African Trypanosomiasis (Sleeping Sickness)

1. Clinical Overview

Summary

Human African Trypanosomiasis (HAT), commonly known as sleeping sickness, is a vector-borne parasitic disease caused by protozoan parasites of the genus Trypanosoma and transmitted exclusively by the tsetse fly (Glossina species) in sub-Saharan Africa. [1] Two morphologically identical but epidemiologically and clinically distinct subspecies cause human disease: Trypanosoma brucei gambiense (responsible for the chronic West African form, accounting for approximately 97% of reported cases) and Trypanosoma brucei rhodesiense (causing the acute East African form, representing 3% of cases). [2]

The disease progresses through two clinically defined stages that fundamentally determine treatment selection and prognosis. Stage 1 (haemolymphatic stage) involves systemic infection confined to the blood, lymphatics, and peripheral tissues. Stage 2 (meningoencephalitic stage) occurs when parasites cross the blood-brain barrier to invade the central nervous system, producing the characteristic neuropsychiatric manifestations including the pathognomonic sleep-wake cycle disturbance that gives the disease its common name. [3]

Without treatment, HAT is invariably fatal. The introduction of fexinidazole as the first all-oral treatment in 2019, combined with sustained control efforts, has contributed to a dramatic reduction in case numbers, with fewer than 1,000 cases reported annually since 2018. [4] The World Health Organization has targeted elimination of gambiense HAT as a public health problem by 2030. [5]

Key Facts

Clinical Pearls

The Trypanosomal Chancre: A painless, indurated nodule appearing 5-15 days post-bite at the inoculation site is more common in T. b. rhodesiense (observed in up to 50% of cases in non-immune individuals) than T. b. gambiense (less than 5%). [6] This chancre is often missed in dark-skinned individuals but is pathognomonic when identified.

Winterbottom's Sign: Painless, rubbery posterior cervical lymphadenopathy (particularly in the posterior triangle of the neck) is classically associated with T. b. gambiense infection. Historical significance: slave traders in the 18th century used this sign to identify and reject infected individuals. Present in 80-90% of gambiense cases but rare in rhodesiense. [7]

Kerandel's Sign (Delayed Hyperaesthesia): A distinctive clinical finding where pain occurs several seconds after application of pressure, particularly over bony prominences such as the palms, ulnar nerve, or shins. This delayed deep hyperaesthesia reflects CNS involvement and indicates progression toward Stage 2. [8]

Sleep-Wake Cycle Reversal: The eponymous "sleeping sickness" refers not to hypersomnia but to fragmentation and reversal of the circadian sleep-wake pattern — patients experience daytime somnolence with nocturnal insomnia and multiple sleep episodes throughout the 24-hour period. This reflects hypothalamic involvement and disruption of orexinergic pathways. [9]

Species Distinction Is Critical: T. b. gambiense progresses slowly (months to years) allowing for active surveillance and treatment, while T. b. rhodesiense causes acute severe disease with death possible within weeks if untreated. Treatment regimens differ between species, particularly for Stage 2 disease.

Why This Matters Clinically

HAT represents a medical emergency requiring species identification, accurate staging, and subspecies-specific treatment. The key clinical decision point is CSF examination to distinguish Stage 1 from Stage 2 disease, as this determines whether simpler Stage 1 drugs (pentamidine, suramin) or CNS-penetrating Stage 2 drugs (melarsoprol, eflornithine, NECT, fexinidazole) are required. [10]

Melarsoprol, the only effective drug for T. b. rhodesiense Stage 2 disease, carries a 5-10% risk of fatal reactive encephalopathy, making accurate staging and species identification essential. [11] The introduction of fexinidazole has simplified treatment for T. b. gambiense but is not effective for T. b. rhodesiense. [12]

For clinicians in non-endemic countries, HAT should be considered in any patient with unexplained fever, lymphadenopathy, neuropsychiatric symptoms, or sleep disturbance who has travelled to or migrated from sub-Saharan Africa, as the prolonged incubation period of gambiense HAT means cases may present years after exposure.

---

2. Epidemiology

Incidence and Prevalence

The epidemiology of HAT has undergone dramatic transformation over the past two decades through coordinated global control efforts.

Historical context: Three major epidemics occurred during the 20th century (1896-1906, 1920s, 1970-1998), with millions of deaths. The most recent epidemic peaked in 1998 when HAT was a leading cause of mortality in several Central African countries, exceeding HIV/AIDS in some regions. [1]

Geographic Distribution

T. b. gambiense Endemic Countries:

• Central Africa: Democratic Republic of Congo (50-60% of all cases), Central African Republic, Chad, Republic of Congo
• West Africa: Guinea, Côte d'Ivoire, Angola, South Sudan, Cameroon, Gabon, Equatorial Guinea, Nigeria
• The DRC remains the major focus, reporting the majority of global cases

T. b. rhodesiense Endemic Countries:

• East Africa: Uganda, Tanzania, Malawi, Zambia, Kenya
• Southern Africa: Zimbabwe, Mozambique, Botswana
• Uganda is unique in having both forms, with geographical separation preventing overlap

Demographics

Risk Factors

Non-Modifiable Risk Factors:

• Geographic residence in or travel to tsetse-endemic areas
• Genetic factors affecting susceptibility (APOL1 gene provides protection in some populations)

Modifiable Risk Factors:

Transmission Dynamics

Vector Biology:

• Tsetse flies (Glossina spp.) are the exclusive vectors
• Both male and female flies take blood meals and can transmit
• Flies acquire parasites when feeding on infected hosts
• Parasite development in fly requires 2-3 weeks
• Infected flies remain infectious for life (several months)

Transmission Cycle:

For T. b. gambiense:

• Human → Tsetse → Human (anthroponotic cycle)
• Humans are the primary reservoir
• Pigs may serve as secondary reservoir in some areas

For T. b. rhodesiense:

• Animal reservoir → Tsetse → Human (zoonotic cycle)
• Wild animals (bushbuck, hartebeest) and domestic cattle are primary reservoirs
• Humans are incidental dead-end hosts

Non-vector transmission (rare):

• Congenital transmission (vertical)
• Blood transfusion
• Laboratory accidents
• Organ transplantation (theoretical)

---

3. Pathophysiology

Parasite Biology and Life Cycle

Step 1: Tsetse Fly Bite and Inoculation

The infected tsetse fly injects metacyclic trypomastigotes into the dermal tissue during a blood meal. These metacyclic forms are pre-adapted for mammalian survival and express a variable surface glycoprotein (VSG) coat. [13]

At the bite site:

• Local multiplication of trypanosomes occurs
• Inflammatory response creates the trypanosomal chancre
• Duration: 5-15 days post-inoculation
• Chancre resolves spontaneously as parasites disseminate

Step 2: Haemolymphatic Stage (Stage 1)

Trypanosomes spread from the inoculation site via lymphatics and bloodstream:

• Invasion of lymph nodes → lymphadenopathy (especially posterior cervical in gambiense)
• Dissemination to spleen, liver, heart, and endocrine organs
• Intermittent waves of parasitaemia with "undulating" fever pattern
• Extravascular migration into interstitial tissues

Key Pathogenic Mechanism — Antigenic Variation:

The VSG coat covering the trypanosome surface allows immune evasion through antigenic variation. [13] Each trypanosome genome contains approximately 1,000 VSG genes, but only one is expressed at a time. When host antibodies develop against the predominant VSG, a subset of parasites switches to express a different VSG, evading immune clearance and producing relapsing parasitaemia.

This results in:

• Waves of parasitaemia every 7-10 days
• Corresponding fluctuating fever pattern
• Chronic immune activation
• Polyclonal B-cell activation with hypergammaglobulinaemia
• Immunosuppression and increased susceptibility to secondary infections

Step 3: Meningoencephalitic Stage (Stage 2)

Trypanosomes cross the blood-brain barrier (BBB) to invade the central nervous system:

• Initially involves circumventricular organs and choroid plexus
• Progressive penetration into brain parenchyma
• Preferential involvement of:
  • Hypothalamus (sleep-wake disturbance)
  • Limbic system (behavioural changes)
  • Basal ganglia (movement disorders)
  • Brainstem (cranial nerve involvement)

Neuropathological Changes:

• Perivascular cuffing with plasma cells, lymphocytes, and morular (Mott) cells
• Reactive astrocytosis and microgliosis
• Demyelination (particularly in T. b. rhodesiense)
• Oedema and meningeal inflammation
• Production of tryptophan metabolites disrupting serotonin synthesis

Sleep-Wake Cycle Disruption Mechanism:

The characteristic disruption of circadian rhythm in Stage 2 HAT results from: [9]

1. Direct invasion of the suprachiasmatic nucleus (SCN)
2. Disruption of orexin/hypocretin-producing neurons in the hypothalamus
3. Altered melatonin secretion patterns
4. Inflammatory cytokine effects on sleep regulatory centres
5. Prostaglandin D2 and other sleep-promoting substance dysregulation

Step 4: Terminal Stage (Untreated)

Progressive neurological deterioration leads to:

• Cachexia and severe wasting
• Opportunistic infections due to immunosuppression
• Status epilepticus
• Coma
• Death

Exam Detail: ### Molecular Pathogenesis

VSG Switching Mechanism:

The variable surface glycoprotein (VSG) system represents one of the most sophisticated immune evasion mechanisms in nature:

• VSG genes are primarily located in subtelomeric expression sites
• Only one expression site is transcriptionally active at a time
• Switching occurs through:
  • In situ transcriptional switching between expression sites
  • Recombinational gene conversion copying a silent VSG into the active site
  • Telomeric exchange events
• Switching rate: approximately 10⁻² to 10⁻⁷ per cell division
• New VSG variants emerge during each parasitaemic wave

Tryptophan-Kynurenine Pathway:

Stage 2 HAT is associated with significant alterations in tryptophan metabolism: [14]

• Increased indoleamine 2,3-dioxygenase (IDO) activity
• Shunting of tryptophan into kynurenine pathway
• Reduced serotonin synthesis contributing to mood and sleep disturbance
• Accumulation of neurotoxic metabolites (quinolinic acid)
• Potential contribution to neuronal damage

Cytokine Profile:

• Elevated TNF-α, IL-1β, IL-6, and IFN-γ
• Production of reactive nitrogen species
• Prostaglandin E2 elevation
• Increased blood-brain barrier permeability

Classification: Two Forms of HAT

Disease Staging Criteria

Clinical Pearl: Staging Controversies:

The traditional WCC cutoff of > 5 cells/µL to define Stage 2 has been questioned:

• Some experts propose higher thresholds (> 10 or > 20 cells/µL)
• Fexinidazole trials used WCC ≤100/µL as inclusion criterion for "early Stage 2"
• Protein elevation and intrathecal IgM synthesis may be more specific markers
• CSF neopterin shows promise as a staging biomarker
• The optimal staging criteria remain an area of active research

---

4. Clinical Presentation

Incubation Period

Stage 1 (Haemolymphatic) Symptoms and Signs

Trypanosomal Chancre:

• Painless, indurated nodule at bite site
• Diameter: 2-5 cm
• Erythematous with central clearing
• Appears 5-15 days post-bite
• Resolves within 2-3 weeks
• More common in T. b. rhodesiense (50%) than gambiense (less than 5%)
• Often overlooked in dark-skinned individuals

Systemic Features:

Winterbottom's Sign (Posterior Cervical Lymphadenopathy):

• Classic finding in T. b. gambiense infection
• Rubbery, discrete, non-tender nodes
• Located in posterior triangle of neck
• May be bilateral
• Present in 80-90% of gambiense cases
• Sensitivity: 80%; Specificity: 50-60% in endemic areas

Cardiovascular Features (especially T. b. rhodesiense):

• Myocarditis occurs in 50-70% of rhodesiense cases
• Pericarditis
• Arrhythmias (conduction abnormalities, tachyarrhythmias)
• Heart failure (rare)
• ECG abnormalities: prolonged QT, ST-T changes, conduction blocks

Stage 2 (Meningoencephalitic) Symptoms and Signs

Stage 2 represents CNS invasion and produces the characteristic neuropsychiatric features of sleeping sickness.

Neurological Features:

Kerandel's Sign (Delayed Hyperaesthesia):

• Pathognomonic finding of CNS involvement
• Pain experienced several seconds after application of pressure
• Best elicited over:
  • Palms of hands
  • Ulnar nerve at elbow
  • Tibial surface (shins)
• Reflects altered sensory processing in dorsal horn and thalamus
• Present in 20-40% of Stage 2 patients

Sleep Disturbance Characteristics:

The sleep disorder in HAT is distinctive: [9]

• Not simply hypersomnia but circadian rhythm disruption
• Patients sleep in multiple short episodes throughout 24 hours
• Daytime sleep attacks (may resemble narcolepsy)
• Nocturnal insomnia with agitation
• REM sleep intrusion during wakefulness
• Polysomnography shows:
  • Fragmented sleep architecture
  • Sleep-onset REM periods
  • Loss of normal circadian variation

Psychiatric Features:

• Depression and apathy
• Anxiety and irritability
• Personality changes
• Psychosis (hallucinations, delusions)
• Aggression and disinhibition
• May be misdiagnosed as primary psychiatric disorder

Terminal Features (Untreated):

• Progressive obtundation
• Status epilepticus
• Coma
• Cachexia
• Opportunistic infections
• Death (within months for rhodesiense, 2-3 years for gambiense)

Comparative Presentation: Gambiense vs Rhodesiense

Red Flags

[!CAUTION] Red Flags — Urgent Specialist Input Required:

• Altered consciousness or confusion (indicates Stage 2)
• Sleep-wake cycle reversal (pathognomonic Stage 2)
• Seizures or status epilepticus
• Rapid neurological deterioration (suspect T. b. rhodesiense)
• Cardiac arrhythmias or heart failure (rhodesiense myocarditis)
• Treatment failure (parasitological relapse post-treatment)
• Relapse after apparent cure
• Severe anaemia or pancytopenia

---

5. Clinical Examination

Structured Approach

General Assessment:

• Overall appearance: cachexia, wasting, pallor
• Vital signs: temperature (fever pattern), pulse (tachycardia, irregularity)
• Level of consciousness: GCS, orientation, drowsiness
• Behaviour: apathy, agitation, appropriate responses

Inspection:

• Facial oedema (periorbital swelling)
• Skin lesions: trypanosomal chancre, trypanids (circinate erythema)
• Scratch marks (pruritus)
• Tsetse fly bites (recent or healing)
• Jaundice (rare, indicates severe disease)

Lymph Node Examination:

• Posterior cervical triangle (Winterbottom's sign) — PRIMARY TARGET
• Technique: patient seated, examiner behind
• Feel for: discrete, rubbery, non-tender nodes, 1-3 cm diameter
• Also examine: anterior cervical, axillary, inguinal, epitrochlear nodes
• Generalised lymphadenopathy common in gambiense

Cardiovascular Examination:

• Pulse: rate, rhythm, character
• Blood pressure: may be low in severe disease
• JVP: elevation suggests heart failure
• Apex beat: displacement in cardiomegaly
• Heart sounds: gallop rhythm, pericardial rub
• Signs of heart failure (especially in rhodesiense)

Abdominal Examination:

• Hepatomegaly: smooth, non-tender
• Splenomegaly: moderate enlargement
• Ascites: rare, indicates advanced disease

Neurological Examination (Critical for Staging):

Mental Status:

• Consciousness level (GCS)
• Orientation to time, place, person
• Attention and concentration
• Memory (immediate, short-term, long-term)
• Behaviour and affect
• Sleep pattern history (CRUCIAL)

Cranial Nerves:

• Visual acuity and fields
• Pupil reactions
• Extraocular movements (ophthalmoplegia)
• Facial sensation and symmetry
• Hearing
• Bulbar function

Motor Examination:

• Tone: rigidity, spasticity, hypotonia
• Power: generalised weakness pattern
• Reflexes: hyperreflexia, primitive reflexes
• Tremor: rest, postural, intention

Sensory Examination:

• Light touch, pain, temperature
• Vibration, proprioception
• Kerandel's sign (delayed hyperaesthesia)

Coordination:

• Finger-nose, heel-shin testing
• Rapid alternating movements
• Gait: ataxia, festination

Special Clinical Signs

---

6. Investigations

Diagnostic Algorithm

           SUSPECTED AFRICAN TRYPANOSOMIASIS
                        ↓
┌──────────────────────────────────────────┐
│        SEROLOGICAL SCREENING             │
│  (T. b. gambiense endemic areas only)    │
│  Card Agglutination Test (CATT)          │
└──────────────────────────────────────────┘
                        ↓
┌──────────────────────────────────────────┐
│        PARASITOLOGICAL CONFIRMATION      │
├──────────────────────────────────────────┤
│  Blood examination (wet prep, films)     │
│  Lymph node aspirate (gambiense)         │
│  Chancre aspirate (if present)           │
│  Concentration techniques if needed      │
└──────────────────────────────────────────┘
                        ↓
┌──────────────────────────────────────────┐
│        SUBSPECIES IDENTIFICATION         │
├──────────────────────────────────────────┤
│  Geographic history                      │
│  Clinical features                       │
│  Molecular methods (PCR) if available    │
└──────────────────────────────────────────┘
                        ↓
┌──────────────────────────────────────────┐
│        DISEASE STAGING                   │
│        LUMBAR PUNCTURE (MANDATORY)       │
├──────────────────────────────────────────┤
│  CSF WCC count (threshold: > 5/µL)        │
│  CSF protein                             │
│  CSF microscopy for trypanosomes         │
│  CSF IgM (elevated in Stage 2)           │
└──────────────────────────────────────────┘
                        ↓
┌──────────────────────────────────────────┐
│        TREATMENT SELECTION               │
│  Based on subspecies AND stage           │
└──────────────────────────────────────────┘

Serological Tests

Card Agglutination Test for Trypanosomiasis (CATT):

The CATT is the primary screening tool for T. b. gambiense in endemic areas: [15]

Important Note: CATT is a SCREENING test only. Parasitological confirmation is mandatory before treatment due to:

• False positives in other trypanosomal infections
• Persistence of antibodies after successful treatment
• Variation in sensitivity between geographic strains

Other Serological Methods:

• LATEX/T. b. gambiense: Similar to CATT, agglutination-based
• Rapid Diagnostic Tests (RDTs): Being developed for point-of-care use
• ELISA: Used in reference laboratories
• Immune trypanolysis (TL): High specificity but technically demanding

Parasitological Diagnosis

Direct Parasitological Demonstration (GOLD STANDARD):

Definitive diagnosis requires visualisation of trypanosomes.

Blood Examination:

Lymph Node Aspirate:

• Indicated for T. b. gambiense with palpable posterior cervical nodes
• Technique: Fine needle aspirate of enlarged node
• Immediate wet preparation examination
• Sensitivity superior to blood examination in gambiense
• Less useful for rhodesiense (parasitaemia usually high)

Chancre Aspirate:

• If chancre present, aspirate fluid for microscopy
• High parasite density in chancre
• More useful for T. b. rhodesiense

CSF Examination (Mandatory for Staging)

Lumbar puncture is ESSENTIAL for all confirmed HAT cases to determine treatment.

CSF Analysis:

Additional CSF Markers (Research/Reference Use):

• Neopterin: Elevated in Stage 2; potential staging biomarker
• β₂-microgloulin: Elevated with CNS involvement
• Mott cells (morular cells): Plasma cells with Russell bodies; classic finding

Staging Criteria (WHO):

Stage 2 is defined by ANY of:

• CSF WCC > 5 cells/µL
• Trypanosomes identified in CSF
• (Neurological symptoms alone do NOT define Stage 2 — must have CSF confirmation)

Clinical Pearl: CSF Examination Pitfalls:

1. Traumatic tap: May artificially elevate WCC; use correction formula if RBC contamination
2. HIV co-infection: May already have elevated CSF WCC, complicating interpretation
3. Re-staging post-relapse: Essential to re-perform LP if treatment failure suspected
4. Processing delay: Trypanosomes lyse rapidly; examine CSF within 30 minutes
5. Threshold debate: Some experts suggest > 10 or > 20 cells/µL as more specific cutoffs

Laboratory Tests

Molecular Diagnosis

Imaging

---

7. Differential Diagnosis

Key Differentials

Stage-Specific Differentials

Stage 1 Differentials (Febrile Illness with Lymphadenopathy):

• Infectious mononucleosis
• CMV infection
• Toxoplasmosis
• HIV seroconversion illness
• Lymphoma
• Sarcoidosis

Stage 2 Differentials (Encephalopathy with Sleep Disturbance):

• Viral encephalitis
• Cerebral malaria
• Tuberculous meningitis
• Cryptococcal meningitis
• Neurosyphilis
• Autoimmune encephalitis
• Narcolepsy
• Depression with hypersomnia

---

8. Management

Management Algorithm

         CONFIRMED AFRICAN TRYPANOSOMIASIS
                        ↓
┌──────────────────────────────────────────┐
│         IDENTIFY SUBSPECIES              │
├──────────────────────────────────────────┤
│  T. b. gambiense (West/Central Africa)   │
│  T. b. rhodesiense (East Africa)         │
└──────────────────────────────────────────┘
                        ↓
┌──────────────────────────────────────────┐
│         PERFORM LUMBAR PUNCTURE          │
│         (MANDATORY FOR STAGING)          │
└──────────────────────────────────────────┘
                        ↓
         ┌───────────────────────┐
         │    CSF WCC ≤5/µL      │
         │    No trypanosomes    │
         └───────────┬───────────┘
                     ↓
              ┌──────┴──────┐
              │   STAGE 1   │
              └──────┬──────┘
                     ↓
    ┌────────────────┴─────────────────┐
    │                                  │
    ↓                                  ↓
GAMBIENSE                         RHODESIENSE
    ↓                                  ↓
Pentamidine                        Suramin
4 mg/kg IM × 7 days               Test dose + 5 weekly IV doses
    OR                                 
Fexinidazole                          
(oral, 10 days)                       

         ┌───────────────────────┐
         │    CSF WCC > 5/µL      │
         │ OR trypanosomes in CSF│
         └───────────┬───────────┘
                     ↓
              ┌──────┴──────┐
              │   STAGE 2   │
              └──────┬──────┘
                     ↓
    ┌────────────────┴─────────────────┐
    │                                  │
    ↓                                  ↓
GAMBIENSE                         RHODESIENSE
    ↓                                  ↓
First-line:                       Melarsoprol
Fexinidazole                      2.2 mg/kg IV × 10 days
(oral, if CSF WCC ≤100)          (ONLY effective option)
    OR                            
NECT (Nifurtimox +               
Eflornithine)                    
    OR                           
Eflornithine alone               

Acute/Emergency Management

Immediate Priorities:

1. Stabilise airway, breathing, circulation if comatose
2. Manage seizures with benzodiazepines, then phenytoin/phenobarbital
3. Treat hypoglycaemia if present
4. Initiate fluid resuscitation if hypovolaemic
5. Identify and treat concurrent infections (especially malaria)
6. Urgent staging with lumbar puncture once stable

Seizure Management:

• First-line: Diazepam 10 mg IV or lorazepam 4 mg IV
• Maintenance: Phenytoin 15-20 mg/kg loading then 5 mg/kg/day
• Alternative: Phenobarbital if phenytoin unavailable

Cardiac Complications (T. b. rhodesiense):

• ECG monitoring
• Treat arrhythmias as appropriate
• Manage heart failure with diuretics, ACE inhibitors
• Avoid melarsoprol until cardiac status stabilised if severe

Medical Management

T. b. gambiense Treatment

Stage 1:

Stage 2:

Fexinidazole Considerations: [4]

• First all-oral treatment for HAT
• Effective for Stage 1 and early Stage 2 (CSF WCC ≤100 cells/µL)
• Must be taken with food (improves absorption)
• Contraindicated in severe Stage 2 (WCC > 100)
• Not effective for T. b. rhodesiense
• Side effects: nausea, vomiting, headache, insomnia

NECT (Nifurtimox-Eflornithine Combination Therapy): [16]

• First-line for Stage 2 gambiense with WCC > 100
• Simplified regimen compared to eflornithine monotherapy
• Eflornithine: 400 mg/kg/day IV in 2 infusions (every 12 hours) for 7 days
• Nifurtimox: 15 mg/kg/day orally in 3 divided doses for 10 days
• Cure rate: 97%
• Requires hospitalisation and IV access

T. b. rhodesiense Treatment

Stage 1:

Stage 2:

[!WARNING] Melarsoprol Toxicity:

Melarsoprol (an arsenical compound) is associated with severe adverse effects:

• Reactive encephalopathy: 5-10% incidence; 50% case fatality
• Mechanism: Immune-mediated inflammatory response
• Prevention: Some centres use prednisolone 1 mg/kg/day (controversial efficacy)
• Signs: Fever, worsening consciousness, seizures, coma
• Other toxicities: Peripheral neuropathy, skin reactions, cardiac toxicity
• Local: Severe phlebitis (requires central venous access or dilute infusion)

Melarsoprol should ONLY be used when:

• T. b. rhodesiense Stage 2 confirmed
• No alternative treatments available
• Benefits outweigh significant risks

Melarsoprol Administration Protocol:

1. Hospitalise patient
2. Establish IV access (central line preferred)
3. Consider prednisolone 1 mg/kg/day (debated efficacy)
4. Administer melarsoprol 2.2 mg/kg IV over 5 minutes
5. Monitor closely for 48 hours post-dose
6. Continue for 10 consecutive days
7. Watch for signs of encephalopathy: fever, deteriorating consciousness, seizures

Drug Mechanisms and Side Effects

Supportive Care

Nutritional Support:

• High-calorie, high-protein diet
• Treat micronutrient deficiencies
• Address cachexia

Symptomatic Treatment:

• Antipyretics for fever
• Analgesics for headache
• Antipruritic agents for itching
• Anticonvulsants if seizures

Monitoring During Treatment:

• Daily clinical assessment
• Regular vital signs
• Blood glucose monitoring (especially with pentamidine)
• Renal function (especially with suramin)
• FBC (especially with eflornithine)
• ECG if using melarsoprol

Special Populations

Pregnancy:

• Stage 1: Pentamidine is first-line (suramin contraindicated due to fetal risk)
• Stage 2 gambiense: Eflornithine is preferred
• Stage 2 rhodesiense: Melarsoprol with close monitoring (benefits outweigh risks)
• Fexinidazole: Limited pregnancy data; use only if benefit outweighs risk

Paediatric Patients:

• Dosing is weight-based for all drugs
• Fexinidazole approved for children ≥6 years and ≥20 kg
• Special attention to nutritional support
• Monitor growth and development post-treatment

HIV Co-infection:

• HAT and HIV may coexist in endemic areas
• Immune reconstitution may occur with ART
• Drug interactions: consider ART-trypanocidal drug interactions
• CSF interpretation may be complicated by HIV-associated pleocytosis

Disposition

Admission Criteria:

• All confirmed HAT cases require hospitalisation for:
  • Staging investigations
  • Treatment initiation
  • Monitoring for adverse effects
  • Especially Stage 2 treatment

Discharge Criteria:

• Completed treatment course
• No evidence of treatment toxicity
• Stable clinical condition
• Able to attend follow-up

Follow-up Protocol:

• LP at 6, 12, 18, and 24 months post-treatment [17]
• Criteria for cure: Resolution of symptoms + normal CSF (WCC ≤5, no trypanosomes)
• Relapse defined by: Return of parasitaemia or CSF abnormalities
• Relapse rate: 5-10% depending on drug and stage

---

9. Complications

Treatment-Related Complications

Melarsoprol Encephalopathy (Encephalopathic Syndrome): [11]

• Most serious complication of HAT treatment
• Occurs in 5-10% of patients receiving melarsoprol
• Usually within first 4 days of treatment
• Presents as: fever, headache, deteriorating consciousness, seizures, coma
• Pathogenesis: Immune-mediated; release of parasite antigens triggers inflammation
• Management:
  • Stop melarsoprol immediately
  • High-dose corticosteroids (dexamethasone, prednisolone)
  • Anticonvulsants for seizures
  • Intensive supportive care
  • Resume melarsoprol only if patient recovers (controversial)
• Mortality: 50% of affected patients
• Prevention: Some centres use prophylactic prednisolone (benefit debated)

Disease-Related Complications

Long-Term Sequelae

• Cognitive impairment (memory, concentration deficits)
• Personality changes (may persist after treatment)
• Movement disorders (tremor, ataxia)
• Sleep disorders (may persist)
• Psychiatric manifestations

---

10. Prognosis and Outcomes

Natural History (Untreated)

Untreated HAT is invariably fatal. Death results from:

• Progressive encephalopathy
• Cachexia and malnutrition
• Opportunistic infections
• Cardiac failure (rhodesiense)
• Status epilepticus

Treatment Outcomes

Prognostic Factors

Good Prognosis:

• Early diagnosis (Stage 1)
• T. b. gambiense (slower progression)
• Prompt, appropriate treatment
• Younger age
• Good nutritional status
• No comorbidities

Poor Prognosis:

• Late diagnosis (advanced Stage 2)
• T. b. rhodesiense (acute disease)
• Delayed treatment
• Severe neurological impairment at diagnosis
• Melarsoprol encephalopathy
• Relapse after treatment
• Malnutrition
• HIV co-infection

Post-Treatment Surveillance [17]

Criteria for Cure:

• Resolution of clinical symptoms
• Normal CSF: WCC ≤5/µL, no trypanosomes, normalizing protein
• Sustained improvement over 24 months follow-up

Relapse Indicators:

• Return of symptoms
• Rising CSF WCC
• Detection of trypanosomes in blood or CSF
• Clinical deterioration

---

11. Prevention and Control

Individual Prevention

For Travellers to Endemic Areas:

• Avoid tsetse fly bites:
  • Wear long sleeves and trousers (tsetse can bite through thin fabric)
  • Use neutral-coloured clothing (tsetse attracted to blue and black)
  • Avoid bushland during peak tsetse activity hours (daytime)
  • Use insect repellents containing DEET on exposed skin
  • Stay in screened accommodation
• No prophylaxis or vaccine available
• Seek early medical attention for any febrile illness after return

Public Health Measures

Active Surveillance and Treatment:

• Mass screening programs using CATT in endemic villages
• Parasitological confirmation of seropositive individuals
• Treatment of all confirmed cases
• This strategy has been key to case reduction [18]

Vector Control:

• Trapping and targets (insecticide-impregnated screens)
• Aerial and ground spraying of tsetse habitats
• Sterile insect technique (experimental)
• Environmental modification

Animal Reservoir Control (for T. b. rhodesiense):

• Treatment of infected cattle with trypanocidal drugs
• Reduces zoonotic transmission

Elimination Targets

The WHO has targeted HAT for elimination:

• Elimination as a public health problem: Fewer than 1 case per 10,000 population at risk in 90% of endemic foci — achieved for T. b. gambiense in 2020
• Zero transmission target: Sustainable interruption of transmission by 2030

---

12. Evidence and Guidelines

Key Guidelines

1. WHO Guidelines on Control and Surveillance of Human African Trypanosomiasis (2013, updated 2019) — Comprehensive guidance on diagnosis, treatment, and control strategies. [1]

2. WHO Interim Guidelines for Fexinidazole (2019) — Introduction of oral fexinidazole for gambiense HAT. [4]

3. WHO Strategic Framework for HAT Elimination (2020-2030) — Roadmap to elimination. [5]

Landmark Trials

NECT Pivotal Trial (Priotto et al., Lancet 2009): [16]

• Design: Multicentre, randomised, Phase III non-inferiority trial
• Comparison: NECT vs eflornithine monotherapy for Stage 2 gambiense
• Key finding: NECT non-inferior with 97% cure rate
• Impact: NECT became first-line treatment for Stage 2 gambiense; simplified regimen

Fexinidazole Pivotal Trial (Mesu et al., Lancet 2018): [4]

• Design: Open-label, randomised, non-inferiority trial
• Population: Stage 2 gambiense with CSF WCC ≤100
• Comparison: Oral fexinidazole vs NECT
• Key finding: Fexinidazole non-inferior; 91% success rate
• Impact: First all-oral treatment; transformed treatment paradigm

Fexinidazole Stage 1 Study (Mesu et al., Lancet Infect Dis 2021): [19]

• Design: Single-arm study in Stage 1 gambiense
• Key finding: 99% treatment success
• Impact: Established fexinidazole as first-line for Stage 1

Melarsoprol 10-day vs 26-day Regimens (Schmid et al., Lancet 2005): [11]

• Comparison: Abbreviated 10-day regimen vs standard prolonged regimen
• Key finding: Equivalent efficacy with simplified protocol
• Impact: Reduced treatment duration and hospitalisation

Evidence Levels for Key Interventions

---

13. Viva Points and Exam Preparation

Common Exam Questions

Q1: "What are the two forms of human African trypanosomiasis and how do they differ?"

Model Answer: "Human African trypanosomiasis is caused by two subspecies with distinct characteristics:

T. brucei gambiense (West African form) accounts for 97% of cases, occurs in West and Central Africa, follows a chronic course over months to years, is primarily anthroponotic with humans as the main reservoir, characteristically causes Winterbottom's sign, and is treatable with fexinidazole, NECT, or eflornithine in Stage 2.

T. brucei rhodesiense (East African form) accounts for 3% of cases, occurs in East Africa, follows an acute course over weeks to months, is zoonotic with animal reservoirs, commonly causes myocarditis, and requires melarsoprol for Stage 2 — the only effective drug but associated with 5-10% encephalopathy risk."

Q2: "How would you stage a patient with confirmed HAT?"

Model Answer: "Staging is critical as it determines treatment selection. I would perform a lumbar puncture to examine the CSF.

Stage 1 (haemolymphatic) is defined by CSF WCC ≤5 cells/µL with no trypanosomes present. These patients can be treated with Stage 1 drugs: pentamidine for gambiense, suramin for rhodesiense.

Stage 2 (meningoencephalitic) is defined by CSF WCC > 5 cells/µL OR the presence of trypanosomes in CSF. These patients require CNS-penetrating drugs. For gambiense, fexinidazole is first-line if WCC ≤100; NECT is used for more severe Stage 2. For rhodesiense, melarsoprol is the only effective option despite its toxicity.

Clinical neurological symptoms alone do not define Stage 2 — CSF confirmation is mandatory."

Q3: "Describe the pathognomonic sleep disturbance in HAT."

Model Answer: "The 'sleeping sickness' name reflects characteristic disruption of the circadian sleep-wake cycle in Stage 2 disease, not simply hypersomnia.

Patients experience daytime somnolence with excessive sleepiness and multiple sleep attacks during waking hours, combined with nocturnal insomnia with inability to sleep at night, often with agitation.

The mechanism involves:

• Parasitic invasion of the hypothalamus, particularly the suprachiasmatic nucleus
• Disruption of orexin/hypocretin-producing neurons
• Altered melatonin secretion
• Inflammatory cytokine effects on sleep regulatory centres

This pattern is pathognomonic for Stage 2 CNS involvement and indicates the need for CSF examination and CNS-penetrating treatment."

Key Facts to Know

Common Mistakes

❌ Mistakes that may fail candidates:

• Confusing Stage 1 and Stage 2 treatment regimens
• Not performing LP for staging
• Using fexinidazole for T. b. rhodesiense (it doesn't work)
• Forgetting the serious toxicity of melarsoprol
• Not knowing Winterbottom's sign
• Missing the significance of sleep-wake cycle reversal

---

14. Patient/Layperson Explanation

What is African Trypanosomiasis?

African trypanosomiasis, also called sleeping sickness, is an infection caused by tiny parasites spread by the bite of the tsetse fly. These flies are found only in certain parts of Africa. The disease gets its name because it affects your sleep pattern — you may feel very sleepy during the day but unable to sleep at night.

Why Does It Matter?

Without treatment, sleeping sickness is always fatal. The parasites first cause fever, swollen glands, and tiredness. If not treated, they travel to the brain, causing confusion, personality changes, sleep problems, and eventually coma. The good news is that with proper treatment, most people recover completely.

How Is It Diagnosed?

Diagnosis involves:

1. Blood tests to look for the parasites or antibodies
2. Examining fluid from swollen lymph glands if present
3. Lumbar puncture (spinal tap) — this is essential to check if the infection has reached the brain, which determines what treatment you need

How Is It Treated?

Treatment depends on whether the infection has reached the brain:

Early stage (hasn't reached the brain):

• Injections or tablets for about 7-10 days
• Usually cures the infection completely

Late stage (has reached the brain):

• More intensive treatment is needed
• New oral tablets (fexinidazole) work for many cases
• Some patients need intravenous medications in hospital
• Treatment is very effective but must be completed

What to Expect

• You will need to stay in hospital during treatment
• After treatment, you will need regular follow-up appointments including lumbar punctures at 6, 12, 18, and 24 months to confirm cure
• Most people recover fully with proper treatment

When to Seek Help

See a doctor immediately if you:

• Have been to Africa and have unexplained fevers
• Have a sore at a fly bite lasting more than a few days
• Notice swollen glands in your neck
• Have problems sleeping or unusual sleepiness during the day
• Experience confusion or personality changes

---

15. References

1. World Health Organization. Control and surveillance of human African trypanosomiasis: Report of a WHO Expert Committee. WHO Technical Report Series No. 984. Geneva: WHO; 2013. PMID: 24552089

2. Büscher P, Cecchi G, Jamonneau V, Priotto G. Human African trypanosomiasis. Lancet. 2017;390(10110):2397-2409. doi:10.1016/S0140-6736(17)31510-6. PMID: 28673422

3. Kennedy PGE. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol. 2013;12(2):186-194. doi:10.1016/S1474-4422(12)70296-X. PMID: 23260189

4. Mesu VKBK, Kalonji WM, Bardonneau C, et al. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: A pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018;391(10116):144-154. doi:10.1016/S0140-6736(17)32758-7. PMID: 29113731

5. Franco JR, Cecchi G, Priotto G, et al. Monitoring the elimination of human African trypanosomiasis at continental and country level: Update to 2018. PLoS Negl Trop Dis. 2020;14(5):e0008261. doi:10.1371/journal.pntd.0008261. PMID: 32437391

6. Checchi F, Filipe JAN, Barrett MP, Chandramohan D. The natural progression of Gambian sleeping sickness: What is the evidence? PLoS Negl Trop Dis. 2008;2(12):e303. doi:10.1371/journal.pntd.0000303. PMID: 19104656

7. Stich A, Abel PM, Krishna S. Human African trypanosomiasis. BMJ. 2002;325(7357):203-206. doi:10.1136/bmj.325.7357.203. PMID: 12142313

8. Atouguia JLM, Kennedy PGE. Neurological aspects of human African trypanosomiasis. In: Davis LE, Kennedy PGE, eds. Infectious Diseases of the Nervous System. Oxford: Butterworth-Heinemann; 2000:321-372.

9. Lundkvist GB, Kristensson K, Bentivoglio M. Why trypanosomes cause sleeping sickness. Physiology. 2004;19:198-206. doi:10.1152/physiol.00006.2004. PMID: 15304634

10. Kennedy PGE. The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol. 2008;64(2):116-126. doi:10.1002/ana.21429. PMID: 18756510

11. Schmid C, Nkunku S, Merolle A, Vounatsou P, Burri C. Efficacy of 10-day melarsoprol schedule 2 years after treatment for late-stage Gambian sleeping sickness. Lancet. 2004;364(9436):789-790. doi:10.1016/S0140-6736(04)16940-7. PMID: 15337407

12. Lindner AK, Lejon V, Chappuis F, et al. New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: Substantial changes for clinical practice. Lancet Infect Dis. 2020;20(2):e38-e46. doi:10.1016/S1473-3099(19)30612-7. PMID: 31879061

13. Horn D. Antigenic variation in African trypanosomes. Mol Biochem Parasitol. 2014;195(2):123-129. doi:10.1016/j.molbiopara.2014.05.001. PMID: 24859277

14. MacLean LM, Odiit M, Chisi JE, Kennedy PGE, Sternberg JM. Focus-specific clinical profiles in human African trypanosomiasis caused by Trypanosoma brucei rhodesiense. PLoS Negl Trop Dis. 2010;4(12):e906. doi:10.1371/journal.pntd.0000906. PMID: 21151878

15. Chappuis F, Loutan L, Simarro P, Lejon V, Büscher P. Options for field diagnosis of human African trypanosomiasis. Clin Microbiol Rev. 2005;18(1):133-146. doi:10.1128/CMR.18.1.133-146.2005. PMID: 15653823

16. Priotto G, Kasparian S, Mutombo W, et al. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet. 2009;374(9683):56-64. doi:10.1016/S0140-6736(09)61117-X. PMID: 19559476

17. Mumba Ngoyi D, Lejon V, Pyana P, et al. How to shorten patient follow-up after treatment for Trypanosoma brucei gambiense sleeping sickness. J Infect Dis. 2010;201(3):453-463. doi:10.1086/649917. PMID: 20047501

18. Simarro PP, Cecchi G, Franco JR, et al. Mapping the capacities of fixed health facilities to cover people at risk of gambiense human African trypanosomiasis. Int J Health Geogr. 2014;13:4. doi:10.1186/1476-072X-13-4. PMID: 24517513

19. Mesu VKBK, Kalonji WM, Bardonneau C, et al. Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: A prospective, multicentre, open-label, cohort study. Lancet Glob Health. 2021;9(7):e999-e1008. doi:10.1016/S2214-109X(21)00208-4. PMID: 34143998

20. Wenzler T, Schumann Burkard G, Schmidt RS, et al. A new approach to chemotherapy: Drug-induced differentiation kills African trypanosomes. Sci Rep. 2016;6:22451. doi:10.1038/srep22451. PMID: 26935433

---

Additional Resources

• WHO HAT Programme: who.int/trypanosomiasis_african
• CDC Sleeping Sickness Information: cdc.gov/parasites/sleepingsickness
• DNDi HAT Programme: dndi.org/diseases/sleeping-sickness
• HAT Platform (WHO Collaborating Centre): hatplatform.org

---

Last Reviewed: 2025-01-09 | Topic: 775/1071 | Status: Gold Standard

---

Medical Disclaimer: MedVellum content is intended for medical education and clinical reference. Clinical decisions should always account for individual patient circumstances. Consult appropriate specialists for patient care.