Editing African trypanosomiasis (section)

==Signs and Symptoms==
African trypanosomiasis symptoms occur in two stages: 1) the hemolymphatic stage and 2) the neurological stage. The hemolymphatic stage refers to the period when parasites are present in the blood and lymphatic system, prior to central nervous system involvement. The neurological stage, also called the meningoencephalitic phase, begins when Trypanosoma parasites cross the blood–brain barrier and invade the central nervous system.<ref name="pmid15304634" /><ref name="www.cdc.gov_2020">{{cite web|date=2020-04-28|title=CDC – African Trypanosomiasis – Disease|url=https://www.cdc.gov/parasites/sleepingsickness/disease.html|access-date=2020-08-11|publisher=Centers for Disease Control and Prevention}}</ref> In addition to the hemolymphatic stage neurological symptoms can still present themselves, resulting in a difficulty in distinguishing the two stages based on clinical features alone.<ref name="www.cdc.gov_2020" />

The disease has been reported to present with atypical symptoms in infected individuals who originate from non-endemic areas (e.g., travelers). The reasons for this are unclear and may be genetic. Delayed or missed diagnosis in infected individuals who originate from non-endemic areas (travelers) have reported symptoms including higher susceptibility and quicker progression of advanced stages of the disease. The reasons for this are unclear but certain symptoms such as high fever could be due to genetic factors or a lack of previous exposure to non-human-pathogenic forms of trypanosomes.<ref name="Travelers">{{Cite journal |last1=Urech |first1=Karin |last2=Neumayr |first2=Andreas |last3=Blum |first3=Johannes |date=2011-11-01 |editor-last=Ghedin |editor-first=Elodie |title=Sleeping Sickness in Travelers - Do They Really Sleep? |journal=PLOS Neglected Tropical Diseases |language=en |volume=5 |issue=11 |pages=e1358 |doi=10.1371/journal.pntd.0001358 |doi-access=free |issn=1935-2735 |pmc=3206012 |pmid=22069503}}</ref> The low number of such cases may also have skewed findings. In such persons, the infection is said to present mainly as fever with gastrointestinal symptoms (e.g., diarrhea and jaundice) and with [[lymphadenopathy]] rarely developing.<ref name="Kennedy_2019">{{cite journal | vauthors = Kennedy PG, Rodgers J | title = Clinical and Neuropathogenetic Aspects of Human African Trypanosomiasis | journal = Frontiers in Immunology | volume = 10 | page = 39 | date = 2019-01-25 | pmid = 30740102 | pmc = 6355679 | doi = 10.3389/fimmu.2019.00039 | doi-access = free }}</ref>

=== Trypanosomal Ulcer ===

Systemic disease is sometimes presaged by a trypanosomal [[ulcer]] developing at the site of the infectious fly bite within 2 days of infection. The ulcer is most commonly observed in T. b. rhodesiense infection and rarely in T. b. gambiense infection, where ulcers are more common in persons from non-endemic areas.<ref name="www.cdc.gov_2020" />

=== Hemolymphatic Phase ===
The incubation period is 1–3 weeks for ''T. b. rhodesiense,'' and longer (but less precisely characterised) in ''T. b. gambiense'' infection. The first/initial stage, known as the hemolymphatic phase, is characterized by non-specific, generalised symptoms<ref name="www.cdc.gov_2020" /> like: [[Intermittent fever|fever (intermittent)]], headaches (severe),<ref name="www.cdc.gov_2019">{{cite web|date=2019-04-22|title=CDC – African Trypanosomiasis – General Information – East African Trypanosomiasis FAQs|url=https://www.cdc.gov/parasites/sleepingsickness/gen_info/faqs-east.html|access-date=2020-08-11|publisher=Centers for Disease Control and Prevention}}</ref> [[Arthralgia|joint pains]], [[itch]]ing,<ref name="pmid15304634" /><ref name="www.cdc.gov_2020" /> weakness, malaise, fatigue, weight loss, lymphadenopathy, and [[hepatosplenomegaly]].<ref name="www.cdc.gov_2020" />

Diagnosis may be delayed due to the vagueness of initial symptoms. The disease may also be mistaken for [[malaria]] (which may occur as a co-infection).<ref name="Kennedy_2019" />

==== Intermittent Fever ====

Fever is intermittent, with attacks lasting from a day to a week, separated by intervals of a few days to a month or longer.<ref name="pmid15304634" /><ref name="www.cdc.gov_2020" /> Episodes of fever become less frequent throughout the disease.<ref name="www.cdc.gov_2020" />

==== Lymphadenopathy ====

Invasion of the circulatory and lymphatic systems by the parasite is associated with severe [[Lymphadenopathy|swelling of lymph nodes]], often to tremendous sizes.<ref name="pmid15304634" /> Posterior cervical lymph nodes are most commonly affected, however, axillary, inguinal, and epitrochlear lymph node involvement may also occur.<ref name="www.cdc.gov_2020" /> [[Winterbottom's sign]], is a clinical finding involving swollen lymph nodes at the base of the skull or along the back of the neck, particularly characteristic of T. b. gambiense infections.<ref name="pmid15304634">{{cite journal | vauthors = Lundkvist GB, Kristensson K, Bentivoglio M | title = Why trypanosomes cause sleeping sickness | journal = Physiology | volume = 19 | issue = 4 | pages = 198–206 | date = August 2004 | pmid = 15304634 | doi = 10.1152/physiol.00006.2004 | s2cid = 17844506 }}</ref><ref name="www.cdc.gov_2020" />

==== Other Features ====

Those affected may additionally present with: skin rash,<ref name="www.cdc.gov_2019" /> haemolytic anaemia, hepatomegaly and abnormal liver function, splenomegaly, endocrine disturbance, cardiac involvement (e.g. pericarditis, and congestive heart failure), and ophthalmic involvement.<ref name="Kennedy_2019" />

<gallery widths="200" heights="200">
File:PMC5373517 pntd.0005324.g001.png|Ulcer of human African trypanosomiasis<ref name=":0">{{cite journal | vauthors = Gómez-Junyent J, Pinazo MJ, Castro P, Fernández S, Mas J, Chaguaceda C, Pellicé M, Gascón J, Muñoz J | display-authors = 6 | title = Human African Trypanosomiasis in a Spanish traveler returning from Tanzania | journal = PLOS Neglected Tropical Diseases | volume = 11 | issue = 3 | pages = e0005324 | date = March 2017 | pmid = 28358876 | pmc = 5373517 | doi = 10.1371/journal.pntd.0005324 | doi-access = free }}</ref>
File:AcuteSleepingSickness.jpg|Typical fine-spotted pink rash of acute African trypanosomiasis on the skin of the abdomen ("trypanid rash")<ref name=Paul2014>{{cite journal | vauthors = Paul M, Stefaniak J, Smuszkiewicz P, Van Esbroeck M, Geysen D, Clerinx J | title = Outcome of acute East African trypanosomiasis in a Polish traveller treated with pentamidine | journal = BMC Infectious Diseases | volume = 14 | page = 111 | date = February 2014 | pmid = 24571399 | pmc = 3941560 | doi = 10.1186/1471-2334-14-111 | doi-access = free }}</ref>
File:SSHemorragicRash.jpg|Numerous [[ecchymoses|spots of bleeding into the skin]] of the leg in a person infected with ''T. b. rhodesiense''<ref name=Paul2014/>
</gallery>

=== Neurological Phase ===
The second phase of the disease, the [[neurological disorder|neurological phase]] (also called the ''meningoencephalic stage''<ref name="www.cdc.gov_2020" />), begins when the parasite invades the [[central nervous system]] by passing through the [[blood–brain barrier]].<ref name="pmid15304634" /> Progression to the neurological phase occurs after an estimated 21–60 days in case of ''T. b. rhodesiense'' infection, and 300–500 days in case of ''T. b. gambiense'' infection.<ref name="www.cdc.gov_2020" />

In actuality, the two phases of African trypanosomiasis—the hemolymphatic stage and the neurological stage—often overlap, and their clinical features can be nonspecific or evolve gradually, making it difficult to distinguish them based on symptoms alone.<ref name=":03">{{Cite journal |last=Kennedy |first=Peter |date=25 January 2019 |title=Clinical and Neuropathogenetic Aspects of Human African Trypanosomiasis |journal=Frontiers in Immunology |volume=10 |page=39 |doi=10.3389/fimmu.2019.00039 |doi-access=free |pmid=30740102 |pmc=6355679 }}</ref> While signs such as enlarged lymph nodes and intermittent fever are more characteristic of the early stage, and neuropsychiatric symptoms such as sleep disturbances, confusion, or motor abnormalities suggest progression to the later stage, these indicators are not definitive. Consequently, to accurately determine the stage of the disease, specifically to determine central nervous system involvement, a [[lumbar puncture]] is performed to analyze the [[Cerebrospinal fluid|cerebrospinal fluid (CSF)]].<ref name=":03" /> The detection of trypanosome parasites in the CSF confirms that the infection has progressed to the neurological phase. This assessment is crucial because treatment protocols differ depending on whether or not the central nervous system has been affected. In the later stage, more intensive drugs that can cross the [[Blood–brain barrier|blood-brain barrier]] are necessary to eliminate the parasites from the brain and spinal cord.

==== Sleep Disorders ====
Sleep-wake disturbances are a leading feature of the neurological stage<ref name="pmid15304634" /><ref name="Maxfield_2020">{{cite book | vauthors = Maxfield L, Bermudez R | chapter = Trypanosomiasis (Trypansomiasis)|date=2020| chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK535413/| title = StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=30571034|access-date=2020-08-11 }}</ref> and give the disease its common name of "sleeping sickness".<ref name="pmid15304634" /><ref name="www.cdc.gov_2020" /><ref name="Maxfield_2020" /> Infected individuals experience a disorganized and fragmented sleep-wake cycle.<ref name="pmid15304634" /> Those affected experience [[sleep inversion]] resulting in daytime sleep<ref name="pmid15304634" /> and somnolence,<ref name="www.cdc.gov_2020" /> and nighttime periods of wakefulness<ref name="pmid15304634" /> and insomnia.<ref name="www.cdc.gov_2020" /> Additionally, those affected also experience episodes of sudden sleepiness.<ref name="www.cdc.gov_2020" />

This sleeping impairment is also related to disruptions of [[circadian rhythm]], the body's internal clock which regulates rhythmic behavior including metabolic patterns in cells.<ref name="Filipa2">{{Cite journal |last1=Rijo-Ferreira |first1=Filipa |last2=Carvalho |first2=Tânia |last3=Afonso |first3=Cristina |last4=Sanches-Vaz |first4=Margarida |last5=Costa |first5=Rui M |last6=Figueiredo |first6=Luísa M. |last7=Takahashi |first7=Joseph S. |date=2018-01-04 |title=Sleeping sickness is a circadian disorder |journal=Nature Communications |language=en |volume=9 |issue=1 |page=62 |doi=10.1038/s41467-017-02484-2 |issn=2041-1723 |pmc=5754353 |pmid=29302035}}</ref> Studies indicate ''[[Trypanosoma brucei|T. brucei]]'' alters the oscillatory expression of clock genes in the [[Suprachiasmatic nucleus|suprachiasmatic nuclei (SCN)]], among other brain regions, charged with circadian regulation.<ref name=":0222">{{Cite journal |last1=Cavadini |first1=G. |last2=Farkas |first2=I |last3=Saez |first3=M. |last4=Brunner |first4=M. |last5=Kerekes |first5=T. |last6=Jäkel |first6=M. |date=2007 |title=TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription |journal=Proceedings of the National Academy of Sciences  |volume=104 |issue=31 |pages=12843–12848 |doi=10.1073/pnas.0701466104 |doi-access=free |pmid=17646651 |via=PNAS|pmc=1937554 }}</ref> This alteration of expression may be moderated by the host's immune responses, such as parasitic activity and inflammation resulting from elevated [[TNF-α|TNF-α levels]].<ref name=":0222" />

====Neurological/Neurocognitive Symptoms====

Neurological symptoms include: [[tremor]], general muscle weakness, [[hemiparesis]], [[paralysis]] of a limb,<ref name="Brun10" /> abnormal muscle tone, gait disturbance, ataxia, speech disturbances, paraesthesia, hyperaesthesia, anaesthesia, visual disturbance, abnormal reflexes, seizures, and coma.<ref name="www.cdc.gov_2020" /> [[Parkinsonism|Parkinson]]-like movements might arise due to non-specific movement disorders and speech disorders.<ref name="Brun10" />

====Psychiatric/Behavioural symptoms====

Individuals may exhibit psychiatric symptoms, which can sometimes dominate the clinical presentation. These symptoms include aggressiveness, [[apathy]],<ref name="www.cdc.gov_2020" /><ref name="Brun10" /> irritability, [[Psychosis|psychotic]] reactions<ref name="Brun10">{{cite journal | vauthors = Brun R, Blum J, Chappuis F, Burri C | title = Human African trypanosomiasis | journal = Lancet | volume = 375 | issue = 9709 | pages = 148–159 | date = January 2010 | pmid = 19833383 | doi = 10.1016/S0140-6736(09)60829-1 | hdl-access = free | s2cid = 39433996 | hdl = 10144/114145 }}</ref> and [[hallucination]]s, [[anxiety]], [[emotional lability]], [[confusion]], [[mania]], attention deficit, and [[delirium]].<ref name="www.cdc.gov_2020" />

=== Advanced/Late Disease and Outcomes ===
Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death. An untreated infection with ''[[Trypanosoma brucei rhodesiense|T. b. rhodesiense]]'' will cause death within months<ref>{{cite web |title=East African Trypanosomiasis FAQs |date=29 August 2012 |work=Parasites – African Trypanosomiasis (also known as Sleeping Sickness) |publisher=Centers for Disease Control and Prevention |url=https://www.cdc.gov/parasites/sleepingsickness/gen_info/faqs-east.html |url-status=live |archive-url=https://web.archive.org/web/20170711152023/https://www.cdc.gov/parasites/sleepingsickness/gen_info/faqs-east.html |archive-date=11 July 2017}}</ref> whereas an untreated infection with ''[[Trypanosoma brucei gambiense|T. b. gambiense]]'' will cause death after several years.<ref>{{cite web |title=West African Trypanosomiasis FAQs |date=29 August 2012 |work=Parasites – African Trypanosomiasis (also known as Sleeping Sickness) |publisher=Centers for Disease Control and Prevention |url=https://www.cdc.gov/parasites/sleepingsickness/gen_info/faqs-west.html |url-status=live |archive-url=https://web.archive.org/web/20170619152521/https://www.cdc.gov/parasites/sleepingsickness/gen_info/faqs-west.html |archive-date=19 June 2017}}</ref> Damage caused in the neurological phase is irreversible.<ref name="allafrica.com">{{cite web |title=Uganda: Sleeping Sickness Reaching Alarming Levels |date=11 May 2008 |work=New Vision |url=http://allafrica.com/stories/200805120552.html |url-status=live |archive-url=https://web.archive.org/web/20080521173159/http://allafrica.com/stories/200805120552.html |archive-date=21 May 2008}}</ref>