Progressive meningoencephalitis in a Sudanese immigrant

Human African trypanosomiasis (HAT or sleeping sickness) is a significant cause of morbidity and mortality in parts of Africa but is rarely seen in Australia. Lack of awareness of this disease among Australian physicians means it may be easily misdiagnosed, delaying timely treatment and resulting in inadvertent adverse outcomes.

HAT is caused by the flagellated protozoan Trypanosoma brucei. Two subspecies cause human disease: T. brucei rhodesiense, which is found only in east Africa and causes an acute, fulminant illness lasting weeks to months (East African HAT); and T. brucei gambiense, which is found in western, central and parts of east Africa, and causes an indolent, chronic infection that may last many months to years (West African HAT).1 The fulminant course of T. b. rhodesiense illness means it is the form more frequently diagnosed outside Africa, in returned travellers.

Infection occurs through injection of saliva containing trypanosomes from the bite of the tsetse fly, and a local skin reaction or chancre may follow. The infection follows two stages. The early (haemolymphatic) stage results from proliferation of parasites in the blood and lymph and presents with headache, fever, malaise, anorexia, anaemia and lymphadenopathy. The late (meningoencephalitis) stage occurs when trypanosomes invade the central nervous system (CNS), causing a range of neurological manifestations including psychiatric changes. Inversion of the sleep–wake cycle is common, resulting in daytime somnolence and nocturnal insomnia. Without treatment, CNS disease eventually results in coma and death.

Our patient probably became infected in Uganda, where both subspecies of trypanosome are known to circulate.2 In retrospect, the initial improvement in her condition was most likely a response to corticosteroid treatment, and the subsequent regression coincided with a reduction in the corticosteroid dose. Cervical lymphadenopathy in the posterior triangle was noted at initial presentation but was recognised only during her second admission as a classic feature of T. b. gambiense disease (the Winterbottom sign3).

Detection of trypanosomes in the CSF, blood or lymph tissue remains the diagnostic “gold standard”. However, methods of parasite detection vary in sensitivity, and the cyclical nature of parasitaemia means parasites are seldom detected in blood, especially in T. b. gambiense disease,4 although detected more often in CSF.5 We were not able to demonstrate trypanosomes in whole blood, lymph node tissue or CSF. In the absence of demonstrable parasites, and where there is clinical suspicion, serological testing is crucial in diagnosis of T. b. gambiense disease. The sensitivity and specificity of currently available serological tests vary from 71% to 100% and 95% to 99%, respectively. In our patient, the high antibody titre supported a diagnosis of active trypanosomal infestation, although titres are known to remain high several years after treatment.6

MRI findings in trypanosomiasis are non-specific, ranging from meningeal enhancement in earlier CNS disease to bilateral confluent hyperintense T2 signals in the subcortical white matter in late disease, as seen in our patient.7 Although not diagnostic, MRI is a useful adjunct in supporting the diagnosis as relatively few conditions cause this distinct MRI appearance, including acute disseminated encephalomyelitis, cerebral gliomatosis, the leukodystrophies and lymphoma, all of which were considered in our patient.

Non-specific CNS findings are meningoencephalitis, comprising leptomeningitis and encephalitis with diffuse perivascular white matter infiltration, microglial nodules and reactive astrocytosis.8 The presence of Mott cells in the CNS and CSF is characteristic of HAT, but these cells are easily overlooked.9 They are morula forms of plasma cells containing prominent eosinophilic cytoplasmic inclusions (Russell bodies) that stain positively with periodic acid-Schiff stain and are composed of immunoglobulin M. Although Mott cells can be found in myeloproliferative disorders, they are considered virtually pathognomonic of HAT in patients with appropriate clinical findings and exposure history.10

Early stage T. b. gambiense disease is treated with pentamidine. Eflornithine, an ornithine decarboxylase inhibitor that interferes with cell division, is the recommended first-line treatment for CNS disease.11 Side effects include seizures, gastrointestinal upset and reversible myelosuppression. As it requires intravenous infusions four times daily over 2 weeks, it is not ideal in resource-constrained settings; recent studies suggest a combination of eflornithine and oral nifurtimox to be as effective but superior in ease of administration and duration of treatment (requiring eflornithine to be given only twice daily for 7 days).12 From May 2009, the WHO has included combination therapy in its essential list of medicines for treatment of West African trypanosomiasis, but was unable to provide nifurtimox for our patient, as its use was approved at that time only for Chagas disease.

To our knowledge, our patient represents the fourth case of HAT identified in Australia. A case of meningoencephalitis thought to be due to T. b. gambiense was diagnosed in Perth in 2008 in an immigrant from Sudan and is also reported in this issue of the Journal13 (page 417). A case due to T. b. rhodesiense was diagnosed at our institution in 1998 in a returned traveller with acute illness after visiting a Tanzanian game park.14 The first case in Australia is said to have occurred after World War II.15

Our patient illustrates the need for clinicians to be aware of HAT as a potential cause of meningoencephalitis, particularly in African immigrants, for months or years after they move to Australia.16 Had this possibility been recognised at presentation and specifically investigated, prompt treatment could have been given, and brain biopsy avoided.