NEUROLOGICAL SYNDROMES AND THE TRAVELLER: AN APPROACH TO DIFFERENTIAL DIAGNOSIS
http://www.100md.com
《神经病学神经外科学杂志》
1 Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, Ho Chi Minh City, VietNam
2 Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, UK
Correspondence to:
Dr J N Day
Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, VietNam; jeremyday@doctors.org.uk
Keywords: tropical infection; travel; meningoencephalitis
In 2001 there were 58 million overseas trips made by UK residents, and over 22 million people visited the UK from abroad. As the relative cost of air travel falls, holidays in exotic destinations have become easier and therefore more common. Travel to such places can be associated with particular health risks, not only through exposure to indigenous pathogens but also through changes in behaviour when released from one’s normal day to day schedule—for example, use of alcohol and illicit drugs, "adventure holidays", transport, and sex. This article will focus on infectious agents that a neurologist may need to consider when asked to see an adult who has recently arrived from abroad. The emphasis will be on developing a logical approach to establishing a differential diagnosis rather than on an exhaustive list of all the potential weird and wonderful infectious agents or on the detailed specifics of treatment.
THE PATIENT’S HISTORY
Detailed history taking is the key to establishing the diagnosis in infectious diseases. The first task is to define the syndrome with which the patient presents, and then to define the particular exposure, or risk, that the patient has faced. This must involve a detailed travel history—some illnesses, such as African trypanosomiasis, occur in small well defined geographical areas within a country’s borders (Fig 1). The differential diagnosis that this generates can then be further refined through knowledge of the incubation period of the suspected diseases. For example, a feverish illness developing on the third day after arrival in West Africa could not be due to malaria, because the minimum incubation period for this infection is one week. Of course, many infections can present with non-specific features leading to a wide variety of different syndromes, or have poorly defined or widely variable incubation periods and thus need to be considered in the differential diagnosis for many patients. Such diseases include those well known to physicians throughout history—tuberculosis, typhoid, malaria, and syphilis can all present in a wide variety of ways and often need to be included in the differential diagnosis. HIV will no doubt take its place in history alongside them. A carefully taken and wide ranging history will usually allow one to narrow the differential. Remember that many travellers travel frequently to different regions of the world and their presenting illness may result from exposure that occurred two or three trips previously—detailed travel histories are crucial. There are also an increasing number of immunocompromised individuals who are travelling abroad; this group in particular are at risk of exotic infections.
Figure 1 Active foci of African trypanosomiasis (copyright A Stich, Medical Mission Institute, Würzburg).
This article is based around table 1, which classifies illnesses according to the syndrome with which they may commonly present, and describes the geographical origins of those illnesses along with their incubation periods, plus any other particular activity that might put the traveller at risk. It is not exhaustive. We have attempted to divide organisms that cause meningoencephalitis according to whether they produce a predominantly meningitic or encephalitic syndrome. Some pathogens will inevitably occur in both groups. Incubation periods are presented as ranges during which most cases of that disease will present. For some pathogens such as malaria, the minimum incubation period is well described (through knowledge gained from using malaria as a treatment for neurosyphilis). For other organisms such as helminths, it is more difficult to be precise. Characteristic features of different syndromes will be described in the text, but unfortunately, particularly early in infection, such signs and symptoms may not be obvious. Infectious agents that are well recognised causes of disease in the UK will not be discussed in detail (for example, herpes simplex). It is important to remember that a patient who has just spent two weeks in Outer Mongolia may have acquired their fever and neurological syndrome in the UK the weekend before departure. Not all fevers in returning travellers are caused by the overseas travel!
Table 1 Predominant syndromes and possible causes with incubation periods and geographical distributions
Three infections are notable for their ability to cause many different syndromes, their high mortality, and the availability of curative or dramatically disease modifying treatment if diagnosed and treated early. They are malaria, typhoid, and HIV infection.
MALARIA
This is the first diagnosis to exclude in any patient returning from an endemic region with a fever. Mosquito bites are often unnoticeable, and chemoprophylaxis and bite avoidance measures cannot provide 100% protection. The expected standard of investigation to exclude malaria is at least three negative malaria blood smears each taken 24 hours apart. There are a number of new rapid malaria detection tests available which are highly sensitive and specific.
Malaria is caused by protozoan parasites of the genus Plasmodium, spread by female anopheline mosquitoes, which require a blood meal for egg development. Four distinct species infect man (table 1). Between 1–3 million people die from malaria each year. Most of these deaths occur in children, or in non-immune adults—those living outside areas with high transmission—and are almost exclusively due to infection with Plasmodium falciparum. In areas of high transmission, immunity develops which does not prevent infection, but limits the severity of disease. This immunity is strain specific and is rapidly lost when a person leaves a hyperendemic region. Clinically, malaria is divided according to whether it is "uncomplicated" or "severe". The features of uncomplicated malaria are common to all four infecting species. The syndrome consists of a prodromal period of lassitude, headache, muscle aches and vague abdominal pain, followed 2–8 hours later with fever: similar symptoms to the common cold or flu. Rigors may occur. With prompt presentation and treatment it is unusual to see the classical patterns of two (ovale and vivax) or three (malariae) day intermittent fevers developing. Hepatosplenomegaly and anaemia may develop as the infection progresses and pronounced diarrhoea, constipation, and even a dry cough may occur.
The neurologist is more likely to be involved in the care of patients with severe or complicated malaria, which is always due to P falciparum. Severe malaria is defined according to World Health Organization (WHO) criteria, last updated in 2000 (see table 2). Neurologists may also be involved in the care of patients with the post-malaria neurological syndromes—relatively rare conditions where neurological symptoms develop after successful parasite clearance.
Table 2 World Health Organization definition of severe malaria (1990, revised 2000)
Cerebral malaria
Cerebral malaria is the most obvious feature of severe malaria and is strictly defined as unrousable coma, but in practice any impairment of conscious level should be considered concerning. It is uniformly fatal in the absence of treatment and the overall mortality of treated cerebral malaria is around 20% in adults. The prodromal illness usually lasts a few days, but can be much shorter in children. However, it is possible to have lethal malaria infection with no impairment of consciousness until death. Many neurological symptoms and signs have been described in severe malaria, including meningism, fits, focal neurological signs, and oculogyric crisis. However, these are rare, and the most common manifestation is that of a symmetrical encephalopathy with no focal neurological signs. Careful examination of eye movements should be performed to exclude subtle seizure activity. A number of abnormalities on fundoscopy have been described, including cotton wool spots, haemorrhages, and papilloedema (less common in adults). Gaze may be divergent but cranial nerve lesions are unusual. Tone and reflexes may be increased, normal or depressed, and abdominal reflexes are often absent. There may be decorticate or decerebrate posturing and opisthotonus. Deep coma, extensor posturing, seizure activity, respiratory distress, hypoglycaemia, hyperlactataemia, and a high parasite load > 4% (that is, more than 4% of all red blood cells parasitised) are poor prognostic signs.
Laboratory findings in severe malaria can include a normocytic normochromic anaemia, thrombocytopenia, normal or low white cell count, and evidence of disseminated intravascular coagulation. Hypoglycaemia occurs as a direct consequence of infection or as a side effect of intravenous quinine treatment, and should be excluded in an unconscious patient or anyone that deteriorates following admission. Hyponatraemia, raised urea and creatinine values, and raised blood lactate may occur. Lumbar puncture may reveal elevated pressure in children, but is usually normal in adults. The cerebrospinal fluid (CSF) is usually normal in cerebral malaria but there may be an elevated protein or mild lymphocytosis. CSF lactate may be raised and glucose may be slightly low.
Treatment
It is important to exclude hypoglycaemia and underlying seizure activity in any unconscious patient with malaria. In the last 10 years there has been a dramatic increase in the incidence and global spread of drug resistance and in many parts of the world P falciparum is now completely resistant to chloroquine. Treatment options are therefore limited and the mainstay of treatment for severe malaria in the UK is intravenous infusion of quinine followed by a second drug, usually doxycycline. The most important side effect of quinine is hypoglycaemia, but tinnitus, deafness, and nausea (cinchonism), and rarely cardiac arrhythmias, can occur. It is likely that the artemisin derivatives, derived from the Chinese Sweet Wormwood plant, will soon be licensed in the UK and may be used more frequently in the future. This ancient remedy has excellent efficacy and few side effects, and in endemic regions may also reduce transmission by killing the sexual stages of the parasite. Treatment of cerebral malaria is a medical emergency and specialist advice should be sought.
Fits are common in cerebral malaria, particularly in children. Phenobarbitone reduces fits in cerebral malaria, but trials in Kenya demonstrated an increase in mortality in children receiving a single prophylactic injection. This may have been related to respiratory depression. The safety of other anticonvulsants such as phenytoin in the setting of severe malaria has not been determined. Corticosteroids are not beneficial in the treatment of cerebral malaria.
Post-malaria neurological syndromes
Up to 3% of adults and 20% of children have a persistent neurological deficit after cerebral malaria. In children this appears to be related to the length of coma, profound anaemia, and prolonged seizures. Deficits include hemiparesis, cortical blindness, tremor and isolated cranial nerve palsies. Post-malaria neurological syndromes (PMNS) have been described in patients who appear to have recovered from their malarial illness but develop a new neurological syndrome a few days or weeks after becoming aparasitaemic. These problems can include acute confusional states, psychosis, generalised convulsions, tremor, or ataxia. PMNS is a relatively rare condition and usually follows severe malaria, but can follow uncomplicated disease and has been associated with the use of mefloquine, although it can occur in patients who have been treated with other drugs. This has led to the recommendation that mefloquine should not be used in the treatment of cerebral malaria unless there is no alternative available. The symptoms are distressing but generally short lived (ranging from a few hours to 10 days). There is also a syndrome of cerebellar ataxia occurring after malaria with symptoms continuing for a few weeks. Mostly these are self-limiting conditions that may have an autoimmune post-infectious aetiology. There is no trial evidence of benefit from treatment with corticosteroids.
TYPHOID
Typhoid is a systemic infection characterised by high fever, headache, and clouding of consciousness. It is caused by Salmonella typhi. Salmonella paratyphi can cause a similar although usually less severe syndrome, and has a shorter incubation period. Up to 300 cases of typhoid are imported to the UK each year, the majority originating from South Asia. The mortality of untreated typhoid is around 20%. With appropriate treatment this falls to less than 1%. The duration of illness is usually about four weeks. Despite common misconceptions, diarrhoea occurs in only about 40% of people with typhoid; 20% have normal bowel habit and 40% are constipated. An initial high fever, headache, malaise, and occasionally dry cough may be followed by abdominal distension, splenomegaly, and rose spots (difficult to see in dark skinned patients) in the second week. Untreated, the patient may develop a pronounced confusional state and complications occur: these include intestinal perforation or abscess formation in sites such as the heart, bones, joints, pleural space, or gall bladder. Sudden and massive intestinal haemorrhage may be life threatening. Meningitis or cerebral abscess may occur. Typhoid may present to the neurologist early in the disease because of an acute confusional state or fits. Later and rarer neurological complications include transverse myelitis, polyneuropathy, cranial mononeuropathy, and demyelinating leucoencephalopathy.
Diagnosis is made through isolation of the organism from blood, stool, urine or bone marrow cultures, and treatment is with quinolone antibiotics guided by antibiotic sensitivity testing and knowledge of the resistance patterns in the country where the infection was acquired.
HIV
Travellers are at increased risk of all sexually transmitted infections. There were over 4200 new diagnoses of HIV infection made in the UK in 2002. Over half of these were in heterosexuals, many having acquired their infection in sub-Saharan Africa. The many different presenting syndromes can be caused by HIV itself, or by opportunistic infection as a result of immunosuppression in established HIV infection. Doctors with an interest in infectious diseases are often asked when HIV should be considered in the differential diagnosis; the answer is usually "all the time". Encephalopathy complicates 6% of all HIV seroconversion illnesses, and a further 6% will develop neuropathy as part of primary infection. There is a clear benefit from starting anti-retroviral therapy before there is severe immunosuppression (CD4 200 cells/ml); and there may be a benefit in treating acute seroconversion syndromes in preserving HIV-specific cytotoxic T cell responses, so it is vitally important to diagnose HIV infection if present. Other neurological syndromes described as part of primary HIV infection include: retro-orbital pain increased with eye movement, myelopathy, brachial neuritis, facial palsy, cauda equina, and Guillan-Barre syndromes.
ENCEPHALITIS
Arboviruses
There are many arthropod borne viruses capable of causing encephalitis. Incubation periods and particular geographical risks are given in table 1. Arboviruses are major causes of encephalitis worldwide, but Japanese encephalitis (JE) virus is probably responsible for more cases of acute encephalitis than all the other arboviruses combined. JE virus appears to be expanding outward from southern China and Southeast Asia and is reaching Russia, the Philippines, Pakistan, and Australia. Depending upon the climate, disease can be transmitted seasonally or year round. Most cases are asymptomatic, but of those with clinically apparent disease 30% will die and 50% will be left with neurological deficit. Treatment is supportive, but an effective vaccine is available. West Nile virus is also increasing its geographical range. Originally confined to Africa and the Middle East, it has caused sporadic cases in humans and horses in Europe since the 1960s, and a Romanian outbreak in 1996 affected 400 adults with 17 deaths. The virus was detected for the first time in the USA in New York in 1999 (resulting in 62 deaths). There is evidence of seropositivity among British birds, but no evidence of disease in the UK yet. A vaccine for tick borne encephalitis is available for hikers/campers travelling to Scandinavia and central Europe.
Enteroviruses
Polio is the most notable enterovirus to cause neurological disease. It appears to have been eradicated from the Americas, and the WHO anticipates global eradication by 2005. There were 2000 cases worldwide last year compared with 350 000 in 1988. Other enteroviruses cause seasonal meningitis and meningoencephalitis, often in children. There was a large outbreak of enterovirus 71 infection in children in Taiwan in 1998, in which there were a large number of neurological complications with a death rate approaching 20%. Patients typically had myoclonus, ataxia, and cranial nerve involvement. Currently treatment is supportive, but pleconaril is a new anti-enteroviral drug currently undergoing evaluation. Japanese encephalitis (and other flaviviruses such as West Nile virus, tick borne encephalitis) can present with a syndrome clinically very similar to polio.
RABIES
Rabies is universally fatal once symptoms become apparent. Infection is caused by viruses of the genus Lyssavirus, usually following a bite from a warm blooded animal. Different animals have different susceptibilities to infection—foxes and coyotes appear most susceptible, while the opossum seems relatively protected. Most human cases are caused by dog bites, but infection can result from apparently trivial contact with bats and other animals. European bat lyssa viruses, which are closely related to the rabies virus, can cause a rabies-like illness in humans; a bat handler died in Scotland in 2002. Volunteer and licensed bat handlers should be vaccinated against rabies.
Following a bite or scratch (or perhaps inhalation of bat respiratory secretions), there is a variable incubation period, usually between 20–90 days, before the development of prodromal symptoms. An incubation period of 19 years has been reported. Forty per cent of patients describe itching or parasthesiae at the healed injury site, and constitutional symptoms include fever, headache, myalgia, and gastrointestinal upset. Over the next few days, progression to one of two syndromes—furious or paralytic rabies—occurs. The former is most common and is characterised by hydrophobic spasms, excitation, aggression, and hallucinations interspersed with periods of calm. There may be opisthotonus and generalised convulsions, arrhythmias, respiratory disturbance, cranial nerve lesions, and autonomic dysfunction. Eventually there is coma, paralysis, and death. Paralytic rabies is characteristic of bat transmitted rabies. Following the prodrome, there is paraesthesia and ascending flaccid paralysis starting from the injury site. There is loss of tendon and plantar reflexes, but sensation is intact. Death occurs after 1–3 weeks.
Treatment consists of good wound toilet and post-exposure immunoglobulin and post-exposure vaccination for those suffering animal bites or scratches. This is extremely effective if given before the development of clinical disease. For established disease, treatment consists of symptom control through sedation. Although admission to intensive care can extend life for weeks and sometimes months, treatment with hyperimmune serum and antiviral drugs has not been effective and death is inevitable. In wealthy countries rabies vaccine is produced from cell culture lines. In less wealthy countries it is sometimes derived from neural tissue, and there is a risk of a post-vaccinal encephalomyelitis which has similar symptoms to paralytic rabies. The incubation period is two weeks to two months. Conventional treatment includes corticosteroids. A fifth of cases are fatal, but if recovery occurs it is usually complete.
AFRICAN TRYPANOSOMIASIS
Human African trypanosomiasis (sleeping sickness) is caused by subspecies of the protozoan Trypanosoma brucei—T b gambiense (West African sleeping sickness, WASS) and T b rhodesiense (East African sleeping sickness, EASS). There has been a notable increase in the prevalence of this disease since the 1980s, and WHO estimates up to 600 000 people are currently infected. There have been clusters of infection of EASS among tourists visiting game parks. The disease is universally fatal if untreated and occurs in localised pockets. It is spread by the painful bite of the Tsetse fly. EASS and WASS differ in their epidemiology and clinical presentation. EASS is a zoonosis, with cattle forming the main reservoir. Humans are the major reservoir in WASS. Disease progression is more rapid in EASS, death occurring within a few weeks compared with months to years in WASS.
East African sleeping sickness
The first stage of disease develops 5–15 days after the infective bite. There may be a chancre at the site of the bite, but this painful, well circumscribed papule is often not seen in Africans. Local lymphadenopathy may develop, and fever accompanies the waves of parasitaemia. Invasion of the central nervous system leads to the second stage of disease—a progressive chronic meningoencephalitis leading to death 6–9 months after the initial bite. Drowsiness is the prominent feature—focal neurological signs are less common than in WASS.
West African sleeping sickness
Incubation is 2–3 weeks, but chancres are uncommon. There is usually an irregular fever, but other symptoms may be absent. Winterbottom’s sign (enlarged posterior cervical lymph nodes) is seen in up to 85% of patients. The asymptomatic period that follows may last for several years and parasites may be difficult to find within the blood. Signs of second stage (central nervous system) infection include motor problems, speech disturbance, or a syndrome resembling parkinsonism. Patients may suffer personality changes or psychosis; change in sleep patterns precede apathy, coma, and death. Most neurological signs reverse with treatment.
Diagnosis and treatment of sleeping sickness
Expert help should be enlisted in the diagnosis and treatment of sleeping sickness. Diagnosis is made through demonstration of parasites in the blood or lymph node aspirates. Blood concentration methods improve detection of parasites and immunological tests are available for the diagnosis of WASS. Treatment depends upon stage of disease. CSF should always be examined for parasites, although one or two doses of treatment are normally given before lumbar puncture to clear parasites from the blood and prevent inadvertent inoculation into the CSF. A CSF leucocyte count of > 5 cells/ml is considered evidence of second stage disease, whether or not parasites are seen.
The treatment for sleeping sickness has significant toxic effects. First stage WASS can be treated with pentamidine. Suramin is used for EASS. Second stage WASS is treated with eflornithine, while EASS is treated with melarsoprol, which causes an encephalopathic syndrome with 50% mortality in 10% of patients.
HERPES B VIRUS
This simian herpes virus is enzootic in macaques, with 80–90% of macaques being infected. It is the equivalent of herpes simplex virus in humans, causing life long infection with intermittent viral shedding, and is the only simian herpes virus known to cause infection in humans. Macaque handlers and travellers who are bitten or scratched by monkeys are at risk, although human infection is rare. Incubation period in humans is typically 2–10 days, but intervals of up to 10 years between exposure and illness may represent reactivation of latent infection. A herpetiform rash may develop at the site of a bite or scratch, accompanied by fever and malaise. An ascending paralysis develops over the following 1–2 weeks, which then leads to a pan-encephalitis. Diagnosis can be made by polymerase chain reaction (PCR) of CSF. Mortality is high at around 60%. Therapeutic experience is limited but intravenous acyclovir is recommended, as is post-exposure acyclovir prophylaxis for those suffering bites or scratches.
CRYPTOCOCCAL MENINGITIS
Cryptococcus neoformans has achieved prominence as the second leading cause of death in HIV positive patients worldwide. In the tropics, particularly northern Australia and Papua New Guinea, there is a variety of C neoformans that affects the immunocompetent (C neoformans var gattii). There is commonly concomitant pulmonary disease. In the environment it is found in close association with the eucalyptus tree, and koala bears are also affected. Treatment is similar to treatment for HIV associated disease, although there may be a role for steroids. Permanent neurological deficit, particularly blindness, is common and the mortality rate is high.
EOSINOPHILIC MENINGITIS
There are many causes of this syndrome. In travellers to Africa, schistosomiasis is the most common helminth infection encountered. Very rarely, an eosinophilic meningitis may result from the presence of ectopic eggs; this requires prolonged infection and a relatively heavy worm burden, and is therefore rare in the tourist. Ectopic deposition of eggs in schistosomiasis can also cause spinal syndromes.
The risk of eosinophilic meningitis is greater for the traveller to Southeast Asia, where the justifiably famous cuisine may include raw or pickled snails, amphibian, or snakes (fig 2). The cautious take a phrase book into the restaurants. It is relatively easy to kill the worms with antiparasitic drugs. However, the physical damage caused by the infection may result in severe neurological deficit. Steroids are recommended as adjuvant treatment.
Figure 2 Culinary sources of causes of eosinophilic meningitis (copyright JN Day).
TICK PARALYSIS
Both hard (Ixodidae) and soft (Argasidae) ticks have been implicated in tick paralysis, due to a neurotoxin contained within tick saliva that causes pre-synaptic neuromuscular block and decreased nerve conduction velocity. Most cases occur in North America and Australia, and the mortality is 10%. The syndrome, which is of a progressive ascending lower motor neurone paralysis, develops 5–6 days after the tick has been embedded. Over the next few days bulbar and respiratory paralysis will develop. There may be vomiting. The attached tick is usually not obvious, and may be in a body fold or on the scalp. There may be more then one tick attached so the whole body should be carefully examined. Symptoms usually resolve rapidly with tick removal. Antitoxin is available in Australia.
SHELLFISH/CIGUATERA TOXIN POISONING
Various toxin producing dinoflagellates (algae) can become concentrated in the food chain and result in poisoning when eaten. Paralytic shellfish poisoning results from eating bivalve molluscs such as clams, oysters, and scallops. Onset is rapid (within 30 minutes) and includes peri-oral anaesthesia, gastrointestinal symptoms, ataxia, and paralysis rapidly progressing to respiratory arrest in 8% of cases. Ciguateratoxin poisoning results from eating carnivorous fish such as snappers and barracuda. Incubation period is minutes to 30 hours after ingestion. Again gastrointestinal symptoms may be present, which accompany a wide variety of neurological symptoms including ataxia, vertigo, flaccid paralysis, and respiratory arrest. Some patients are reported to suffer reversed perception of hot and cold. The neurological symptoms may persist for many years.
MEDICATION AND VACCINATIONS
Neurological illnesses may occur as a result of pre-travel vaccinations or a side effect of antimalarial drugs. Rarely Japanese B encephalitis vaccination has been associated with encephalomyelitis (around 1 in 10 000), although the risk may have been overstated. Many people taking a number of anti-malarial drugs report mild neuropsychiatric side effects. Mefloquine may cause dizziness, vertigo, and fits, and very rarely may be associated with severe neuropsychiatric effects.
SUMMARY
Despite the large number of exotic infecting agents that may cause neurological syndromes, the returning traveller is more likely to be infected with an organism that is well known to the temperate physician. Meningitis will most likely be due to organisms indigenous to the UK, encephalitis will most likely be due to herpes simplex virus. The two most commonly imported life threatening tropical infections are malaria and typhoid, and these illnesses should be excluded quickly in all patients. Detailed history taking, particularly regarding travel, activities while away, sexual history and immunisation history helps to narrow the differential diagnosis. A methodical approach and basic knowledge of incubation periods can help to limit unnecessary investigation.
REFERENCES
Cook GC, Zumla A, eds. Manson’s tropical diseases, 21st ed. Saunders 2003, Elsevier Science Ltd, Edinburgh, UK.
The standard tropical diseases text.
Newton PN, Angus BJ, Chierakul W, et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003;37:7–16.
Nguyen TH, Day NP, Ly VC, et al. Post-malaria neurological syndrome. Lancet 19965;348:917–21.
Important paper describing this syndrome and the association with mefloquine treatment.
Crawley J, Waruiru C, Mithwani S, et al. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 2000;355:701–6.
Seminal paper demonstrating increased mortality in children with severe malaria given prophylactic phenobarbital.
Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens . Lancet 2002;359:507–13.
World Health Organization. http://www.who.int/health_topics/malaria/en/.
WHO malaria site detailing epidemiology, "Roll Back Malaria" campaign, definitions, and treatment.
Legros D, Ollivier G, Gastellu-Etchegorry M, et al. Treatment of human African trypanosomiasis – present situation and needs for research and development . Lancet Infect Dis 2002;2:437–40.
Good description of currently available treatment and future research objectives.
Solomon T. Recent advances in Japanese encephalitis . J Neurovirol 2003;9:274–83.
Shakir R, Newman P, Poser C, eds. Tropical neurology. Philadelphia: Saunders, 1995.
A good summary of neurological problems associated with the tropics.(J N Day1 and D G Lalloo2)
2 Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, UK
Correspondence to:
Dr J N Day
Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, VietNam; jeremyday@doctors.org.uk
Keywords: tropical infection; travel; meningoencephalitis
In 2001 there were 58 million overseas trips made by UK residents, and over 22 million people visited the UK from abroad. As the relative cost of air travel falls, holidays in exotic destinations have become easier and therefore more common. Travel to such places can be associated with particular health risks, not only through exposure to indigenous pathogens but also through changes in behaviour when released from one’s normal day to day schedule—for example, use of alcohol and illicit drugs, "adventure holidays", transport, and sex. This article will focus on infectious agents that a neurologist may need to consider when asked to see an adult who has recently arrived from abroad. The emphasis will be on developing a logical approach to establishing a differential diagnosis rather than on an exhaustive list of all the potential weird and wonderful infectious agents or on the detailed specifics of treatment.
THE PATIENT’S HISTORY
Detailed history taking is the key to establishing the diagnosis in infectious diseases. The first task is to define the syndrome with which the patient presents, and then to define the particular exposure, or risk, that the patient has faced. This must involve a detailed travel history—some illnesses, such as African trypanosomiasis, occur in small well defined geographical areas within a country’s borders (Fig 1). The differential diagnosis that this generates can then be further refined through knowledge of the incubation period of the suspected diseases. For example, a feverish illness developing on the third day after arrival in West Africa could not be due to malaria, because the minimum incubation period for this infection is one week. Of course, many infections can present with non-specific features leading to a wide variety of different syndromes, or have poorly defined or widely variable incubation periods and thus need to be considered in the differential diagnosis for many patients. Such diseases include those well known to physicians throughout history—tuberculosis, typhoid, malaria, and syphilis can all present in a wide variety of ways and often need to be included in the differential diagnosis. HIV will no doubt take its place in history alongside them. A carefully taken and wide ranging history will usually allow one to narrow the differential. Remember that many travellers travel frequently to different regions of the world and their presenting illness may result from exposure that occurred two or three trips previously—detailed travel histories are crucial. There are also an increasing number of immunocompromised individuals who are travelling abroad; this group in particular are at risk of exotic infections.
Figure 1 Active foci of African trypanosomiasis (copyright A Stich, Medical Mission Institute, Würzburg).
This article is based around table 1, which classifies illnesses according to the syndrome with which they may commonly present, and describes the geographical origins of those illnesses along with their incubation periods, plus any other particular activity that might put the traveller at risk. It is not exhaustive. We have attempted to divide organisms that cause meningoencephalitis according to whether they produce a predominantly meningitic or encephalitic syndrome. Some pathogens will inevitably occur in both groups. Incubation periods are presented as ranges during which most cases of that disease will present. For some pathogens such as malaria, the minimum incubation period is well described (through knowledge gained from using malaria as a treatment for neurosyphilis). For other organisms such as helminths, it is more difficult to be precise. Characteristic features of different syndromes will be described in the text, but unfortunately, particularly early in infection, such signs and symptoms may not be obvious. Infectious agents that are well recognised causes of disease in the UK will not be discussed in detail (for example, herpes simplex). It is important to remember that a patient who has just spent two weeks in Outer Mongolia may have acquired their fever and neurological syndrome in the UK the weekend before departure. Not all fevers in returning travellers are caused by the overseas travel!
Table 1 Predominant syndromes and possible causes with incubation periods and geographical distributions
Three infections are notable for their ability to cause many different syndromes, their high mortality, and the availability of curative or dramatically disease modifying treatment if diagnosed and treated early. They are malaria, typhoid, and HIV infection.
MALARIA
This is the first diagnosis to exclude in any patient returning from an endemic region with a fever. Mosquito bites are often unnoticeable, and chemoprophylaxis and bite avoidance measures cannot provide 100% protection. The expected standard of investigation to exclude malaria is at least three negative malaria blood smears each taken 24 hours apart. There are a number of new rapid malaria detection tests available which are highly sensitive and specific.
Malaria is caused by protozoan parasites of the genus Plasmodium, spread by female anopheline mosquitoes, which require a blood meal for egg development. Four distinct species infect man (table 1). Between 1–3 million people die from malaria each year. Most of these deaths occur in children, or in non-immune adults—those living outside areas with high transmission—and are almost exclusively due to infection with Plasmodium falciparum. In areas of high transmission, immunity develops which does not prevent infection, but limits the severity of disease. This immunity is strain specific and is rapidly lost when a person leaves a hyperendemic region. Clinically, malaria is divided according to whether it is "uncomplicated" or "severe". The features of uncomplicated malaria are common to all four infecting species. The syndrome consists of a prodromal period of lassitude, headache, muscle aches and vague abdominal pain, followed 2–8 hours later with fever: similar symptoms to the common cold or flu. Rigors may occur. With prompt presentation and treatment it is unusual to see the classical patterns of two (ovale and vivax) or three (malariae) day intermittent fevers developing. Hepatosplenomegaly and anaemia may develop as the infection progresses and pronounced diarrhoea, constipation, and even a dry cough may occur.
The neurologist is more likely to be involved in the care of patients with severe or complicated malaria, which is always due to P falciparum. Severe malaria is defined according to World Health Organization (WHO) criteria, last updated in 2000 (see table 2). Neurologists may also be involved in the care of patients with the post-malaria neurological syndromes—relatively rare conditions where neurological symptoms develop after successful parasite clearance.
Table 2 World Health Organization definition of severe malaria (1990, revised 2000)
Cerebral malaria
Cerebral malaria is the most obvious feature of severe malaria and is strictly defined as unrousable coma, but in practice any impairment of conscious level should be considered concerning. It is uniformly fatal in the absence of treatment and the overall mortality of treated cerebral malaria is around 20% in adults. The prodromal illness usually lasts a few days, but can be much shorter in children. However, it is possible to have lethal malaria infection with no impairment of consciousness until death. Many neurological symptoms and signs have been described in severe malaria, including meningism, fits, focal neurological signs, and oculogyric crisis. However, these are rare, and the most common manifestation is that of a symmetrical encephalopathy with no focal neurological signs. Careful examination of eye movements should be performed to exclude subtle seizure activity. A number of abnormalities on fundoscopy have been described, including cotton wool spots, haemorrhages, and papilloedema (less common in adults). Gaze may be divergent but cranial nerve lesions are unusual. Tone and reflexes may be increased, normal or depressed, and abdominal reflexes are often absent. There may be decorticate or decerebrate posturing and opisthotonus. Deep coma, extensor posturing, seizure activity, respiratory distress, hypoglycaemia, hyperlactataemia, and a high parasite load > 4% (that is, more than 4% of all red blood cells parasitised) are poor prognostic signs.
Laboratory findings in severe malaria can include a normocytic normochromic anaemia, thrombocytopenia, normal or low white cell count, and evidence of disseminated intravascular coagulation. Hypoglycaemia occurs as a direct consequence of infection or as a side effect of intravenous quinine treatment, and should be excluded in an unconscious patient or anyone that deteriorates following admission. Hyponatraemia, raised urea and creatinine values, and raised blood lactate may occur. Lumbar puncture may reveal elevated pressure in children, but is usually normal in adults. The cerebrospinal fluid (CSF) is usually normal in cerebral malaria but there may be an elevated protein or mild lymphocytosis. CSF lactate may be raised and glucose may be slightly low.
Treatment
It is important to exclude hypoglycaemia and underlying seizure activity in any unconscious patient with malaria. In the last 10 years there has been a dramatic increase in the incidence and global spread of drug resistance and in many parts of the world P falciparum is now completely resistant to chloroquine. Treatment options are therefore limited and the mainstay of treatment for severe malaria in the UK is intravenous infusion of quinine followed by a second drug, usually doxycycline. The most important side effect of quinine is hypoglycaemia, but tinnitus, deafness, and nausea (cinchonism), and rarely cardiac arrhythmias, can occur. It is likely that the artemisin derivatives, derived from the Chinese Sweet Wormwood plant, will soon be licensed in the UK and may be used more frequently in the future. This ancient remedy has excellent efficacy and few side effects, and in endemic regions may also reduce transmission by killing the sexual stages of the parasite. Treatment of cerebral malaria is a medical emergency and specialist advice should be sought.
Fits are common in cerebral malaria, particularly in children. Phenobarbitone reduces fits in cerebral malaria, but trials in Kenya demonstrated an increase in mortality in children receiving a single prophylactic injection. This may have been related to respiratory depression. The safety of other anticonvulsants such as phenytoin in the setting of severe malaria has not been determined. Corticosteroids are not beneficial in the treatment of cerebral malaria.
Post-malaria neurological syndromes
Up to 3% of adults and 20% of children have a persistent neurological deficit after cerebral malaria. In children this appears to be related to the length of coma, profound anaemia, and prolonged seizures. Deficits include hemiparesis, cortical blindness, tremor and isolated cranial nerve palsies. Post-malaria neurological syndromes (PMNS) have been described in patients who appear to have recovered from their malarial illness but develop a new neurological syndrome a few days or weeks after becoming aparasitaemic. These problems can include acute confusional states, psychosis, generalised convulsions, tremor, or ataxia. PMNS is a relatively rare condition and usually follows severe malaria, but can follow uncomplicated disease and has been associated with the use of mefloquine, although it can occur in patients who have been treated with other drugs. This has led to the recommendation that mefloquine should not be used in the treatment of cerebral malaria unless there is no alternative available. The symptoms are distressing but generally short lived (ranging from a few hours to 10 days). There is also a syndrome of cerebellar ataxia occurring after malaria with symptoms continuing for a few weeks. Mostly these are self-limiting conditions that may have an autoimmune post-infectious aetiology. There is no trial evidence of benefit from treatment with corticosteroids.
TYPHOID
Typhoid is a systemic infection characterised by high fever, headache, and clouding of consciousness. It is caused by Salmonella typhi. Salmonella paratyphi can cause a similar although usually less severe syndrome, and has a shorter incubation period. Up to 300 cases of typhoid are imported to the UK each year, the majority originating from South Asia. The mortality of untreated typhoid is around 20%. With appropriate treatment this falls to less than 1%. The duration of illness is usually about four weeks. Despite common misconceptions, diarrhoea occurs in only about 40% of people with typhoid; 20% have normal bowel habit and 40% are constipated. An initial high fever, headache, malaise, and occasionally dry cough may be followed by abdominal distension, splenomegaly, and rose spots (difficult to see in dark skinned patients) in the second week. Untreated, the patient may develop a pronounced confusional state and complications occur: these include intestinal perforation or abscess formation in sites such as the heart, bones, joints, pleural space, or gall bladder. Sudden and massive intestinal haemorrhage may be life threatening. Meningitis or cerebral abscess may occur. Typhoid may present to the neurologist early in the disease because of an acute confusional state or fits. Later and rarer neurological complications include transverse myelitis, polyneuropathy, cranial mononeuropathy, and demyelinating leucoencephalopathy.
Diagnosis is made through isolation of the organism from blood, stool, urine or bone marrow cultures, and treatment is with quinolone antibiotics guided by antibiotic sensitivity testing and knowledge of the resistance patterns in the country where the infection was acquired.
HIV
Travellers are at increased risk of all sexually transmitted infections. There were over 4200 new diagnoses of HIV infection made in the UK in 2002. Over half of these were in heterosexuals, many having acquired their infection in sub-Saharan Africa. The many different presenting syndromes can be caused by HIV itself, or by opportunistic infection as a result of immunosuppression in established HIV infection. Doctors with an interest in infectious diseases are often asked when HIV should be considered in the differential diagnosis; the answer is usually "all the time". Encephalopathy complicates 6% of all HIV seroconversion illnesses, and a further 6% will develop neuropathy as part of primary infection. There is a clear benefit from starting anti-retroviral therapy before there is severe immunosuppression (CD4 200 cells/ml); and there may be a benefit in treating acute seroconversion syndromes in preserving HIV-specific cytotoxic T cell responses, so it is vitally important to diagnose HIV infection if present. Other neurological syndromes described as part of primary HIV infection include: retro-orbital pain increased with eye movement, myelopathy, brachial neuritis, facial palsy, cauda equina, and Guillan-Barre syndromes.
ENCEPHALITIS
Arboviruses
There are many arthropod borne viruses capable of causing encephalitis. Incubation periods and particular geographical risks are given in table 1. Arboviruses are major causes of encephalitis worldwide, but Japanese encephalitis (JE) virus is probably responsible for more cases of acute encephalitis than all the other arboviruses combined. JE virus appears to be expanding outward from southern China and Southeast Asia and is reaching Russia, the Philippines, Pakistan, and Australia. Depending upon the climate, disease can be transmitted seasonally or year round. Most cases are asymptomatic, but of those with clinically apparent disease 30% will die and 50% will be left with neurological deficit. Treatment is supportive, but an effective vaccine is available. West Nile virus is also increasing its geographical range. Originally confined to Africa and the Middle East, it has caused sporadic cases in humans and horses in Europe since the 1960s, and a Romanian outbreak in 1996 affected 400 adults with 17 deaths. The virus was detected for the first time in the USA in New York in 1999 (resulting in 62 deaths). There is evidence of seropositivity among British birds, but no evidence of disease in the UK yet. A vaccine for tick borne encephalitis is available for hikers/campers travelling to Scandinavia and central Europe.
Enteroviruses
Polio is the most notable enterovirus to cause neurological disease. It appears to have been eradicated from the Americas, and the WHO anticipates global eradication by 2005. There were 2000 cases worldwide last year compared with 350 000 in 1988. Other enteroviruses cause seasonal meningitis and meningoencephalitis, often in children. There was a large outbreak of enterovirus 71 infection in children in Taiwan in 1998, in which there were a large number of neurological complications with a death rate approaching 20%. Patients typically had myoclonus, ataxia, and cranial nerve involvement. Currently treatment is supportive, but pleconaril is a new anti-enteroviral drug currently undergoing evaluation. Japanese encephalitis (and other flaviviruses such as West Nile virus, tick borne encephalitis) can present with a syndrome clinically very similar to polio.
RABIES
Rabies is universally fatal once symptoms become apparent. Infection is caused by viruses of the genus Lyssavirus, usually following a bite from a warm blooded animal. Different animals have different susceptibilities to infection—foxes and coyotes appear most susceptible, while the opossum seems relatively protected. Most human cases are caused by dog bites, but infection can result from apparently trivial contact with bats and other animals. European bat lyssa viruses, which are closely related to the rabies virus, can cause a rabies-like illness in humans; a bat handler died in Scotland in 2002. Volunteer and licensed bat handlers should be vaccinated against rabies.
Following a bite or scratch (or perhaps inhalation of bat respiratory secretions), there is a variable incubation period, usually between 20–90 days, before the development of prodromal symptoms. An incubation period of 19 years has been reported. Forty per cent of patients describe itching or parasthesiae at the healed injury site, and constitutional symptoms include fever, headache, myalgia, and gastrointestinal upset. Over the next few days, progression to one of two syndromes—furious or paralytic rabies—occurs. The former is most common and is characterised by hydrophobic spasms, excitation, aggression, and hallucinations interspersed with periods of calm. There may be opisthotonus and generalised convulsions, arrhythmias, respiratory disturbance, cranial nerve lesions, and autonomic dysfunction. Eventually there is coma, paralysis, and death. Paralytic rabies is characteristic of bat transmitted rabies. Following the prodrome, there is paraesthesia and ascending flaccid paralysis starting from the injury site. There is loss of tendon and plantar reflexes, but sensation is intact. Death occurs after 1–3 weeks.
Treatment consists of good wound toilet and post-exposure immunoglobulin and post-exposure vaccination for those suffering animal bites or scratches. This is extremely effective if given before the development of clinical disease. For established disease, treatment consists of symptom control through sedation. Although admission to intensive care can extend life for weeks and sometimes months, treatment with hyperimmune serum and antiviral drugs has not been effective and death is inevitable. In wealthy countries rabies vaccine is produced from cell culture lines. In less wealthy countries it is sometimes derived from neural tissue, and there is a risk of a post-vaccinal encephalomyelitis which has similar symptoms to paralytic rabies. The incubation period is two weeks to two months. Conventional treatment includes corticosteroids. A fifth of cases are fatal, but if recovery occurs it is usually complete.
AFRICAN TRYPANOSOMIASIS
Human African trypanosomiasis (sleeping sickness) is caused by subspecies of the protozoan Trypanosoma brucei—T b gambiense (West African sleeping sickness, WASS) and T b rhodesiense (East African sleeping sickness, EASS). There has been a notable increase in the prevalence of this disease since the 1980s, and WHO estimates up to 600 000 people are currently infected. There have been clusters of infection of EASS among tourists visiting game parks. The disease is universally fatal if untreated and occurs in localised pockets. It is spread by the painful bite of the Tsetse fly. EASS and WASS differ in their epidemiology and clinical presentation. EASS is a zoonosis, with cattle forming the main reservoir. Humans are the major reservoir in WASS. Disease progression is more rapid in EASS, death occurring within a few weeks compared with months to years in WASS.
East African sleeping sickness
The first stage of disease develops 5–15 days after the infective bite. There may be a chancre at the site of the bite, but this painful, well circumscribed papule is often not seen in Africans. Local lymphadenopathy may develop, and fever accompanies the waves of parasitaemia. Invasion of the central nervous system leads to the second stage of disease—a progressive chronic meningoencephalitis leading to death 6–9 months after the initial bite. Drowsiness is the prominent feature—focal neurological signs are less common than in WASS.
West African sleeping sickness
Incubation is 2–3 weeks, but chancres are uncommon. There is usually an irregular fever, but other symptoms may be absent. Winterbottom’s sign (enlarged posterior cervical lymph nodes) is seen in up to 85% of patients. The asymptomatic period that follows may last for several years and parasites may be difficult to find within the blood. Signs of second stage (central nervous system) infection include motor problems, speech disturbance, or a syndrome resembling parkinsonism. Patients may suffer personality changes or psychosis; change in sleep patterns precede apathy, coma, and death. Most neurological signs reverse with treatment.
Diagnosis and treatment of sleeping sickness
Expert help should be enlisted in the diagnosis and treatment of sleeping sickness. Diagnosis is made through demonstration of parasites in the blood or lymph node aspirates. Blood concentration methods improve detection of parasites and immunological tests are available for the diagnosis of WASS. Treatment depends upon stage of disease. CSF should always be examined for parasites, although one or two doses of treatment are normally given before lumbar puncture to clear parasites from the blood and prevent inadvertent inoculation into the CSF. A CSF leucocyte count of > 5 cells/ml is considered evidence of second stage disease, whether or not parasites are seen.
The treatment for sleeping sickness has significant toxic effects. First stage WASS can be treated with pentamidine. Suramin is used for EASS. Second stage WASS is treated with eflornithine, while EASS is treated with melarsoprol, which causes an encephalopathic syndrome with 50% mortality in 10% of patients.
HERPES B VIRUS
This simian herpes virus is enzootic in macaques, with 80–90% of macaques being infected. It is the equivalent of herpes simplex virus in humans, causing life long infection with intermittent viral shedding, and is the only simian herpes virus known to cause infection in humans. Macaque handlers and travellers who are bitten or scratched by monkeys are at risk, although human infection is rare. Incubation period in humans is typically 2–10 days, but intervals of up to 10 years between exposure and illness may represent reactivation of latent infection. A herpetiform rash may develop at the site of a bite or scratch, accompanied by fever and malaise. An ascending paralysis develops over the following 1–2 weeks, which then leads to a pan-encephalitis. Diagnosis can be made by polymerase chain reaction (PCR) of CSF. Mortality is high at around 60%. Therapeutic experience is limited but intravenous acyclovir is recommended, as is post-exposure acyclovir prophylaxis for those suffering bites or scratches.
CRYPTOCOCCAL MENINGITIS
Cryptococcus neoformans has achieved prominence as the second leading cause of death in HIV positive patients worldwide. In the tropics, particularly northern Australia and Papua New Guinea, there is a variety of C neoformans that affects the immunocompetent (C neoformans var gattii). There is commonly concomitant pulmonary disease. In the environment it is found in close association with the eucalyptus tree, and koala bears are also affected. Treatment is similar to treatment for HIV associated disease, although there may be a role for steroids. Permanent neurological deficit, particularly blindness, is common and the mortality rate is high.
EOSINOPHILIC MENINGITIS
There are many causes of this syndrome. In travellers to Africa, schistosomiasis is the most common helminth infection encountered. Very rarely, an eosinophilic meningitis may result from the presence of ectopic eggs; this requires prolonged infection and a relatively heavy worm burden, and is therefore rare in the tourist. Ectopic deposition of eggs in schistosomiasis can also cause spinal syndromes.
The risk of eosinophilic meningitis is greater for the traveller to Southeast Asia, where the justifiably famous cuisine may include raw or pickled snails, amphibian, or snakes (fig 2). The cautious take a phrase book into the restaurants. It is relatively easy to kill the worms with antiparasitic drugs. However, the physical damage caused by the infection may result in severe neurological deficit. Steroids are recommended as adjuvant treatment.
Figure 2 Culinary sources of causes of eosinophilic meningitis (copyright JN Day).
TICK PARALYSIS
Both hard (Ixodidae) and soft (Argasidae) ticks have been implicated in tick paralysis, due to a neurotoxin contained within tick saliva that causes pre-synaptic neuromuscular block and decreased nerve conduction velocity. Most cases occur in North America and Australia, and the mortality is 10%. The syndrome, which is of a progressive ascending lower motor neurone paralysis, develops 5–6 days after the tick has been embedded. Over the next few days bulbar and respiratory paralysis will develop. There may be vomiting. The attached tick is usually not obvious, and may be in a body fold or on the scalp. There may be more then one tick attached so the whole body should be carefully examined. Symptoms usually resolve rapidly with tick removal. Antitoxin is available in Australia.
SHELLFISH/CIGUATERA TOXIN POISONING
Various toxin producing dinoflagellates (algae) can become concentrated in the food chain and result in poisoning when eaten. Paralytic shellfish poisoning results from eating bivalve molluscs such as clams, oysters, and scallops. Onset is rapid (within 30 minutes) and includes peri-oral anaesthesia, gastrointestinal symptoms, ataxia, and paralysis rapidly progressing to respiratory arrest in 8% of cases. Ciguateratoxin poisoning results from eating carnivorous fish such as snappers and barracuda. Incubation period is minutes to 30 hours after ingestion. Again gastrointestinal symptoms may be present, which accompany a wide variety of neurological symptoms including ataxia, vertigo, flaccid paralysis, and respiratory arrest. Some patients are reported to suffer reversed perception of hot and cold. The neurological symptoms may persist for many years.
MEDICATION AND VACCINATIONS
Neurological illnesses may occur as a result of pre-travel vaccinations or a side effect of antimalarial drugs. Rarely Japanese B encephalitis vaccination has been associated with encephalomyelitis (around 1 in 10 000), although the risk may have been overstated. Many people taking a number of anti-malarial drugs report mild neuropsychiatric side effects. Mefloquine may cause dizziness, vertigo, and fits, and very rarely may be associated with severe neuropsychiatric effects.
SUMMARY
Despite the large number of exotic infecting agents that may cause neurological syndromes, the returning traveller is more likely to be infected with an organism that is well known to the temperate physician. Meningitis will most likely be due to organisms indigenous to the UK, encephalitis will most likely be due to herpes simplex virus. The two most commonly imported life threatening tropical infections are malaria and typhoid, and these illnesses should be excluded quickly in all patients. Detailed history taking, particularly regarding travel, activities while away, sexual history and immunisation history helps to narrow the differential diagnosis. A methodical approach and basic knowledge of incubation periods can help to limit unnecessary investigation.
REFERENCES
Cook GC, Zumla A, eds. Manson’s tropical diseases, 21st ed. Saunders 2003, Elsevier Science Ltd, Edinburgh, UK.
The standard tropical diseases text.
Newton PN, Angus BJ, Chierakul W, et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003;37:7–16.
Nguyen TH, Day NP, Ly VC, et al. Post-malaria neurological syndrome. Lancet 19965;348:917–21.
Important paper describing this syndrome and the association with mefloquine treatment.
Crawley J, Waruiru C, Mithwani S, et al. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 2000;355:701–6.
Seminal paper demonstrating increased mortality in children with severe malaria given prophylactic phenobarbital.
Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens . Lancet 2002;359:507–13.
World Health Organization. http://www.who.int/health_topics/malaria/en/.
WHO malaria site detailing epidemiology, "Roll Back Malaria" campaign, definitions, and treatment.
Legros D, Ollivier G, Gastellu-Etchegorry M, et al. Treatment of human African trypanosomiasis – present situation and needs for research and development . Lancet Infect Dis 2002;2:437–40.
Good description of currently available treatment and future research objectives.
Solomon T. Recent advances in Japanese encephalitis . J Neurovirol 2003;9:274–83.
Shakir R, Newman P, Poser C, eds. Tropical neurology. Philadelphia: Saunders, 1995.
A good summary of neurological problems associated with the tropics.(J N Day1 and D G Lalloo2)