Tripanosomiasis Afrika (Sleeping Sickness)

01Pathophysiology

African trypanosomiasis begins when an infected tsetse fly (Glossina species) inoculates metacyclic trypomastigotes into the dermis during a blood meal. At the inoculation site, the parasites multiply locally and may produce a trypanosomal chancre, an indurated, erythematous nodule that appears within days to weeks. From this site, trypomastigotes disseminate through the lymphatics and bloodstream, initiating the hemolymphatic stage (Stage 1).

The hallmark of trypanosomal survival is antigenic variation through variable surface glycoprotein (VSG) switching. The parasite's surface is coated with a dense VSG coat. Each time the host mounts an effective antibody response and clears the dominant variant, a small subpopulation of trypanosomes has already switched to a new, antigenically distinct VSG. This produces the characteristic relapsing, wave-like parasitemia and intermittent fever pattern. The immune system is perpetually one step behind, which is why spontaneous clearance essentially does not occur.

The persistent immune activation triggers polyclonal B-cell stimulation and markedly elevated IgM levels, both in the serum and later in the cerebrospinal fluid. This is why IgM elevation is such a diagnostically useful finding. Lymph node enlargement, particularly of the posterior cervical chain (Winterbottom sign), results from this intense lymphoproliferative response.

If left untreated, trypanosomes eventually cross the blood-brain barrier, initiating the meningoencephalitic stage (Stage 2). In the CNS, parasites trigger a chronic inflammatory meningoencephalitis with perivascular infiltration by lymphocytes and Morula cells of Mott. This inflammation disrupts the suprachiasmatic nucleus and its regulation of circadian rhythm, producing the pathognomonic sleep-wake cycle inversion: the patient becomes somnolent during the day and restless or wakeful at night. Progressive CNS damage leads to confusion, personality changes, motor disturbances (tremor, ataxia), and eventually coma and death if untreated.

Understanding the two subspecies is critical for exam purposes:

• T.b. gambiense (West African form) is responsible for over 95% of reported cases. Humans are the primary reservoir, transmission is anthroponotic, and the disease course is chronic and indolent, progressing over months to years before CNS involvement becomes clinically evident.

• T.b. rhodesiense (East African form) is a zoonosis with cattle and wild game serving as the reservoir. It causes an acute and rapidly progressive illness, with CNS invasion occurring within weeks. Myocarditis is a notable complication in this form and can cause early death before CNS signs develop.

02Classification and Clinical Manifestation

03Diagnostic Workup

The workup begins differently depending on the subspecies suspected. For T.b. rhodesiense, parasitemia is typically high enough that a thick or thin blood smear or a buffy coat concentration technique will directly reveal motile trypomastigotes. This is the best initial diagnostic step when acute East African disease is suspected.

For T.b. gambiense, parasitemia is low and fluctuating due to the chronic nature of the disease, making blood smear sensitivity poor. The best initial screening test in endemic areas is the Card Agglutination Trypanosomiasis Test (CATT), which detects antibodies against a fixed VSG antigen of T.b. gambiense. A positive CATT result must be confirmed by direct parasitological demonstration through lymph node aspirate (particularly from enlarged posterior cervical nodes), buffy coat, or serial blood examinations.

Once a parasitological diagnosis is confirmed, the single most critical next step is lumbar puncture with CSF analysis. This is not optional. The entire treatment strategy depends on staging. The CSF is examined for:

• WBC count >5 cells/$\mu \backslash mu$L or presence of trypanosomes: either finding confirms Stage 2 disease

• Elevated CSF IgM: a strongly suggestive finding

• Morula cells of Mott: plasma cells stuffed with IgM-containing Russell bodies, essentially pathognomonic for CNS trypanosomiasis

Failure to perform a lumbar puncture before initiating treatment is a critical error, because Stage 1 drugs do not cross the blood-brain barrier and will fail to clear CNS infection, and Stage 2 drugs (particularly Melarsoprol) carry severe toxicity that should not be used unnecessarily.

04Management and Treatment

Stage 1 Management

For Stage 1 T.b. gambiense, the drug of choice is Pentamidine, an aromatic diamidine administered at 4 mg/kg/day intramuscularly or intravenously for 7 days. It is generally well tolerated but can cause hypoglycemia (due to pancreatic beta-cell toxicity and insulin release), hypotension, and nephrotoxicity. Pentamidine does not achieve adequate CNS penetration, which is why it is restricted to Stage 1 disease.

For Stage 1 T.b. rhodesiense, the drug of choice is Suramin, given intravenously. A test dose is given first because of the risk of anaphylaxis. Key adverse effects include nephrotoxicity (proteinuria must be monitored) and peripheral neuropathy. Suramin also does not cross the blood-brain barrier.

Stage 2 Management

For Stage 2 T.b. gambiense, the current WHO-recommended first-line therapy is Fexinidazole, an oral nitroimidazole compound. It is given as 1800 mg orally once daily with food for 4 days, followed by 1200 mg once daily for 6 days (total 10-day course). This is a significant advancement because it is the first all-oral treatment for sleeping sickness that covers both stages. However, fexinidazole is approved only for gambiense disease with CSF WBC $\le \backslash leq$ 100 cells/$\mu \backslash mu$L. If CSF WBC exceeds this threshold, or if the patient is in severe clinical condition, the alternative is NECT (Nifurtimox-Eflornithine Combination Therapy): Eflornithine 200 mg/kg IV every 12 hours for 7 days combined with Nifurtimox 15 mg/kg/day orally in 3 divided doses for 10 days. Eflornithine is an irreversible inhibitor of ornithine decarboxylase, an enzyme essential for polyamine synthesis in trypanosomes. It is sometimes called the "resurrection drug" because it can reverse even advanced neurological disease. Eflornithine is effective only against T.b. gambiense because T.b. rhodesiense has higher ornithine decarboxylase turnover and is inherently resistant.

For Stage 2 T.b. rhodesiense, the only effective option is Melarsoprol, a trivalent arsenical compound that crosses the blood-brain barrier. The dose is 2.2 mg/kg/day IV for 10 consecutive days. Melarsoprol carries a well-known and feared complication: reactive arsenical encephalopathy, which occurs in approximately 5-10% of patients and carries a fatality rate of up to 50% among those affected. Corticosteroids (prednisolone) are co-administered to reduce this risk. This toxicity profile is exactly why accurate staging matters: you never want to expose a Stage 1 patient to Melarsoprol unnecessarily.

High-yield mnemonic for drug selection:

Think of it geographically, "West to East, Pent to Sur":

• Pentamidine for Stage 1 gambiense (West)

• Suramin for Stage 1 rhodesiense (East)

• Fexinidazole / NECT (Eflornithine + Nifurtimox) for Stage 2 gambiense

• Melarsoprol for Stage 2 rhodesiense

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get questions about African trypanosomiasis wrong is by failing to stage the disease before selecting treatment. A vignette will describe a patient with confirmed trypanosomiasis and ask for the next best step. The temptation is to jump straight to a drug, but the correct answer is almost always lumbar puncture first. Without CSF analysis, you cannot determine whether the patient has Stage 1 or Stage 2 disease, and the treatment for each is entirely different. Choosing Pentamidine for a Stage 2 patient is a lethal mistake because it does not cross the blood-brain barrier and will leave CNS infection untreated. Choosing Melarsoprol for a Stage 1 rhodesiense patient exposes them to unnecessary arsenical toxicity.

The second trap involves confusing the two subspecies and their corresponding drugs. Students may recall that Eflornithine works for Stage 2 disease but forget that it is effective only against T.b. gambiense. If the vignette describes a patient from East Africa (Kenya, Tanzania, Uganda) with rapidly progressive disease and myocarditis, that is rhodesiense, and the only Stage 2 option is Melarsoprol, despite its toxicity.

A third common distractor involves the Winterbottom sign. It is classically tested as posterior cervical lymphadenopathy. Students sometimes confuse this with anterior cervical lymphadenopathy seen in pharyngitis or head/neck infections, or with generalized lymphadenopathy seen in HIV or lymphoma. The posterior cervical location is the distinguishing clue.

Finally, do not confuse African trypanosomiasis with Chagas disease. Both are caused by trypanosomes, but they differ in every testable dimension: continent, vector, clinical features, and management. If the vignette mentions the Americas and a "kissing bug," it is Chagas. If it mentions Africa and a tsetse fly, it is sleeping sickness. The examiners rely on students conflating the two.

The core competency being tested is your ability to integrate geographic and epidemiological clues with clinical staging to select the correct pharmacological intervention, and to recognize that staging via lumbar puncture is an indispensable step before any treatment decision.