Case of the Month

December 2010

Dr Philip Botha, Infectious Diseases Specialist, Tygerberg Hospital

Dr Albie de Frey and Lee Baker – South African Society of Travel Medicine

We describe two clinical cases, one originating from South Africa and the other from Australia. Both cases demonstrate the importance of a good history including a good travel history, meticulous attention to detail and the importance of good laboratory facilities to back the clinical diagnosis.

Case 1:

A previously fit and healthy, self-employed, middle aged South African engineer was admitted to a private hospital on the Highveld. He presented with erratic ‘soft’ neurological symptoms including inconsistent disorientation for time and place, inappropriate humour and mildly anti-social behaviour drawing the attention of the nursing supervisor on night duty. He did not have any obvious motor loss. He complained about a headache and there was mention of a low grade fever. All other vital signs and physical examination were normal.

He had a history of admission for ‘cerebral malaria’ to the ICU of the same hospital approximately three weeks before. He spent about a week in ICU and responded well to IV Quinine followed by oral doxycycline for seven days. He did not require mechanical ventilation nor renal dialysis.

In the period in-between admissions he was well with normal behaviour only complaining of a degree of fatigue ascribed to his infection and stay in ICU.

It had been assumed that he had contracted Plasmodium falciparum malaria in Nampula, Mozambique but he had travelled to the north of Zimbabwe for business a few weeks earlier. There was no other travel history.

This resembled a similar case that had occurred previously. See Case 2.

Case 2:

A sixty year old Australian Camp manager returned to work on a mine in West Africa two months after being admitted to a hospital in Australia for what had been diagnosed as P falciparum malaria whilst on home leave.

He was a well controlled, known insulin independent diabetic and other than having lost approximately 10kg he was considered fit and well. The weight loss had been ascribed to his spat with malaria including a week long stay in ICU.

Approximately ten days after his return to site he presented to the mine clinic with confusion, memory loss and disorientation for time and place.

He was thought to have malaria again in spite of the absence of a documented fever and a negative malaria antigen test. He was sent to Johannesburg, South Africa for further investigation and management.

Question 1: What is your differential diagnosis in Case 1?

Answer to Q1

  1. Malaria: Recrudescence of P falciparum. This could not be a newly acquired infection as there is no malaria on the Highveld. (Except ‘taxi’ malaria….) Both recrudescent and relapsing infections manifest as return of disease after its apparent cessation. Recrudescence occurs most often within days or weeks; relapse occurs within weeks or months. In recrudescence, parasites remain in the bloodstream undetected due to ineffective treatment or host immunological response (or both). In relapse, new hypnozoites are released from liver cells causing another parasitaemia. P. falciparum is the usual cause of recrudescent infections, although P. malariae can remain dormant for years; P. vivax and P. ovale may cause relapse months after the primary blood stage infection is cured, as these species have hypnozoite forms.
  2. Malaria: Relapse of P vivax or ovale (If he had had a mixed infection previously. P falciparum is responsible for 95% of the malaria in Sub-Saharan Africa).
  3. Trypanosomiasis: This is not known to occur in the Nampula area of Mozambique but could occur in the region. He had however been to the Zambezi Valley where Sleeping Sickness does occur. There are two forms of the disease, one of which occurs mainly in East Africa and is caused by the parasite Trypanosoma brucei rhodesiense. The other arises mainly in West and Central Africa and is caused by Trypanosoma brucei gambiense. They are both transmitted by the tsetse fly and have identical morphologic appearances. However, the clinical infections differ in presentation and prognosis. Both are characterized by an early stage, during which trypanosomes are found circulating in the blood or in lymph nodes, and a late stage in which there is prominent involvement of the central nervous system (CNS). T. b. gambiense is a slowly progressive infection, and the asymptomatic phase can last for months or years. In contrast, T. b. rhodesiense tends to progress rapidly, and CNS involvement is often detectable within weeks of infection. Both infections are fatal if untreated. In T. b. gambiense, early symptoms include intermittent headache, fevers, malaise and arthralgias. These symptoms are frequently intermittent, corresponding with successive waves of parasitaemia and antibody production. Organomegaly, in particularly splenomegaly, is a common finding. Generalized lymphadenopathy is also often present. Other nonspecific symptoms may be present, including pruritus, rash, weight loss and facial swelling. Neuroendocrine disturbances leading to amenorrhea in women or impotence in men may also be seen. In the later stages of T. b. gambiense disease, progressive diffuse meningoencephalitis and parenchymal edema of the brain develop. Perivascular and meningeal inflammatory infiltrates, cerebral hemorrhages, and widespread multifocal white matter demyelination occur. Symptoms include: headache, difficulty concentrating, personality changes, psychosis, sensory disorders, tremor and ataxia. Meningismus and focal neurologic signs may occur but are unusual. An alteration of the circadian sleep/wake cycle leading to daytime somnolence also frequently develops. Convulsions may occur, especially in children. Progressive deterioration occurs until the patient is in a stuporous state. A similar sequence of events is seen with T. b. rhodesiense, but the presentation and progression are typically much more rapid. Rather than asymptomatic periods and slow deterioration, Rhodesian trypanosomiasis causes an acute, severe febrile disease that rapidly progresses to involve the CNS over weeks to a few months. Worsening coma and death ultimately occur in both infections. Infections in tourists, which are usually acquired in game parks in East Africa, may have an incubation period as short as a few days. Individuals develop fever, headache, and malaise. Rash is also common. Progressive neurologic involvement will develop if the infection is not treated. Since T. b. gambiense can present years after exposure, a thorough travel history should be obtained in patients who present with chronic neurologic symptoms, since the diagnosis can be missed when the index of suspicion is low. Several nonspecific laboratory findings may be associated with infection. Anemia is common and is thought to be due at least in part to immune-mediated haemolysis. Leukocytosis may be seen. Thrombocytopenia may be present, possibly related to splenic sequestration. Hypergammaglobulinaemia, largely related to raised levels of polyclonal IgM, is also characteristic. Hypoalbuminemia, elevated erythrocyte sedimentation rate, and low levels of complement are frequently found. Patients with neurologic involvement often have abnormal electroencephalograms (EEGs), usually demonstrating slow wave oscillations (delta waves). A definitive diagnosis of infection requires the demonstration of the parasite, usually from the blood, lymph node aspirate or cerebrospinal fluid (CSF).
  4. Drug associated neurocognitive disorder: Psychosis may result from ingestion of prescribed medications, alcohol, or illicit drugs, or from withdrawal of alcohol or sedative/hypnotic drugs such as barbiturates or benzodiazepines. In most instances the presence of offending substances is detectable; however, cases of persistent psychosis for days or weeks after a drug is cleared from the body have been described, especially with hallucinogens and amphetamines.
  5. Herpes simplex encephalitis: Herpes simplex encephalitis (HSE) is a severe viral infection of the human central nervous system. It affects at least 1 in 500,000 individuals per year. About a third of cases result from primary HSV-1 infection, predominantly affecting individuals under the age of 18; 2 in 3 cases occur in seropositive persons, few of whom have history of recurrent orofacial herpes. Approximately half of individuals that develop HSE are over 50 years of age. Most cases of HSE show a decrease in their level of consciousness and an altered mental state presenting as confusion and personality changes. Increased numbers of white blood cells can be found in patient's cerebrospinal fluid, without the presence of pathogenic bacteria and fungi. Patients are usually febrile and may present with convuslions. The electrical activity of the brain changes as the disease progresses, first showing abnormalities in one temporal lobe of the brain, which spread to the other temporal lobe 7–10 days later. Without appropriate treatment the disease results in rapid death in approximately 70% of cases. HSE is deadly in around 20% of treated cases causing serious long-term neurological sequelae in the majority of survivors.
  6. Acute psychosis: Psychosis is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality". It is one of the more severe forms of psychiatric disorder during which hallucinations and delusions and impaired insight may occur. Psychotic patients may report hallucinations or delusional beliefs and may exhibit personality changes and thought disorder. This may be accompanied by unusual or bizarre behaviour as well as difficulty with social interaction and impairment in carrying out the daily life activities. A variety of central nervous system diseases caused by external toxins and / and internal physiologic illness may produce symptoms of psychosis. Both patients demonstrated abnormal cognitive and emotional behaviour as their primary presenting symptoms but neither had a prior psychiatric history and the natural progress of their respective illness was not in keeping with psychosis and cleared up spontaneously without further psychiatric intervention.
  7. Chronic subdural haematoma: A subdural subdural haematoma follows on traumatic brain injury in which blood gathers within the outermost meningeal layer between the dura and arachnoid mater enveloping the brain. Acute subdural haematomas are often life-threatening but chronic subdural hematomas are usually not deadly if treated. Chronic subdural bleeds develop over the period of days to weeks, often after minor, even unnoticed head trauma. They may not be discovered until they present clinically months or years after a head injury. They may present with the classical signs of raised intracranial pressure or any of the following: Other signs and symptoms of subdural hematoma can include any combination of the following: Loss of consciousness or fluctuating levels of consciousness, irritability, epilepsy, numbness, headache (either constant or fluctuating), dizziness, disorientation, amnesia, weakness or lethargy, nausea and / or vomiting, loss of appetite, personality changes, speech disturbance, ataxia, difficulty walking, vision disturbance, abnormal breathing patterns, abnormal gaze or ocular movement. Both subjects had normal CT and MRI scans of the cranium and brain excluding this option as a diagnosis.
  8. HIV Encephalopathy: Changes in memory, mood, attention, and motor skills are common in HIV-infected patients and present a diagnostic challenge to the clinician. Since these symptoms can represent a wide variety of disorders, accurate diagnosis is critical for patient treatment. HIV associated dementia (HAD) typically presents with the classic triad of symptoms of subcortical dementia: memory and psychomotor speed impairment, depressive symptoms and movement disorders. Early symptoms — At the onset, patients usually experience subtle symptoms that may be overlooked or attributed to fatigue or other illness, such as slight difficulty with reading, comprehension, memory, and mathematical skills. Early motor symptoms include unsteady gait, leg weakness, and tremor. Other early manifestations may include apathy, lethargy, loss of sexual drive, and diminished emotional responsiveness. Early language deficits are uncommon. Both subjects were HIV negative.

Question 2: What is your differential diagnosis in Case 2?

Answer to Q2

  1. Malaria: Newly acquired P falciparum. The minimum incubation period for P falciparum is seven days – he had been back in Senegal for ten days. This is where he previously acquired malaria.
  2. Malaria: Relapse of P vivax or ovale (If he had had a mixed infection previously. P falciparum is responsible for 95% of the malaria in Sub-Saharan Africa).
  3. West African Trypanosomiasis: Occurs in the region and he had been in rural West Africa for several years
  4. Drug associated neurocognitive disorder
  5. Herpes simplex encephalitis
  6. Hyper or Hypoglycaemia: He is a known previously well controlled diabetic. All metabolic parameters were normal.
  7. Diabetes associated cognitive impairment: The patient is a well-controlled insulin-dependent diabetic with no other signs of overt target-organ disease.
  8. Acute psychosis
  9. Chronic subdural haematoma
  10. HIV Encephalopathy

Question 3: What important question, absent from the history above must be answered?

Answer to Q3

Have either one of them recommenced on malaria prophylaxis and if so, what? One of three WHO acknowledged malaria prophylactics might have been commenced: Mefloquine may have been commenced in either case in anticipation of return to Mozambique and prior to actually returning to Senegal. Mefloquine is known to cause neuropsychiatric illness. Severe neuropsychiatric reactions (psychosis, convulsions) are infrequent with prophylactic doses and occur in approximately 1/10 000 to 1/13 000 persons. The frequency of mild neuropsychiatric effects is probably much higher. Malanil® has been associated with neuropsychiatric illness, but only in exceptional cases. Doxycycline is an acknowledged malaria prophylactic as well but not associated with neuropsychiatric side-effects.

Question 4: Which special investigations would you call for?

Answer to Q4

  • Repeat Full blood count
  • Malaria smear for falciparum and non-falciparum malaria.
  • Trypanasomiasis smear (Special request - the parasites are not necessarily seen on a malaria smear)
  • Lumbar puncture
  • Blood glucose
  • Liver function
  • Urea and electrolytes
  • CT / MRI scan of the brain
  • EEG
  • Drug screen
  • HIV / AIDS Screen


  1. Matias G, Canas N, Antunes I. Vale J. Acta Med Port Jul-Aug 2008:21(4): 387-90. Abstract accessed on Pubmed.
  2. Nguyen TH, Day NP, Ly VC, Waller D, Mai NT, Bethell DB, Tran TH, White NJ. Post-malaria neurological syndrome. Lancet 5Oct 1996;348(9032):917-21 (abstract)
  3. Kochar DK, Sirohi P, Kochar SK, Bindal D, Kochar A, Jhajharia A, Goswami J. Post-malaria neurological syndrome – a case of bilateral facial palsy after Plasmodium vivax malaria. J Vect Borne Dis Sept 2007;44:227-229.
  4. Prendki V, Elziere C, Durand R, Hamdi A, Cohen Y, Onnen I, Bouchaud O. Short report: Post-malaria neurological syndrome – two cases in patients of African origin. Am J Trop Med Hyg 2008;78(5):699-701
  5. Marsala SZ, Ferracci F, Cecottu L, Gentile M, Conte F, Candeago RM, Marchini C. Post-malaria neurological syndrome: clinical and laboratory findings in one patient. Neurol Sci 2006;27:442-444
  6. Trypanosomiasis. NICD Communicable diseases communiqué. November 2010. Vol 9 (11)
  7. Leder K, Weller PF. Baron EL. Epidemiology and clinical manifestations of African trypanosomiasis. UpToDate 2010;18.2
  8. Guidelines for the prevention of malaria in South Africa. Department of Health, Republic of South Africa. 2009
  9. Thompson AW, Pieper AA, Treisman GJ Dementia and delirium in HIV-infected patients. UpToDate 2010;18.2
Outcome of the Case


The patient was transferred to a tertiary care facility in Pretoria and submitted to a battery of tests and investigations similar to that of Case 2 earlier on. Everything proved negative or normal and he showed good neurocognitive improvement over a period of about one week.

The neurologist elected to administer a short course of high dose steroids.

The patient was discharged with a diagnosis of organic brain syndrome in the context of malaria illness


In a Johannesburg Hospital he had normal vital signs and a non-remarkable physical examination but was still disorientated for time and place and did not recognise persons well known to him. An MRI scan which was normal. A Iumbar puncture demonstrated an elevated protein of 0.96 and 2 lymphocytes but all other investigations including repeat malaria smears were normal. EEG was normal. He returned to his home country with an escort for further assessment and was subsequently admitted to hospital in his home town.

The patient could not remember much of the past 6-8 weeks. He felt febrile, was lethargic and admitted to being confused. On examination he was mildly drowsy. He was able to say the day and year but not the date or month. Registration was normal. The digit span was normal. He was not able to spell the word 'WORLD' backwards. He could remember 0 to 3 objects at 3 minutes. He was able to follow a three stage command and the speech was normal. He had retrograde amnesia for the previous 8 weeks.

There were no focal motor or sensory signs. There was no neck stiffness and Kernig's & Brudzinki's signs were negative. The cranial nerves were normal. General examination was again within normal limits. A repeat MRI scan was normal. A cerebral blood flow study was normal. An EEG was normal. The CRP was less than 1 and the white cell count was 5.7. The malarial blood film was negative.

At follow-up for several weeks later he was noted to have a limited concentration span and memory lapses.

The final diagnosis was post-malaria Neurological Syndrome.

Lessons learnt:

The two cases bear witness to a complication of malaria that is seldom described in the South African context. A literature search provided no documented case studies from South Africa.

Two cases from Africa were described in the French literature.

Although uncommon this complication is debilitating in the context of the patient and his family who are dependent on him as an expatriate breadwinner who may be incapable of working for a period of several weeks.

Neurological symptoms in acute malaria are usually associated with severe Plasmodium falciparum infection, when sequestration of parasitized red blood cells within the cerebral vessels can result in local ischaemic damage. The presence of impaired consciousness, seizures and visual and auditory problems can also be associated with hypoglycaemia (malaria- or quinine-induced) or with the toxicity of antimalarials. More recently however, a discreet transient neurological syndrome after recovery from severe malaria infections has been described: Post-malaria neurologic syndrome (PMNS). PMNS is a rare neurological complication that occurs after the successful treatment of Plasmodium falciparum malaria. It presents as an acute onset of neurological or neuro-psychiatric syndrome. What distinguishes it from cerebral malaria is that the patient has already recovered from the malaria infection and the blood smear is negative for parasites. In cerebral malaria, the neurological symptoms occur during the parasitaemia period. Clinical features that have been reported include: generalized convulsions, an acute confusional state, psychosis, tremors, cerebellar ataxia, motor aphasia and generalized myoclonus. The first description of a post-infectious neurological complication of malaria was cerebellar ataxia, identified in Sri Lanka in 1984, and it has been described a number of times since then. The pathogenesis is unknown but is probably immunologically mediated. Symptoms usually manifest any time from a few days to nine weeks after parasite clearance, continue for a few days, and resolve spontaneously, without any treatment. Patients with severe encephalopathy may however require corticosteroid therapy. The diagnosis of PMNS is therefore largely one of exclusion. The diagnostic criteria currently are:

  1. A recent recovery from Plasmodium falciparum malaria
  2. A blood smear negative for parasites at the onset of symptoms
  3. A complete recovery without any therapy within ten days

A prospective study on PMNS was conducted in Vietnam over 4 years, and of 18,124 patients with P. falciparum malaria, (1176 of whom had severe infections), 19 adults and 3 children had subsequent PMNS. The overall incidence was 1.2 per 1000 and in 21 of the 22 patients, the syndrome followed severe malaria. (Relative risk after severe vs uncomplicated malaria was 299). The syndrome was self-limiting with a median duration of 60 hours (range 24-240 hours) Whereas clinicians in tropical disease and travel health practice should consider this as a diagnosis in the correct setting it is equally important to exclude, inter alia, the various diagnoses listed earlier on as many of these require urgent medical or surgical intervention that may mean the difference between life and death. By contrast PMNS is a self-limiting condition with no specific treatment other than re-assurance and emotional support as it may be disruptive to careers and normal daily life. This is particularly true if the patient is employed as an expatriate in a region with limited medical and psycho-social support.

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