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\begin{document}

\title{Neuromeningeal cryptococcosis in HIV-uninfected patient: a case report}



\author[1]{Armel Mamihaja Andrianiaina}%
\author[1]{Rova Malala Fandresena Randrianarisoa}%
\author[2]{Solohery Jean Noel  Ratsimbazafy }%
\author[1]{Lalao Nomenjanahary Rakotonirina}%
\author[1]{Hanta Marie Danielle Vololontiana}%
\affil[1]{University of Antananarivo Faculty of Medicine}%
\affil[2]{University of Madagascar}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
We report a 24-year-old female patient with a neurological deficit
without fever or meningeal syndrome. HIV serology was negative and CD4
count was normal. Cerebrospinal fluid analysis revealed the presence of
Cryptococcus neoformans. Neuromeningeal cryptococcosis was suspected.
The initial course was favourable with antifungal therapy.%
\end{abstract}%



\sloppy


\textbf{Neuromeningeal cryptococcosis in HIV-uninfected patient: a case
report}

\textbf{Short title:} \textbf{Cryptococcosis in immunocompetent patient}

Armel Mamihaja Andrianiaina\textsuperscript{1} \textbar{} Rova Malala
Fandresena Randrianarisoa\textsuperscript{1} \textbar{} Solohery Jean
Noel Ratsimbazafy\textsuperscript{2} \textbar{} Lalao Nomenjanahary
Rakotonirina \textsuperscript{3} \textbar{} Hanta Marie Danielle
Vololontiana\textsuperscript{1}

\textsuperscript{1}Department of Internal Medicine, Joseph Raseta
Befelatanana University Hospital, Antananarivo, Madagascar

\textsuperscript{2} Department of Internal Medicine, Soavinandriana
Hospital, Antananarivo, Madagascar

\textsuperscript{3}Departemet of Rheumatology, Joseph Raseta
Befelatanana University Hospital, Antananarivo, Madagascar

\textbf{Correspondence}

Department of Internal Medicine (PSB)

Joseph Raseta Befelatanana University Hospital

Antananarivo, Madagascar

Email~: armelandrianiaina@gmail.com

\textbf{ABSTRACT}

We report a 24-year-old female patient with a neurological deficit
without fever or meningeal syndrome. HIV serology was negative and CD4
count was normal. Cerebrospinal fluid analysis revealed the presence
of\emph{Cryptococcus neoformans} . Neuromeningeal cryptococcosis was
suspected. The initial course was favourable with antifungal therapy.

\textbf{KEWORDS}

case report, cryptococcal meningitis, Cryptococcus neoformans,
HIV-negative

\textbf{KEY CLINICAL MESSAGE}

Cryptococcosis is common in HIV-uninfected patients. Testing
for\emph{Cryptococcus} should not be limited to immunocompromised
patients. The Indian ink staining technique should be used routinely for
any cerebrospinal fluid analysis.

\textbf{INTRODUCTION}

Cryptococcosis is a mycotic disease that usually occurs in
immunocompromised patients, particularly those infected with the Human
Immunodeficiency Virus (HIV) {[}1{]}. The most common clinical form is
meningoencephalitis, which is fatal if untreated. In the literature,
cases have been reported in immunocompetent patients, remaining unusual
forms {[}2{]}. We report a new case of neuromeningeal cryptococcosis in
an HIV-uninfected patient.

\textbf{OBSERVATION}

A 24-year-old woman was admitted to the Department of Internal Medicine
with functional impotence of the right hemisphere. The disease had
started 6 days before admission with a sudden onset of abnormal movement
of the right upper limb followed by functional impotence of the right
hemisphere, headache and aphasia. The general condition was altered
without fever.

In the history, she was 5 months postpartum, not immunocompromised, and
did not have long-term corticosteroid therapy or recurrent infection.
She was neither diabetic nor hypertensive.

Physical examination revealed right hemiparesis and Broca's aphasia. She
was conscious and had no intracranial hypertension or meningeal
syndrome. She had bilateral, painless oedema of the lower limbs,
hepatalgia and hepatojugular reflux.

The blood count was normal with no lymphopenia (lymphocytes 1709/mm3)
and the C-reactive protein was negative. Serum creatinine, ionogram and
liver function tests were normal. HIV and hepatitis serologies were
negative. The polymerase chain reaction test for SARS-COV-2 was
negative.

Serum protein electrophoresis revealed hypoalbuminemia (29.48 g/L) with
no abnormalities in other fractions (alpha-1 2.97 g/L, alpha-2 6.88 g/L,
beta-1 4.35 g/L, beta-2 2.20 g/L, gamma 9.13 g/L). The CD4 T-cell count
was 508/mm\textsuperscript{3}.

The brain CT scan showed left parietal hypodensity with meningeal
enhancement and cortico-frontal calcification raising suspicion of
meningoencephalitis (\textbf{Figure 1} ).

Cerebrospinal fluid (CSF) examination revealed clear fluid with high
pressure, normal cellularity, normal glucose (2.63 mmol/L) and protein
(0.25 g/L) levels and sterility on routine direct
examination.\emph{Cryptococcus neoformans} was present on Indian ink
staining.

Due to the asthenic context and the SARS-COV-2 epidemic, a chest CT scan
was performed and showed images consistent with infectious lung disease.

Transthoracic echocardiography showed left chamber dilatation, high left
ventricular filling pressure, global hypokinesia suggestive of heart
failure with impaired ejection fraction (38\%).

The diagnosis of neuromeningeal cryptococcosis in non-immunocompromised
patient was retained. The presentation was associated with
decompensation of postpartum heart disease and bacterial pneumonia.

Amphotericin B injection 1 mg/kg was started for 2 weeks, followed by
Fluconazole cp 400 mg daily for 6 weeks. Lumbar CSF drainage was
performed. Pneumopathy was treated with CEFTRIAXONE IV 1g for 7 days.
The rest of the management consisted of treatment of cardiac disease and
clinical-biological monitoring.

After 3 evacuation sessions, the CSF pressure had normalized. The
neurological evolution was favourable with regression of the hemiparesis
and aphasia on the 7th day. Hemodynamic parameters were stable and signs
of cardiac decompensation had disappeared.

Three months after hospitalisation, the patient had died at home. The
cause of death has not been determined.

\textbf{DISCUSSION}

Cryptococcosis is one of the most common invasive fungal infections with
a variable prevalence. In the United States, the annual incidence is 0.8
cases per 100,000 population {[}3{]}. In France, the prevalence is 0.2
cases per 100,000 population {[}4{]}. In African regions, which are most
affected by HIV, it is the main cause of infectious meningitis {[}5{]}.

The causative agent is an encapsulated yeast that is usually transmitted
by inhalation of fungal spores. \emph{Cryptococcus neoformans} is found
in soil, wood and bird droppings. \emph{Cryptococcus gattii} is mainly
found in tropical regions {[}6{]}.

Cryptococcosis is the second most common opportunistic infection in AIDS
after toxoplasmosis. According to the World Health Organisation
classification, it is included in stage 4 of HIV infection, affecting
patients with a CD4 count of less than 100/mm\textsuperscript{3}{[}7{]}.

Cases have been reported in HIV-uninfected patients with haematological
malignancy, cancer, diabetes, cirrhosis, systemic disease and
immunosuppressive therapy {[}8,9,10,11{]}. Cryptococcosis in non-HIV
patients is often associated with an underlying disease and remains an
unusual form. Men are most commonly affected according to observations
{[}9,12,13,14{]}. In our case, the patient presented with concomitant
heart failure.

Cryptococcosis is one of the infections with a neurotropism.
Cryptococcal meningitis has a highly variable prevalence, ranging from
2.1\% to 35.8\% in sub-Saharan Africa {[}15{]}. Clinical manifestations
are often less typical of meningitis, making diagnosis difficult
{[}11{]}. Headache and fever are frequently reported. Convulsion,
confusion and neurological deficit are rarely described. Diagnosis is
based on direct examination for \emph{Cryptococcus} using India ink
staining, cryptococcal antigen testing or culture on Sabouraud medium.
Biochemical analysis of CSF may show neither hypercytosis nor
hyperproteinorachy.

The neurological picture presented by our patient directed us in first
intention towards a vascular or tumoral etiology, reinforced by the
absence of fever and meningeal syndrome. The lumbar puncture was
performed only after the result of the brain CT scan. The clinical
polymorphism of neuromeningeal cryptococcosis may delay diagnostic and
therapeutic management. The Indian ink staining technique should be
performed routinely for all CSF analysis, regardless of the patient.

For immunocompetent hosts with the neuromeningeal form, the standard
treatment is a combination of Amphotericin B and Flucytosine for 6-10
weeks. An alternative is a 2-week treatement followed by Flucanazole for
a minimum of 10 weeks. Consolidation treatment with Fluconazole can be
continued for up to 6-12 months, depending on the patient's clinical
condition {[}6{]}. Regular lumbar CSF drainage is recommended if the
pressure is excessive. In this case, the patient received Amphotericin
for 2 weeks and Fluconazole for 6 weeks.

Neuromeningeal cryptococcosis is a serious infection, progressing to
death in the absence of treatment. The prognosis remains guarded even in
immunocompetent patients. The mortality rate in HIV-uninfected subjects
remains at around 15\% in spite of well-conducted treatment. The rapid
evolution of the symptoms, the presence of intracranial hypertension and
disturbance of consciousness, the low cellularity in the CSF and
hypoglycorrachia are factors of poor prognosis.

\textbf{CONCLUSION}

Cryptococcosis is common in HIV-uninfected patients. These patients
often have a concomitant underlying disease. The neuromeningeal form is
often atypical, delaying diagnosis. The search for
\emph{Cryptococcus}should not be limited to immunocompromised patients.

\textbf{ABBREVIATIONS}

CSF: Cerebrospinal fluid

HIV: Human Immunodeficiency Virus

\textbf{ACKNOWLEDGEMENTS}

The authors thank the staff of the Internal Medicine Department of the
Soavinandriana and Befelatanana hospitals.

\textbf{CONFLICTS OF INTEREST}

The authors declare that they have no conflicts of interest.

\textbf{AUTHOR CONTRIBUTIONS}

AM Andrianiaina: followed up the patient, collected the clinical data
and drafted the report. RMF Randrianarisoa, LN Rakotonirina SJN
Ratsimbazafy: designed and critically revised the report.

HMD Vololontiana: validated the report.

All authors have read and accepted the final version of the article.

\textbf{CONSENT TO PUBLICATION}

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

The patient has given informed consent for this publication. Only
information necessary for scientific understanding was shared. Anonymity
was respected.

\textbf{DATA AVAILABILITY STATEMENT}

All data generated are included in the article.

\textbf{FUNDING}

The authors declare that they have no source of funding from a specific
organisation.

\textbf{REFERENCES}

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\textbf{FIGURE LEGENDS}

\textbf{FIGURE 1} Brain CT scan without and with injection

Left parietal hypodensity (A), meningeal enhancement (B) and
parasagittal cortico-frontal calcification (C) suggestive of
meningoencephalitis.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/FIGURE-1/FIGURE-1}

\end{center}
\end{figure}

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