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\begin{document}

\title{Acute Necrotizing Encephalopathy of Childhood from Eastern Africa}



\author[1]{Hilary Chipongo}%
\author[1]{Shaffin Rajan}%
\author[1]{Abizer Sarkar}%
\author[1]{Ronald McLarty}%
\author[1]{Esmail Sangey}%
\affil[1]{Shree Hindu Mandal Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\textbf{Acute Necrotizing Encephalopathy of Childhood from Eastern
Africa}

\emph{Hilary Chipongo\textsuperscript{1}, Shaffin
Rajan\textsuperscript{1}, Abizer Sarkar} \textsuperscript{2}
\emph{Ronald Mclarty} \textsuperscript{3}\emph{, Esmail
Sangey\textsuperscript{1}}

\emph{\textsuperscript{1}Department of Critical Care Unit, Shree Hindu
Mandal Hospital, P.O BOX 581 Dar es Salaam, Tanzania}

\emph{\textsuperscript{2}Department of Radiology, Shree Hindu Mandal
Hospital, P.O BOX 581 Dar es Salaam, Tanzania}

\emph{\textsuperscript{3}Department of Pediatrics and Child Health,
Shree Hindu Mandal Hospital, P.O BOX 581 Dar es Salaam, Tanzania}

KEY CLINICAL MESSAGE:

Acute Necrotizing Encephalopathy leads to devastating neurological
sequelae and even death. Clinician should try to miss this diagnosis
whenever there is a viral infection with neurological deficit especially
in pediatric age group.

ABSTRACT

Acute Necrotizing Encephalopathy (ANE) is a rare disease affecting the
central nervous system. It leads to devastating neurological sequelae
with a mortality rate of approximately 30\%. Clinicians should have high
suspicion whenever there is neurologic deficit and history of viral
infections especially involving upper respiratory tract in the
paediatric age group.

INTRODUCTION

Acute necrotizing encephalopathy (ANE) is a rare cause of acute
encephalopathy which was first described in 1995 by Mizuguchi whereby it
was thought to affect population of Eastern Asia particularly
children.{[}1{]} The condition affects the central nervous system and is
characterized by altered level of consciousness usually accompanied with
seizures. It has been described as having a radiological hallmark of
multiple symmetrical lesions involving the thalami, brainstem, and
tegmentum.{[}2, 3{]} This is preceded by viral infections which mainly
affect the central nervous system leading to life threatening
neurological sequelae and even death.{[}3{]} After the advancement of
imaging modalities such as magnetic resonance imaging (MRI), sporadic
cases have been reported to occur elsewhere especially in the western
countries.{[}2{]} As per the previous reports, this condition
predominantly affects not only children but also adolescents and, in a
few cases, the adult population.{[}3{]} We report the first case of
acute necrotizing encephalopathy of childhood from Tanzania treated with
a good outcome.

CASE PRESENTATION

A 9-year-old male patient of African descent was seen at our emergency
department (ED) with a three-day history of inability to speak. The
informant was his father who reported that his son's symptoms started
suddenly which were accompanied by decreased level of consciousness and
excessive sleepiness over the period. Prior to the alarming symptoms
mentioned above, the patient had severe headache which he reports to be
excruciating to the point that the child was crying all the time. At the
beginning of his illness, he was taken to the near-by clinic whereby he
was prescribed analgesics and antibiotics for presumptive upper
respiratory tract infections, since the child had features suggestive of
tonsillitis.

On examination at our ED, the child was well nourished boy but ill
looking, semi-conscious with Glasgow coma score (GCS) E4V1M5 = 10. He
had nasogastric tube (NGT) in-situ, and his airway was patent and
protected. His pupils were equally reactive to light, motor function on
both the upper and lower limbs power were 3/5 and 2/5 respectively. The
patient had opisthotonos posture with positive Kernig's sign which
initially made us think of meningitis. Due to the patient's decreased
level of consciousness assessing all cranial nerves was not easy.
However, at least he had a normal gag reflex that he could protect his
airway. His haematological and biochemistry laboratory investigations
were unremarkable including procalcitonin level, except for the raised
serum transaminases ALT 56.3 (1 -- 50 U/L) and AST 139.2 (1 -- 50 U/L).
He was also screened for dengue, malaria, SARS-CoV-2, and HIV which were
all negative. Other viral serology tests were unavailable at our centre.
Lumbar puncture was not done due to evidence of cerebral oedema in brain
computed tomography (CT) scan (Figure 1). The patient was then given
hypertonic saline 150 ml of 3\% sodium chloride, antibiotics, and
antiviral as empirical treatment for meningitis.

Despite the initial therapy until the third day, the patient's condition
was not improving hence a brain MRI was done showed bilateral thalami
involvement with hyper intensity on flair images with central
haemorrhagic transformation. The putamen and central white matter showed
restricted diffusion (figure 2). Based on these findings a new diagnosis
of ANE was made. Thus, the decision of administering intravenous
immunoglobulin (IVIG) was sought and he was given 25g as a single dose.
After 7 days of treatment, the patient's GCS improved, and later he was
discharged through physiotherapy clinic. The patient was seen after 2
weeks at our hospital clinic as a follow-up. There was a remarkable
improvement in his motor function as he was able to walk on his own
without any support. He was well coherent with the conversation except
for his slurred speech, otherwise all other cranial nerves were intact.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Figure 1: CT SCAN image showing evidence of cerebral oedema.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

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\end{figure}

Figure 2: MRI \textbf{Image A} showing bilateral thalamic and putamen
involvement with restricted diffusion (blue arrows) \textbf{Image
B}shows flair image showing bilateral thalamus
hyperintensity.\textbf{Image C} is the T2 heme axial sequence showing
haemorrhagic transformation (red arrow).

DISCUSSIONS

Acute necrotizing encephalopathy of childhood is a rare form of
encephalopathy, its aetiology is yet unknown. It is often associated
with viral infections such as influenza A and B, parainfluenza, and
human herpes virus-6 (HSV-6).{[}4{]} There are few cases being reported
in adult population especially in western countries although most of the
cases affect children and adolescents, in which majority of them are
seen to be of Asian origin.{[}2, 5{]}

The main pathogenesis of the disease remains unknown though several
hypotheses have been made such as the autoimmune response inducing
cytokine storm that later leads to neurovascular damage.{[}6{]} Another
hypothesis is related to specific geographical location as described in
some previous literature which has shown that Eastern Asian countries
have genetic predisposition for region specific pathogens causing
ANE.{[}7{]} This is in contrast with our patient who had no travel
history to any of Eastern Asian countries.

ANE presents like any other forms of encephalopathy with non-specific
prodromal symptoms including fever, cough, and gastrointestinal
disturbances. As the disease progresses, in few days life threatening
symptoms occur including seizures, ataxia and coma.{[}6{]} Reports from
Eastern Asian countries showed the affected ages are usually between 6
to18 months old which accounts 50\% of cases.{[}2{]} The onset of
neurological dysfunction usually occurs from 12 to 72 hours after the
onset in which 40\% of the cases present with seizures.{[}2{]} A review
done more recently by Yuan et al., showed that 94\% of the cases have
early seizure activity most frequently being persistent tonic-clonic in
nature.{[}8{]} In our case, the patient presented with altered level of
consciousness for the past 3 days, aphasia and excessive drowsiness. The
symptoms were preceded by headache, but no seizures were reported.

The diagnosis of ANE significantly depends on the radiological hallmark
with symmetrical lesions involving thalami, tegmentum of upper thalami
and other regions of the brain such as the white matter, basal ganglia,
brain stem and cerebellum.{[}9{]} The laboratory findings are not
specific for the diagnosis as they are mainly supportive, most cases
present with elevated white blood cell counts, C-reactive protein (CRP)
and erythrocyte sedimentation rate (ESR).{[}10{]} Serum transaminase,
lactate dehydrogenase (LDH), and creatinine kinase (CK) are frequently
observed to be elevated as there is direct relation to increased fibrin
degradation products.{[}8{]} Occurrence of electrolyte imbalance is
uncommon. Cerebral spinal fluid (CSF) analysis though it accounts to be
non-specific in most cases, has been observed to have raised protein
concentration.{[}2,8{]}

Most of the reported causes of acute necrotizing encephalopathy are
viral infections such as influenza, HSV-6, parainfluenza, and other
related viral infections such as dengue virus hence it is important also
to do the serology to understand the causative agent which may be of
benefit in the treatment and outcome. In our case from the history and
clinical presentation of the patient, meningitis was the main
provisional diagnosis, then later ANE was added into our diagnosis list.
Viral infections cause cytokine activation which leads to the trigger of
coagulation cascade.{[}1{]} It is seen that chronic viral infections are
associated with thrombotic complications while acute infections may
cause both thrombosis and haemorrhagic complications{[}12{]}, such as in
our case, there was evidence of haemorrhagic transformation in the
thalamic region.

The working diagnosis changed when MRI brain was done as the patient's
condition was not improving, and this is when acute necrotizing
encephalopathy as an incidental finding was noted. The laboratory
findings were not alarming for any central nervous system infection
except for elevated transaminase level which is usually noted in acute
necrotizing encephalopathy, lumbar puncture was contraindicated due to
presence of cerebral oedema.

Currently there is no consensus on the treatment for acute necrotizing
encephalopathy. Treatment is mainly based on a symptomatic approach
which includes use of empirical antiviral treatment.{[}11{]} Depending
on the patient's clinical condition, intensive care admission may be
required such as in cases with active convulsions or other
life-threatening conditions such as septic shock. Most of the
literatures recommend the use of intravenous glucocorticoids and
immunoglobulins as it has been seen to improve the patient's clinical
condition remarkably.{[}6, 10{]} In our patient a combination of
intravenous immunoglobulin, antiviral medications together with
antibiotics were empirically prescribed medications during his hospital
stay. Although immunoglobulin injection was not initiated early, its
efficacy in this case cannot be predicted.

The outcome of ANE of childhood is generally poor. The mortality rate
has been reported to be 30\%. The survivors may be subjected to serious
neurological complications such as muscle spasticity and speech
disorders, but less than 10\% of cases have recovered without any
neurological sequelae.{[}8{]} Abnormal laboratory investigation with
significant elevated levels of serum aminotransferase and CSF protein
makes the prognosis of the disease to be worse.{[}10{]} With the aid of
physiotherapy our patient could walk on his own in contrast with his
initial presentation of being bed-bound with limited neuro-motor
activities on his both upper and lower limbs.

CONCLUSION

It is unknown whether similar cases of ANE have been taking place in our
setting and may obviously go unnoticed. This leads to delay in
establishing early diagnoses and later to poor patient outcome. Our
emphasis is to always maintain a high level of suspicion in similar
clinical presentations to ensure ANE does not go unrecognized.

\textbf{ACKNOWLEDGMENTS}

We thank the Critical Care Unit (CCU) team of the Shree Hindu Mandal
Hospital (SHMH) for their involvement in the treatment and care of this
patient. Published with written consent of the patient.

\textbf{CONFLICT OF INTEREST}

None declared.

\textbf{AUTHOR CONTRIBUTIONS}

Hilary Chipongo gathered the data and wrote the original draft. Abizer
Sarkar involved in tracing the best radiological image and reporting.
Esmail Sangey, Shaffin Rajan and Ronald Mclarty involved in editing of
the manuscript. Esmail Sangey involved in supervision and submission of
the manuscript. All took care of the patient and have approved the final
version of the manuscript.

\textbf{CONSENT}

Informed and written consent was obtained from the patient to publish in
this case report.

REFERENCES

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\end{enumerate}\selectlanguage{english}
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