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1.1.1   Anopheles Mosquito

1.1.2 TRANSMISSION OF MALARIA & LIFE CYCLE Sporogony within the Mosquito ASEXUAL CYCLE Pre-erythrocytic phase (schizogony in the liver) Erythrocytic Schizogony


1.1.4 CLINICAL FEATURES OF MALARIA Headache: Body ache, back ache and joint pains: Dizziness, vertigo: Convulsions, coma: Cough: Weakness: Jaundice: of lids: Secondary infections: 

1.1.5 OCULAR EFFECTS OF MALARIA Neuro-ophthalmic manifestations Retinal manifestations






1.3       AIM OF STUDY



1.6       HYPOTHESIS












3.2.1 Inclusion Criteria

3.2.2 Exclusion Criteria



3.4.1 Case History

3.4.2 Visual Acuity

3.4.3 External exam Using Penlight

3.4.4 Ocular Motility Test

3.4.5 Amplitude of Accommodation

3.4.6 Ophthalmoscopy

















Malaria is probably one of the oldest diseases known to man, that has affected social, economic and mental development. The history of malaria is as ancient as civilization. Malaria was linked with poisonous vapours of swamps or stagnant water on the ground since time immemorial. This probable relationship was so firmly established that it gave the two most frequently used names to the disease mal'aria, later shortened to one word malaria. The term malaria (from the Italian mala "bad" and aria "air") was used by the Italians to describe the cause of intermittent fevers associated with exposure to marsh air or miasma. The word was introduced to English by Horace Walpole, who wrote in 1740 about a "horrid thing called mal’aria that comes to Rome every summer and kills one." The term malaria, without the apostrophe, evolved into the name of the disease only in the 20th century. Up to that point the various intermittent fevers had been called jungle fever, marsh fever, paludal fever, or swamp fever.



Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of America, Asia and Africa (Barat, 2006). Despite intensive efforts over the last century to understand and control malaria, to date it remains the greatest cause of debility and mortality through-out the world. Malaria has remained a great worldwide problem despite its eradication in Northern America and most parts of Europe towards the Second World War. In Africa sub-regions such as Nigeria, malaria remains endemic. Over 40 per cent of the world’s population live in the regions where malaria is most prevalent, around the equatorial zone, although climate change may be promoting the spread of malaria to adjacent regions (UNICEF, 2007).

Country-level burden estimates available for 2010 show that an estimated 80% of malaria deaths occur in just 14 countries. Together, the Democratic Republic of the Congo and Nigeria account for over 40% of the estimated total of malaria deaths globally (W.H.O., 2013). Malaria is a major public problem in Nigeria; Nigeria contributes a quarter of malaria burden in Africa. Over 90 per cent of the country’s 167 million people are at risk. It is estimated that malariarelated illnesses and mortality cost Africa’s economy about $12 billion annually (Vanguard, 2013).

The malaria situation in Nigeria is no different from the African regions. Due to its endemic nature, it is cliché to attribute any pyrexia to malaria in the absence of differential laboratory tests. This high rate of occurrence of malaria has made people to result to self-medication of anti-malaria drugs upon the onset of fever and headache, or even malaise and occasionally dizziness. Some of the malaria drugs are of the class artemether&lumefantrine, quinine and Artesunate. Though it is gradually reducing, but it is still worthy to note that some persons still resort to herbal remedies which comprises of extract of roots, barks and leaves of trees such as Azadrichata indica (‘Dogonyaro’). These herbal remedies does have anti-malaria properties, but it pose a danger to the patient due to the inadequate knowledge of its pharmacological properties such as the active constituents, therapeutic dosage and side effects.


The most prevalent plasmodia species in Africa is plasmodium falciparum which unfortunately causes the highest mortality rate.

Children under age five are most likely to suffer from the severe effects of malaria because they have not developed sufficient naturally acquired immunity to the parasite.

Malaria during pregnancy can range from an asymptomatic infection to a severe lifethreatening illness depending on the epidemiological setting. In areas of stable malaria transmission most adult women have developed enough natural immunity that infection does not usually result in symptoms, even during pregnancy. In such areas the main impact of malaria infection is malaria- related anaemia in the mother and the presence of parasites in the placenta, contributing to low birth weight, a leading cause of impaired development and infant mortality. In areas of unstable malaria transmission women have acquired little immunity and thus at risk of severe malaria and death.


Malaria is caused by intra-erythrocytic protozoa of the genus Plasmodium, with humans being infected by one or more of the following species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Plasmodia are primarily transmitted by the bite of an infected female Anopheles mosquito. (Zaki and Shanbag, 2011). Infections can also occur through exposure to infected blood products and by congenital transmission.



1.1.1   Anopheles Mosquito

Malaria is transmitted from man to man by the female anopheles mosquito. This genus of mosquito was first described and named by J.W Meigen in 1818. About 460 species has been recognized; while over 100 can transmit human malaria, only 30-40 commonly transmit parasites of the genus plasmodium, which cause malaria in humans in endemic regions. Anopheles gambiae is best known, because of its predominant role in the transmission of the most dangerous malaria parasite specie to humans-plasmodium falciparum.

The genome of A.gambiae has now been cracked and the effort is expected to help in future research into mosquito control strategies.

The female mosquito has a specialised apparatus to penetrate the skin of its victim.

Once through the skin, the mosquito's proboscis begins probing for a tiny blood vessel. Inside the proboscis are two hollow tubes, one that injects saliva into the microscopic wound and one that withdraws blood. The mosquito's saliva includes a combination of antihemostatic and anti- inflammatory enzymes that disrupt the clotting process and inhibit the pain reaction. (Park, 2007; Paniker, 2007).

Mosquito need human blood because female mosquito lays 30-150 eggs every 2-3 days. Human blood is needed to nourish these eggs and Anopheles shows the most regular cycles of blood feeding and egg laying. The average life span of a mosquito is 2-3 weeks. (Paniker, 2007). It can be longer in ideal living conditions. 

Anopheles mosquitoes breed in clean water collections. Therefore, breeding increases dramatically in the rainy season because many artificial water collections occur. During the rains, water collects in bottles, tins, tender coconut shells, buckets, tyres etc., that are thrown out in the open and these provide ample breeding ground. Also wells, ponds, water tanks, etc., act as breeding grounds. Usually it takes about a week for the eggs to develop into adults.



Principal mode of spread of malaria is by the bites of female anopheles mosquito. 

Other modes of transmission

 Rarely malaria can spread by the inoculation of blood from an infected person to a healthy person. In this type of malaria, asexual forms are directly inoculated into the blood and preerythrocytic development of the parasite in the liver does not occur. Therefore, this type of malaria has a shorter incubation period and relapses do not occur. Others include

        Blood transfusion (Transfusion malaria).

        Mother to the growing fetus (Congenital malaria)

        Needle stick injury (Paniker, 2007; Zaki and Shanbag, 2011).


The malaria parasite has a complex, multistage life cycle (fig.1.1.2) occurring within two living beings, the vector mosquitoes and the vertebrate hosts. The parasite passes through several stages of development such as the:

        Sporozoites (Gr. Sporos = seeds; the infectious form injected by the mosquito)

        Merozoites (Gr. Meros = piece; the stage invading the erythrocytes),

        Trophozoites (Gr. Trophes = nourishment; the form multiplying in erythrocytes),and 

        Gametocytes (sexual stages) and all these stages have their own unique shapes and structures and protein complements. The surface proteins and metabolic pathways keep changing during these different stages thus help the parasite to evade the immune clearance, while also creating problems for the development of drugs and vaccines.(Floren et al, 2002).


Figure 1.1.2: Plasmodium life cycle. Image courtesy Centre for Disease Control Sporogony within the Mosquito

Mosquitoes are the definitive hosts for the malaria parasites, wherein the sexual phase of the parasite's life cycle occurs. The sexual phase is called sporogony and results in the development of innumerable infecting forms of the parasite within the mosquito that induce disease in the human host following their injection with the mosquito bite.

When the female Anopheles draws a blood meal from an individual infected with malaria, the male and female gametocytes of the parasite find their way into the gut of the mosquito. The molecular and cellular changes in the gametocytes help the parasite to quickly adjust to the insect host from the warm-blooded human host and then to initiate the sporogonic cycle. The male and female gametes fuse in the mosquito gut to form zygotes, which subsequently develop into actively moving ookinetes that burrow into the mosquito mid-gut wall to develop into oocysts. Growth and division of each oocyst produces thousands of active haploid forms called sporozoites. After the sporogonic phase of 8–15 days, the oocyst bursts and releases sporozoites into the body cavity of the mosquito, from where they travel to and invade the mosquito salivary glands. When the mosquito thus loaded with sporozoites takes another blood meal, the sporozoites get injected from its salivary glands into the human bloodstream, causing malaria infection in the human host. It has been found that the infected mosquito and the parasite mutually benefit each other and thereby promote transmission of the infection. The Plasmodium-infected mosquitoes have a better survival and show an increased rate of bloodfeeding, particularly from an infected host. (Park, 2007, Paniker 2007, Fauci et al., 2008). ASEXUAL CYCLE Pre-erythrocytic phase (schizogony in the liver)

Man is the intermediate host for plasmodium, and it is man the asexual cycle is completed. With the mosquito bite, tens to a few hundred invasive sporozoites are introduced into the skin. Following the intradermal deposition, some sporozoites are destroyed by the local macrophages, some enter the lymphatics, and some others find a blood vessel. (Ashley M., 2008; Lucy M., 2007). The sporozoites that enter a lymphatic vessel reach the draining lymph node wherein some of the sporozoites partially develop into exo-erythrocytic stages and may also prime the T cells to mount a protective immune response. (Michael & Denise, 2007).  The sporozoites that find a blood vessel reach the liver within a few hours. It has recently been shown that the sporozoites travel by a continuous sequence of stick-and-slip motility, using the thrombospondin-related anonymous protein (TRAP) family and an actin–myosin motor. (Sylvia M et al 2009; Baum J. et al 2006). The sporozoites then negotiate through the liver sinusoids, and migrate into a few hepatocytes, and then multiply and grow within parasitophorous vacuoles. Each sporozoite develop into a schizont containing 10,000–30,000 merozoites (or more in case of P. falciparum). The pre-erythrocytic phase remains a “silent” phase, with little pathology and no symptoms, as only a few hepatocytes are affected. (Ashley M. et al, 2008). This phase is also a single cycle, i.e. it occurs just once.

The merozoites that develop within the hepatocyte are contained inside host cell-derived vesicles called merosomes that exit the liver intact, thereby protecting the merozoites from phagocytosis by Kupffer cells. These merozoites are eventually released into the blood stream at the lung capillaries and initiate the blood stage of infection thereon. (Maria M et al, 2008). Erythrocytic Schizogony

The merozoites released from the liver cells attach onto the red blood cell membrane and by a process of invagination, enter the red cell. Within the red blood cell, the asexual division starts and the parasites develop through the stages of rings, trophozoites, early schizonts and mature schizonts; each mature schizont consisting of thousands of erythrocytic merozoites. These merozoites are released by the lysis of the red blood cell and they immediately invade uninfected red cells. This repetitive cycle of invasion - multiplication - release - invasion continues. The intra erythrocytic cycle takes about 48 hours in P. vivax, P. ovale and P. falciparum infections and 72 hours in case of P. malariae infection.

The process of attachment, invasion, and establishment of the merozoite into the red cell is made possible by the specialized apical secretory organelles of the merozoite, called the micronemes, rhoptries, and dense granules. The initial interaction between the parasite and the red cell stimulates a rapid “wave” of deformation across the red cell membrane, leading to the formation of a stable parasite–host cell junction. Following this, the parasite pushes its way through the erythrocyte bilayer with the help of the actin–myosin motor, proteins of the thrombospondin-related anonymous protein family (TRAP) and aldolase, and creates a parasitophorous vacuole to seal itself from the host-cell cytoplasm, thus creating a hospitable environment for its development within the red cell. At this stage, the parasite appears as an intracellular “ring”. (Cowman and Crabb, 2006).

The content of the infected cells are released with the lysis of RBC that stimulate Tumor Necrosis Factor and other cytokines, which results in the characteristic clinical manifestation of the disease.

A small proportion of asexual parasites do not undergo schizogony but differentiate into the sexual stage gametocytes. These male or female gametocytes are extracellular and nonpathogenic and help in transmission of the infection to others through the female anopheles mosquitoes, wherein they continue the sexual phase of the parasite's life cycle.




Pathology associated with all malarial species is related to the rupture of infected erythrocytes, release of parasite material and metabolites and cellular debris. The growing parasite consumes and degrades the intracellular proteins, mainly haemoglobin (fig.1.1.3). The transport properties of the erythrocyte cell membranes are altered and new parasite derived proteins are inserted. P.falciparum has some unique adhesive characteristics that no other strains possess. Erythrocytes containing mature forms of P.falciparum adhere to microvascular endothelium (cytoadherence) and disappear from the circulation. This is called sequestration. Sequestration can be increased when adherent infected erythrocytes bind to other infected erythrocytes (autoagglutination) or non-infected erythrocytes (rosetting) or use platelets to bind to other infected erythrocytes (platelet-mediated clumping). The major advantage of sequestration for the parasite is avoidance of the spleen and subsequent elimination from the body. In addition, the low oxygen tensions in deep tissues may provide a better metabolic environment. Sequestration within the blood vessels reduces microvascular flow. In addition, the presence of parasites inside erythrocytes decreases the ability of the cells to deform so that they have more difficulty passing through the microvasculature, causing rupture. (Dondorp et al., 1997).

This occurs predominantly in the venules of vital organs. The consequence of microcirculatory obstruction are activation of the vascular endothelium and reduced oxygen and substrate supply, which leads to anaerobic glycolysis, lactic acidosis and cellular dysfunction. Once the mirocirculatory flow is affected, a range of manifestations can occur including hypoxia, release of toxic and pharmaco-active substances (free radicals, nitric oxide etc.), and disruption of capillary flow. (Rahul S, 2011).

 fig.1.1.3: pathogenesis of malaria. Courtesy nature Reviews.




Malaria infection covers a wide spectrum from asymptomatic infection to fulminant disease.

Important determinants of the clinical patterns are: 

      Species of the parasite


      Immune status, and 

      The degree of malaria endemicity. (Rahul S, 2011).


The hallmark of all forms of malaria is fever, which can occur at regular 2 to 3 day intervals in P.vivax and P.malariae, or more irregularly with P.falciparum. Fever is associated with lassitude, loss of appetite and vague pains in bones and joints. Other symptoms include tachycardia, hypotension, cough, headache, back pain, nausea, abdominal pain, vomiting, diarrhea and altered consciousness. (Rahul S., 2011). In highly endemic areas, malaria may present with various atypical manifestations listed below, with or without the presence of fever. Headache: headache maybe a presenting feature of malaria with or without fever. It can be unilateral or bilateral. Sometimes the headache could be so intense that it may mimic intra-cranial infections or intra-cranial space occupying lesions. It may also mimic migraine, .sinusitis etc. Presence of projectile vomiting, papilloedema, neck stiffness and focal neurological signs would suggest other possibilities. Body ache, back ache and joint pains: 

These symptoms are fairly common in malaria. These can occur even during the prodromal period and at that stage these are generally ignored and diagnosis of malaria is impossible owing to lack of peripheral parasitemia. They are also common accompaniments of the malaria paroxysm. Sometimes, malaria may present only with these symptoms, particularly in cases of recurrent malaria. Dizziness, vertigo: 

Some patients may present with dizziness or vertigo, with or without fever. They may also have associated vomiting and/or diarrhoea. This may mimic labyrinthitis, Menniere's disease, vertebro-basilar insufficiency etc. Rarely patients may present with swaying and cerebellar signs. Drugs like chloroquine, quinine, halofantrine and mefloquine can also cause dizziness, vertigo, and tinnitus. Convulsions, coma: 

Patients with cerebral malaria present with generalised seizures and deep unarousable coma. Sometimes one single fit can precipitate deep, unarousable coma. These could also be due to hypoglycemia and all patients presenting with these manifestations should be administered 2550% dextrose immediately. Drugs like chloroquine, quinine, mefloquine and halofantrine may also trigger convulsions. Cough:  

Cough maybe a presenting feature of malaria especially P.falciparum. The present may present with pharyngeal congestion and features of mild bronchitis. Patients that have persistent cough and/or fever even after clearance of parasitemia should be evaluated for secondary bacterial pneumonias/ bronchopneumonia and bronchitis. Weakness: 

Sometimes patients may present with history of weakness, malaise and prostration. On examination they may have significant pallor, hypotension, dehydration etc. the patient may not have fever at all. Chloroquine is also known to cause profound muscular weakness and a new disease called macrophagicmyofacitis has been described in patients receiving chloroquine. Jaundice: 

Patients may present with history of yellowish discoloration of eyes and urine. Mild jaundice is fairly common in malaria and may be seen in 20-40% of the cases. 

Deeper jaundice with serum bilirubin of more than 3 mg/dL is seen in severe P. falciparum malaria and is associated with anemia, hyperparasitemia and malarial hepatitis with elevated serum enzymes. Malaria must be considered as a differential diagnosis for all cases of jaundice in a malarious area. of lids: 

Occasionally patients may present with puffiness of lids, with or without renal dysfunction. Secondary infections: 

Malaria produces significant immune suppression and this can result in secondary infections. Common among them are pneumonia, aspiration bronchopneumonia (in the elderly), urinary tract infection, colitis etc. Meningitis and enteric fever have also been reported. In falciparum malaria, severe infection can lead to septicaemic shock (algid malaria). Persistence of fever, neutrophilic leucocytosis and focal signs of infection should always alert the clinician to this possibility of secondary infections.

(Harris V.K. et al, 2001; Sen R. et al, 1994; Bruneel F. et al, 2003; Gayathri K. et al, 2000; Oh M.D. et al, 2001; Song H.H et al, 2003).



Many patients with uncomplicated malaria have no significant intraocular abnormalities. (Lewallen, 1997). However, malaria patients may develop oedema and hyperaemia of the eyelids, chemosis of the conjunctiva, conjunctival haemorrhage and anterior uveitis (Biswas J. et al 1996; Hidayat A.A. et al 1993).

However, the scenario with complicated malaria is different. The eye “acts as a window to the brain” and therefore looking at the retina in the eyes of patients with cerebral malaria can provide a vital insight into why malaria infection in the brain is so deadly. This is because retinal and cerebral tissues are embryologically the same (neuro-ectodermal) in origin and therefore share structural and functional similarities. (White V.A et al, 2001).



 Neuro-ophthalmic manifestations

These occur primarily in a patient with cerebral malaria and are due to anaemia, vascular occlusion, inflammation and increased intracranial pressure. As a result, patients may develop a variety of visual sensory disorders during the course of the disease such as visual field defects, cortical blindness, optic neuritis, papilloedema and opticatrophy. Papilloedema is caused by raised intracranial pressure, which in patients with cerebral malaria has been hypothesised to be a result of increased intravascular blood volume arising from the presence of sequestered biomass (Rahul S., 2011). Cortical blindness is a neurological sequelae of cerebral malaria and because it is reversible, its pathogenesis has been attributed to transient ischaemia. (Idro R. et al, 2010). Occasionally, patients develop brainstem infarcts and these may produce disturbances of ocular motility related to the location and extent of the infarct. Common signs include changes in pupillary size and reaction, and disorders of conjugate gaze and eye movements. Absence of corneal and oculocephalic reflexes are associated with increased mortality. (Molyneux M.E., 1989). Retinal manifestations

Malarial retinopathy is characterized by retinal whitening, vessel changes and/or haemorrhages (figure1.1.5.2).

Retinal whitening consists of irregular patchy areas that may be localised or diffused in all segments of the retina. The retinal colour of the affected portion varies from subtle pallor to dense white. The pattern of retinal whitening is distinctive in its distribution, affecting both the central macula (sparing the foveola) and peripheral retina, although it can occur independently of each other.

Retinal whitening is similar in appearance to that observed in patches in ischaemic central retinal vein occlusion (CRVO), but has a different retinal distribution.Vessel changes manifest as discolouration (white or orange) and occur mainly in the peripheral fundus. Discrete sections of vessels or peripheral trees can be involved or larger vessels and capillaries can be involved with distinctive features (Looareesuwan S. et al, 1983). This discoloration occurs due to the absence of haemoglobin in parasitized erythrocytes, which are sequestered within the retinal vasculature and cannot reflect the normal red colour. Changes in larger vessels are commonly segmental, affecting variable lengths of scattered arterioles and venules but capillary whitening can affect large area of the fundus, often co-localizing with retinal whitening. (Rahul S., 2011) While retinal haemorrhages can occur in other conditions causing coma, in malaria (particularly when white centred) it is highly suggestive of a diagnosis of cerebral malaria. (Beare N.A., et al, 2009). It has also been observed that the number of retinal haemorrhages correlates with the number of brain haemorrhages in patients who die from cerebral malaria.


Fig1.1.5.2: Retinal manifestations of malaria. Image courtesy of White N. (2000).




Accommodation is a process where the crystalline lens increases its converging power so that diverging rays of light emanating from an object of regard is brought to focus on the retina. The amplitude of accommodation (AOA) measured in Dioptres (D) represents the maximal accommodative level, or closest near focusing response, that can be produced with maximal voluntary effort in the fully corrected eye.


The near point of convergence (NPC) measured in centimetres (cm) is defined as the amplitude of convergence (punctum proximum of convergence), or the closest point in space where the patient can hold fusion when the two eyes move-in to see one target (Borish,

1975). People with inadequate NPC may complain of eyestrain, binocular vision problems and difficulty performing near work. As a result, NPC findings are used as a screening for obvious convergence insufficiencies (Brinkley and Walonker, 1983).According to literatures, the normal value for NPC varies, and this may be due to the measuring technique used. Von Noorden, (1990) noted that the normal NPC should be 8-10cm.


For many years, severe malaria was pictured as essentially two major syndromes, with relatively simple underlying pathogenic processes: 

(i)                 Severe anaemia caused by the destruction of red blood cells (RBCs); and 

(ii)               Cerebral malaria (CM) caused by obstruction of small vessels of the brain by sequestered parasites. (Mackintosh et al, 2004).

 A major change in recent years has been the recognition that severe malaria is a complex multisystem disorder with many similarities to sepsis syndromes. At the clinical level, this is evident in the recognition of metabolic acidosis (leading to the clinical picture of respiratory distress) as the strongest predictor of death in severe malaria. (Taylor et al, 1993).The pathogenesis of metabolic acidosis is poorly understood. Hypovolaemiais a major feature of severe malaria and, when further exacerbated by anaemia and micro-vascular obstruction from sequestered parasites, is likely to lead to decreased delivery of oxygen to tissues, anaerobic metabolism and lactic acidosis.


Visual acuity is the resolving power of the eye, or the ability to see two separate objects as separate (Grosvenor, 2007). There are various measuring instruments or chart for visual acuity, e.g are snellen chart, Cardiff acuity chart, LogMAR acuity chart etc. 



Ø To determine the ocular complications of malaria.




Ø  To determine the ocular complications of malaria with its relationship with the paediatric population.


Ø  To determine if these complications are dependent on the severity of malaria parasitemia. 




This study will be able to help us find out the retina and ocular adnexa signs that are common in children with malaria in our environment. Also it will help us to assess the burden of malaria in our environment and on health services.



H10: There are no known ocular complications associated with malaria parasitaemia in the paediatric population. H1o=HA.

H1A: There are ocular complications associated with malaria parasitaemia in the paediatric population. H1o≠H1A.

H20: Malaria ocular complications are not dependent on the severity of malaria parasitaemia.


H2A: Malaria complications are dependent on the severity of malaria parasitaemia. H2o≠H2A

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