump together . Thrombocytopenia is associated with the activation of platelets due to PfEMP1 interacting with CD36 on the platelets and is commonly found in those returning from Africa to the UK and is specific to P.falciparum (Khan et al.,2012). This results in a reduced platelet count as the immune system is supressed and unable to keep up with the production of them as they are lost quickly by self-destruction or clump together. The patient has low haemoglobin count(Hb) which doesn’t fit the reference range of 130-180 g/L (Gloshospitals.nhs.uk, 2015). The presence of Hb is reduced particularly in this patient due to a high presence of parasites in the blood. Low levels of Hb are usually associated to anaemia which can develop as a result of CM, though this is usually in children and the patient being 22 years old may not definitely have this disorder. This condition is however linked to a loss of consciousness meaning that it is likely that the patient has this, anaemia in CM involves he sequestration of red blood cells and both are induced by P.falciprum. There is a significant decrease in the production of erythrocytes in the bone marrow which can result in reduced levels of oxygen especially when circulating to the brain which can result in a coma (Haidar and Mohandas, 2009).
By looking at the symptoms and FBC, other tests can be completed to confirm the presence of CM and the complications related. However, the main issue is that neural tissues cannot be tested from patients due to the risk of neural injury meaning that results come from autopsies. Blood films on the other hand are normally used to confirm diagnosis based on Hb, these are categorised into thick and thin blood films. Thin films involve the drying of red cells and are fixed with methanol. Thick blood films involve a dried drop of blood put onto a film several layers thick fixed and stained without methanol allowing only red cells to undergo lysis not the parasites. Blood films test for numerous factors: Parisitaemia, being the quantity of red cells infected; parasite maturity where a greater amount of schizonts are present and observing the presence of malarial pigments known as polymorphs in blood polymorphs (Pasvol, 2006). The films are magnified at x1000 and normally if the results are negative it is repeated after 12-48 hours. Another method is using a dipstick to detect that PfHRP2 and pLDH, P.falciprum antigens are present (Dondorp, 2005). To make sure that the patient has not got meningitis he must have his cerebrospinal fluid examined and it should appear normal is meningitis is not present. Hypoglycaemia is related so a glucose tolerance test should be completed to check for high levels of glucose in addition to the usual rapid diagnostic tests (Ali et al., 1995).
In terms of the prognosis and treatment like all diseases it depends on the severity of the disease but the most common method of treatment is oral medication to prevent progression if CM is not too severe. However malarial chemotherapy is provided containing Quinine this is known as paternal antimalarial treatment. Quinine works by acting against the mature form of P.falciparum (Dondorp,2005). But in general, it is recommended that the symptoms are treated first as this can reduce progression of CM in the 22-year-old.
It can be determined that due to the patient experiencing CM related symptoms and presenting low levels of platelets and haemoglobin, CM is the most likely cause. As the duration of the patient experiencing symptoms is unknown one cannot presume the severity of the disease; so if only fever and body aches have been an issue it is best to primarily treat these symptoms to prevent progression of the disease. However, if the patient has experienced a loss of consciousness and rapid diagnostic tests show high parasite maturity and presence then antimalarial treatment should be provided. If these guidelines are followed the patient is likely to survive.