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\begin{document}

\title{Mild encephalopathy with a reversible splenial lesion syndrome (MERS) Is
this a new side effect of Rituximab?}



\author[1]{Amira Atig}%
\author[1]{Maissa Thabet}%
\author[2]{Neila Fathallah}%
\author[1]{Nouha Ghriss}%
\author[1]{Ahmed Guiga}%
\author[1]{Wissal Ben Yahia}%
\author[2]{Chaker Ben Salem}%
\author[1]{Neirouz Ghannouchi }%
\affil[1]{University of Sousse}%
\affil[2]{Universite de Sousse Faculte de Medecine de Sousse}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Mild encephalitis/encephalopathy with a reversible splenial lesion
syndrome (MERS) is a rare clinico-radiological entity. Its occurrence
after Rituximab (RTX) has never been described. We report the first case
of MERS following RTX in a patient treated for IgG4 related disease
(IgG4-RD). It was about a 33-year-old patient diagnosed since 2017, with
an IgG4-RD. This diagnosis was made in front of a prolonged fever, sicca
syndrome, hepatic damage and renal pseudotumor associated to a high
level of IGg4 at 2.8 g/l with suggestive renal histology. The patient
was treated with corticosteroid therapy with persistence of renal
impairment and nephrotic syndrome that's why RTX has been indicated. The
patient received his first dose of RTX and presented few hours after,
neurological and respiratory impairments. An infectious investigation
comprising a SARS CoV-2 PCR and viral PCRs (VZV, Herpes and CMV) on
cerebrospinal fluid (CSF) were negative. The HBV, HCV, HIV, Parvo B19,
CMV, EBV, Herpes, Mycoplasma and syphilis serologies as well as
Legionella antigenuria were also negative. The patient had received
methylprednisone boli, intravenous immunoglobulin's associated with
sodium valproate with good evolution. The diagnosis of MERS induced by
RTX is likely. However the viral aetiology is not excluded.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Mild encephalitis/encephalopathy with a reversible splenial lesion
syndrome (MERS) is a rare clinical-radiological syndrome. It was first
identified by Carlos Garcia-Monco \textbf{{[}1{]}} in 2011. The most
common neurological symptoms are behavioral changes, altered
consciousness and seizures \textbf{{[}2{]}.} The diagnosis is based on
Brain magnetic resonance imagings (MRIs) showing a transient anomalies
mainly in the corpus callosum or sometimes extending to adjacent
parenchyma \textbf{{[}1{]}.} This syndrome mostly recovers without
treatment \textbf{{[}1{]}.} Biotherapy was reported to be efficient in
MERS in some cases. \textbf{{[}3, 4{]}} This syndrome was reported in
patients with viral infections, particularly rotavirus, herpes simplex
virus, adenovirus, coxsackie virus, echoviruses, mumps, influenza A/B
virus, and recently SARS CoV-2 \textbf{{[}5-12{]}.} In few cases MERS
was induced by some drugs such ipilimumab \textbf{{[}13{]}} and mumps
vaccination \textbf{{[}14{]}.} Here, we describe an original case of
MERS appearing few hours after RTX treatment in a patient with IgG4-RD.

\textbf{Case report}

It was about a 33-year-old man followed since 2017 for IgG4 related
disease. The diagnosis was retained in front of glandular involvement
with xerostomia and xerophtalmia, hypergammaglobulinemia at 28g/L with
IgG level at 23g/L and IGg4 level at 2.9 g/L, hepatic involvement with
cytolysis, cholestasis and positive anti smooth muscles antibodies
(ASMA). Radiologic findings were highly suggestive of malignancy.
Therefore, the patient underwent right nephrectomy with the presence of
IgG4 at direct immunofluorescence technique (DIFT) at the histology.

The patient was treated by corticosteroid therapy at a dose of 0.6
mg/kg/day for 2 months then progressive decrease with improvement in
glandular and hepatic involvement. Six months after treatment
initiation, the patient exhibited an edema of the lower limbs with
hematuria. Biological tests showed proteinuria at 15 ng/24H with a
creatinine value at 413\selectlanguage{greek}µ\selectlanguage{english}mol/l. Thus, an impure nephrotic syndrome was
retained and the patient was prescribed RTX as this complication was
thought to be a corticosteroid-resistant IgG4-RD manifestation.

The patient was hospitalized to receive RTX cure. On admission, his
temperature was 37\selectlanguage{ngerman}°C without obvious infectious foci. The
pre-therapeutic assessment had shown a CRP at 14 IU, an ESR at 2min, the
absence of hyperleukocytosis, negative SARSCoV-2 PCR and sterile ECBU
culture. The Natremia was normal at 142mmol/l and the AANs were
negative. The chest scanner was without abnormalities.

The patient received his first RTX cure at a dose of 1g. During the
course of this later treatment, he manifested a headach. Pressure blood
measurement showed a hypertensive peak at 150/80mmHg which regressed
spontaneously. Six hours after the end of the treatment, the patient
described paresthesias in the left lower limb with ataxia on walking. He
presented also, a fever peak at 40°C with a rapid alteration of
consciousness, a state of confusion, vomiting with myoclonus and
tremulation without motor or sensory deficit and with normal
osteotendinous reflexes. The patient became polypneic at 28cycles per
minute with crackling rales at lung bases.

A lumbar puncture was performed showing a clear fluid, presence of 100
white elements with 94 lymphocytes, proteinorrachia at 0.8g/L with
normal glycorrhachia at 4mmol/l.

Two hours later he presented a status epilepticus requiring intensive
care with intubation and mechanical ventilation. A cerebral angio-MRI
was performed showing high signal intensity on T2 weightned images and
diffusion weighted images \textbf{(figure 1).}

A second SARSCoV-2 PCR was done and was negative. Viral and bacterial
multiplex PCRs on cerebrospinal fluid were negative. The infectious
tests (HBV, HCV, HIV, Parvo B19, CMV, EBV, Herpes, Mycoplasma and
syphilis serologies as well as Legionella antigenuria) were negative.
ECBU and blood culture test are steriles.

The patient received a bolus of methylprednisone (15mg/Kg/day) for 3
days with intravenous immunoglobulin cures associated with sodium
valproate and he was extubated 48 hours later with a calm awakening and
a gradual recovery of his state of consciousness. The diagnosis of MERS
induced by RTX was most likely.

\textbf{Discussion}

We reported herein the first case of MERS occurding after RTX. This
diagnosis was retained in front of multiple symptoms appeared post
treatment and suggestive neurologic radiologic anomalies.

MERS is characterized by a reversible lesion with homogenously reduced
diffusion in the corpus callosum. It usually develops in children
between the ages of 0 and 16 years and occasionally in adults

\textbf{{[}15{]}.}

The clinical symptoms of MERS syndrome are nonspecific and diverse. The
most common manifestation is fever which was the prodromal symptom in
our patient \textbf{{[}16{]}.} Fever may precede or accompanies
neurological symptoms. Other general clinical symptoms including
headache and digestive tract disturbances (vomiting and
diarrhea)\textbf{{[}10, 17{]}} have been also reported. Consciousness
disturbance, seizures, behavior changes, drowsiness, confusion, acute
urinary retention, and delirium may also be the common neurological
symptoms associated with MERS \textbf{{[}10; 18, 19, 20{]}.} In our
case, gastro-intestinal involvement and consciousness disturbance were
predominant.

Typically, MRI features show reversible hyperintense signals on T2\selectlanguage{english}-
weighted images, fluid\selectlanguage{english}-attenuated inversion recovery images (FLAIR), and
diffusion\selectlanguage{english}-weighted images (DWI) in the splenium of the corpus callosum
(SCC) (classified in MERS type I) \textbf{{[}16{]}.} Sometimes,
radiologic abnomalies can extend to other areas of the corpus callosum
and adjacent periventricular white matter in a symmetrical pattern
(classified in MERS type II). Our patient was a MERS type II case.

Yuan et al, in their review reported that the total of 29 patients
recovered completely within a month \textbf{{[}6, 19{]}.} In rare cases,
patients, especially those with type II lesions on MRI, may develop
neurological sequelae and lesions may persist on MRI for months even if
their size diminishes \textbf{{[}21{]}.}

Several mechanisms have been proposed for the pathogenesis of MERS but
this is still unclear. There are several hypotheses, including
intramyelinic edema \textbf{{[}18{]},} hyponatemia \textbf{{[}17{]},}and
oxidative stress \textbf{{[}22{]},} neuroaxonal damage\textbf{{[}23{]},}
autoimmune processes \textbf{{[}24{]},} and cytotoxic edema
\textbf{{[}25{]}.} The possible explanation for this is intramyelinic
edema resulting from separation of myelin layers\textbf{{[}26, 27{]}}
and local infiltration of inflammatory cells

\textbf{{[}17, 18{]}.}

Moreover, most cases of reversible lesions demonstrate the evidence that
cytotoxic edema of the SCC is an important mechanism in this
syndrome\textbf{{[}28{]}.} Miyata R et al \textbf{{[}16{]},} reported
that patients with MERS has an elevated IL-6 and IL-10 levels in CSF.
Cytotoxic edema in the neurons, astrocytes, and oligodendrocytes of the
SCC, caused by cytokines, may offer the best explanation. Recently,
these lesions have been called cytotoxic lesions of the corpus callosum
or CLOCC lesions \textbf{{[}28, 29{]}.} This could explain the elevated
white cells in the CSF as it is the case of our patient. A recent review
study \textbf{{[}19{]}} found that more than half (15/23) cases had
elevated white cells in the CSF. Even if we take all these hypotheses
into account, MERS still be a rare syndrome with unclear pathogenesis
and none of the existing hypotheses may explain why MERS specially
involves the site splenium.

In addition, serum sodium levels were significantly lower in patients
with MERS than in age matched controls. These data support the
hypothesis that a transient cerebral edema may develop as a result of
hyponatremia \textbf{{[}17{]}.}

RTX is a murine/human\selectlanguage{english}-chimeric monoclonal antibody that depletes CD20+ B
cells through both cell\selectlanguage{english}-mediated and complement mediated cytotoxic
effects \textbf{{[}30{]}.} It is widely used in malignancy and
immune\selectlanguage{english}-mediated diseases in combination with corticosteroids and other
immunosuppressive drugs.

RTX is also effective for both induction therapy and treatment of
relapses in IgG4-RD specially in nephrologic flare refractory to
corticosteroids \textbf{{[}31{]}.} Its administration rarely causes
serious neurologic adverse events. However, it was reported to lead to
complement activation, cell lysis and subsequent massive release of
cytokines, culminating in cytokine release syndrome and systemic
inflammatory response syndrome \textbf{{[}32-35{]}.} This could, in
part, explain the early development of MERS after rituximab in our
patient. But MERS induced by Rituximab has never been reported before.

However, Posterior reversible encephalopathy syndrome (PRES), which may
be a differential diagnoses for MERS, has been reported to be related to
RTX \textbf{{[}3{]}.}

PRES is a rare clinical disorder which has nearly clinical symptoms to
MERS. It manifests also with headache, convulsions, altered level of
consciousness and reversible cerebral edema. It is also a reversible
disorder that requires rapid diagnosis by demonstrating the presence of
characteristic vasogenic edema on brain MRI in the appropriate clinical
context {[}36, 37{]}.

Progressive multifocal leukoencephalopathy (LEMP) after RTX, which is a
rare opportunistic infection due to reactivation of JC virus into the
central nervous system, is described \textbf{{[}38{]}.}

Acute disseminated encephalomyelitis (ADEM) is being the main
differential radiologic diagnosis of MERS \textbf{{[}39{]}} but RTX is
effective for this disease \textbf{{[}40{]}.}

The neurological manifestations presented by the patient cannot also be
related to his underlying disease. IgG4-related disease can involve
nearly any organ system, including the central and peripheral nervous
systems but MERS has never been reported \textbf{{[}41{]}.}

Furthermore, MERS is a rare disease and evidence on the therapeutic
approaches is currently not yet available. Methylprednisolone pulse
therapy and IVIG were prescribed in MERS patients without any evidence
of efficacy of these treatments. However, many patients without
methylprednisolone pulse therapy or IVIG recovered clinically
completely, which suggests that those treatments may not be
necessary\textbf{{[}42{]}.} Our patient was treated by
methylprednisolone pulse therapy and IVIG as we had a severe
neurological involvement and we were face an auto immune disease
(IgG4-RD).

\textbf{Conclusion}

We reported a case of an adult onset MERS after RTX cure. Taken together
with the previously reported cases, we suggest that MERS in adults is an
entity with a broad clinico-radiological spectrum and the prognosis is
good. The early recognition of MERS can avoid unnecessary treatments and
provide reassurance about good outcomes.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 1:} A cerebral angio-MRI was performed showing high
signal intensity on T2 weightned images and diffusion weighted images.

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\selectlanguage{english}
\FloatBarrier
\end{document}

