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\begin{document}

\title{Delayed cerebellar ataxia induced by Plasmodium falciparum malaria: A
rare complication}



\author[1]{Emmanuel Siddig}%
\author[2]{Dr. SARAH  MISBAH EL-SADIG}%
\author[1]{Hala Eltigani}%
\author[1]{Ahmed Musa}%
\author[1]{Nouh Mohamed}%
\author[1]{Ayman Ahmed}%
\affil[1]{University of Khartoum}%
\affil[2]{University of Khartoum Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\textbf{Delayed cerebellar ataxia induced by \emph{Plasmodium
falciparum} malaria: A rare complication}

Emmanuel Edwar Siddig\textsuperscript{1,2,*}, Sarah Misbah
EL-Sadig\textsuperscript{3}, Hala Fathi Eltigani\textsuperscript{1},
Ahmed Mudawi Musa\textsuperscript{4}, Nouh Saad
Mohamed\textsuperscript{5}, Ayman Ahmed\textsuperscript{4,6,7}

1 Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan

2 Faculty of Medical Laboratory Sciences, University of Khartoum,
Khartoum, Sudan.

3 Faculty of Medicine, University of Khartoum, Khartoum, Sudan

4 Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan

5 Molecular Biology Unit, Sirius Training and Research Centre, Khartoum,
Sudan

6 Swiss Tropical and Public Health Institute (Swiss TPH), Allschwil
4123, Switzerland

7 University of Basel, Petersplatz 1, Basel 4001, Switzerland

* Correspondance: Emmanuel Edwar Siddig; University of Khartoum,
Khartoum, Sudan.

Email: emanwelleds389@gmail.com

ORCID: 0000-0001-6314-7374

\textbf{Consent for Publication}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.



\section*{Acknowledgments}

{\label{acknowledgments}}

None.

\textbf{Funding:}

None



\section*{Disclosure}

{\label{disclosure}}

The author reports no conflicts of interest in this work.



\textbf{Abstract:}

Here, we report the clinical manifestation, investigations, and outcomes
of a patient developed delayed cerebellar ataxia following a malaria
infection; which is considered an unusual complication. This report
highlights the diagnostic challenges associated with identifying
cerebellar ataxia and the underlying infection in a country endemic with
several infectious diseases.

\textbf{Keywords:} Neurology; infectious diseases; Critical care
medicine



\textbf{Introduction:}

Cerebellar ataxia (CA) is a neurological condition involving a loss of
coordination caused by a dysfunction in the cerebellum of the brain
{[}1{]}. It can be caused by a variety of conditions such as stroke,
tumours, toxins, and infections with different diseases such as
arboviral diseases and malaria {[}2{]}. Sudan is endemic with several
infectious diseases that are involved in the development of CA including
COVID-19 {[}3,4{]}, arboviruses such as Chikungunya {[}5,6{]},
Crimean-Congo Hemorrhagic Fever (CCHF) {[}7{]}, dengue {[}8,9,10{]},
Rift Valley fever {[}11,12,13{]}, West Nile virus {[}14, 15{]}, Zika
{[}15, 16{]}, and Yellow fever {[}15, 17{]} as well as emerging
infectious diseases like schistosomiasis, TB, and different fungal
infection {[}18,19{]}. Furthermore, malaria is hyper endemic in Sudan
{[}20{]} and in addition to it is major role in the development of CA,
it involves in several other neurological disorders {[}21{]}.

Delayed cerebellar ataxia following malaria was first described by
Senanayake et al in Sri Lanka in 1984 and is an acute, transient
condition that occurs following the resolution of the pyrexial phase of
malaria or as a side effect of anti-malarial drugs {[}22{]}. In this
report, we discuss delayed cerebellar ataxia as a complication of
a\emph{P. falciparum} malarial infection and highlight the importance of
considering it in the differential diagnosis, especially in
malaria-endemic regions.

\textbf{Case presentation:}

A 49- year-old female presented to a hospital in Khartoum state, central
Sudan with slurred speech, tremors affecting her upper limbs, and a
sense of imbalance and dizziness while walking which lasted for five
days. Twelve days prior, she reported a 3-day history of fever with
chills for which she took paracetamol tabs 500 mg four time per day. The
patient had no history of a rash, common cold, nor headache as well as
no neck pain, sensory or motor deficit. Also, she has no history of
bulbar symptoms, vomiting, recent vaccination, or alcohol abuse as well
as no smoking, joint pains, or fluctuation in body weight. Before
admission, she was not diagnosed with malaria, nor did she receive any
antimalarial therapy.

On the clinical examination, the patient was conscious and oriented to
time, place and person. She had a normal pulse rate (76/min),
respiratory rate (17/min), blood pressure (90/50), and temperature
(39\selectlanguage{ngerman}°C). Neurological examination showed no evidence of meningism.
However, the patient had an ataxic gait, dysarthria, tremor of the upper
limbs, dysdiadochokinesia, and hypotonia, but no bradykinesia, rigidity
and nystagmus. Furthermore, she had normal sensation. Magnetic resonance
imaging (MRI) of the brain was done in order to rule out the possibility
of post-infectious cerebellitis and it showed normal brain structures;
ventricular system; no evidence of haemorrhage or infarct and no midline
shift. An electroencephalogram was done and was normal.

A blood sample was collected from the patient and sent to the laboratory
for routine investigations. Further investigations revealed microcytic
hypochromic anaemia and confirmed the presence of \emph{Plasmodium
falciparum} gametocytes in the peripheral blood smear. Viral screening
for Epstein-Barr virus (EBV), Cytomegalovirus (CMV), major endemic
arboviruses, human immunodeficiency (HIV) and Hepatitis viruses were
negative. Liver function test revealed a serum bilirubin 0.7 mg/dl,
total protein 7.6 g/dl, serum albumin 5.8 g/dl, alkaline phosphatase 79
U/l, aspartate aminotransferase (AST) 21 U/L, and alanine
aminotransferase (ALT) 26 U/l. Renal functional test showed a normal
value of urea in blood (27 mg/dL) and serum creatinine (0.71 mg/dL).
Complete blood count examination showed leucocytosis (12.3
x10\textsuperscript{3}), haemoglobin 11.0 g/dl and platelets count
149x10\textsuperscript{3}. A sputum sample was collected and was
negative for acid-fast bacilli.

The patient received artemether/lumefantrine four tablets (20 mg
artemether; 120 mg lumefantrine per tablet) orally (PO) as an initial
dose, followed by four tablets P.O. 8 hours later, then four tablets
P.O. twice daily (morning and evening) for two days for a total course
of 24 tablets. She responded well after three days. The patient was
discharged 21 days after admission. She has recovered and regained a
normal health status.

\textbf{Discussion:}

In this communication, we reported a case of delayed cerebellar ataxia
due to \emph{P. falciparum} infection with the onset of slurred speech,
bilateral tremors affecting both upper limbs, and an unsteady gait
during walking. Cerebellar involvement in \emph{P. falciparum} malaria
can occur during the acute stage of fever, as a consequence of cerebral
malaria, as a delayed cerebellar ataxia (DCA), or as a side effect of
anti-malarial therapy {[}23 -- 28{]}. This case of DCA that is induced
by malaria infection has occurred in a hyper endemic area in central
Sudan, Khartoum state. The development of DCA in this case could be
mainly attributed to the lack of detecting the malaria infection during
the initial presentation of the patient at outpatient clinic. This delay
in reaching a final accurate diagnosis is of high risk particularly in
settings like Sudan that are endemic with several life-threatening
infection like hemorrhagic fevers. Such delay commonly lead to the
development of disease severe sequelae and complication such as
neurological syndromes including Guillain\selectlanguage{english}-Barre syndrome (GBS) {[}29{]}
and CA.

Cerebellar ataxia can be caused by many conditions including alcohol
misuse, stroke, brain degeneration, multiple sclerosis, drugs, genetic
and autoimmune diseases as well as several infectious diseases {[}23{]}.
Malaria is one of the leading causes for the development of CA {[}24 -
28{]}. Malaria in humans is commonly caused by one of five species of
plasmodium, and \emph{P. falciparum} is the species most associated with
the development of neurological complications {[}30{]}.

Acute cerebellar ataxia can be caused by a wide range of infections
including viral, bacterial, fungal, and parasitic infections.
Interestingly, in our reported patient, there was no clinical or
molecular evidence of any infection other than \emph{P. falciparum} .
Co-infection with main viral infections of public health importance in
the country with potential involvement in the development of CA were
excluded by screening the blood sample serologically and molecularly
{[}31 - 40{]}. Additionally, in our reported case, hyperpyrexia is
unlikely to cause cerebellar ataxia as our patient developed DCA after
an afebrile period. Therefore, the development of DCA can be directly
attributed to \emph{P. falciparum} infection. The pathogenesis of DCA
due to malaria infection is attributable to an immune mechanisms that
include elevated levels of certain cytokines such as Interleukin (IL)-2,
IL-6, and tumour necrosis factor alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}), as these cytokines were
found in the cerebrospinal fluid of patients with DCA {[}41{]}.

Therefore, in countries like Sudan that are endemic with malaria and
other infectious diseases that are involved in the development of CA, it
is very important to investigate patients with cerebellar ataxia for
these infections. Early diagnosis and effective case management of
patients with infectious diseases is the main strategy to reduce the
development and prevalence of CA in the country. Therefore, physicians
work in such settings should be vigilant and improve the differential
diagnosis of cerebellar ataxia by taking a comprehensive medical and
travel histories combined with a complete clinical examination and
recommendations for the corresponding laboratory investigation to
improve the diagnosis. Furthermore, in countries endemic with several
infectious diseases with overlapped clinical manifestation, more
investment should be made on improving the diagnostic capacity.

Although malaria is hyper endemic in Sudan with \emph{P. falciparum} ,
as the predominant species, yet development of neurological syndromes
that are associated with malaria infection including CA are
understudied. Therefore, more investment is needed to further study
sequelae and severe complications that are associated with endemic
diseases. Particularly that, such studies are warrant to generate
evidence to inform and guide policymaking and strategic intervention to
reduce the health and socioeconomic burden of such preventable health
condition.

\textbf{Key clinical message:}

In endemic areas, malaria induced cerebellar ataxia should be suspected
in patients presenting with slurred speech, tremors, and a sense of
imbalance and dizziness while walking. Healthcare providers should be
aware to properly investigate and early detect the causation of
cerebellar ataxia to improve the case management and clinical outcome
cost-effectively.

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