Dear Editor,
A 35-year-old female patient was admitted to our emergency department with impairment
of consciousness, and somnolence. It was learned that the patient had been suffering
from headache and anorexia over the last week. The clinic had begun abruptly, and
the patient deteriorated over the last 5 hours before admission. The other medical
history was unremarkable, and the patient had no history of recent drug use or an
infection. The vital signs at admission to the emergency service were within normal
limits. The neurological examination revealed that the patient was nonoriented and
mildly cooperative. She could not cooperate properly with the examination and an increase
in motor and psychological activity was apparent that was compatible with agitation.
Other investigations including motor, sensory, and cerebellar tests were roughly within
normal limits. The Kernig's and Brudzinski's signs were negative. The laboratory investigations
revealed severe iron deficiency anemia (hemoglobin [Hb]: 5.3 mg/dL, serum ferritin:
30 μg/L), mild hyponatremia (131 mM/L [136–146 mM/L]), hyperkalemia (5.1 mM/L), neutrophilic
leukocytosis (neutrophil: 89%), and increment of C-reactive protein (27.9 [0–0.8]).
The results of the other investigations including liver-kidney functions, thyroid
functions, vitamin B12, and folic acid were within normal limits. The initial cranial
magnetic resonance imaging (MRI), performed on the 9th hour of the clinic, was normal
([Fig. 1]). Lumbar puncture investigations revealed normal cerebrospinal fluid (CSF) biochemistry,
microscopic examination, and the result of the CSF culture was negative. The infectious
disease specialist did not consider an infectious etiology of the central nervous
system to explain the clinic. Routine electroencephalogram showed mild slow background
activity (7 Hz) without discharge and focal slow activity. At this point, the MRI
was repeated the day after, which showed restricted diffusion in the splenium, bilateral
corona radiata, and left hippocampus ([Fig. 1]). Two-unit red blood cell (RBC) transfusion was administered for deep anemia (the
follow-up test revealed Hb level of 8.3 mg/dL and Na level of 134 mM/L) and methylprednisolone
1 g intravenous treatment was initiated considering a possible underlying limbic encephalitis
or autoimmune encephalitis. However, after the RBC transfusion, a marked and rapid
clinical improvement was achieved, and the patient completely recovered after 2 days,
and methylprednisolone was stopped at the second day of therapy. She was fully oriented
and cooperative, and the Glasgow Coma Scale was evaluated as 15 points. The results
of the screening tests for tumors including computed tomography (CT) thorax, CT abdomen,
and pelvic ultrasound were unremarkable. Besides, the tumor markers were within normal
limits. The anti-NMDAR antibody, anti-AMPA1 antibody, anti-AMPA2 antibody, CASPR2
antibody, GABARB1/B2 antibody, and LGI1 antibody tests results were negative. The
follow-up MRI, performed 1 week later, showed total resolution of the diffusion-restricted
lesions ([Fig. 2]). The retrospective analyses of the results, in light of the related literature
data, revealed the diagnosis of reversible splenial lesion syndrome (RESLES).
Fig. 1 (A) The cranial magnetic resonance imaging (MRI), performed at admission (9 hours after
initiation of the clinic), shows a normal appearance. (B,C) The second cranial MRI (performed 1 day after the initiation of clinic) showing
diffusion restriction in the corpus callosum, bilateral corona radiate, and left hippocampus
(B represents the diffusion-weighted imaging [DWI] sequences; C represents the apparent diffusion coefficient [ADC] sequences).
Fig. 2 The cranial magnetic resonance imaging (MRI) shows complete resolution of the diffusion-restricted
lesions (A represents diffusion-weighted imaging [DWI] sequences, B represents apparent diffusion coefficient [ADC] sequences, C represents fluid-attenuated inversion recovery [FLAIR] sequences).
Discussion
RESLES has been reported secondary to several disorders, including acute or subacute
encephalitis/encephalopathy, antiepileptic drug (AED) toxicity or withdrawal, high-altitude
cerebral edema, hypoglycemia, or hypernatremia. Particularly, the refractory seizures,
AED usage, and metabolic conditions constitute prominent etiological factors for RESLES.[1] Classically, RESLES has an excellent prognosis, resulting in complete recovery without
neurological sequelae after the acute disease course.[2] Therefore, recognition of this entity may be important for predicting the clinical
course and appropriate management of these patients. In our patient, the prominent
metabolic impairment was deep anemia; however, mild hyponatremia was also present
at admission. The RBC transfusion provided improvement of Hb to 8.3 mg/dL and the
clinic markedly improved. Therefore, we did not continue the methylprednisolone 1 g
intravenous therapy which was initiated considering the possibility of an underlying
limbic encephalitis or autoimmune encephalitis. In addition to the clinical course,
the results of the following investigations (limbic encephalitis antibodies and screening
tests for malignancy) also excluded these diagnoses. The association between RESLES
and various metabolic disturbances including endocrine disorders, hypernatremia and
hypoglycemia, and multiple vitamin deficiencies have been well defined.[3]
[4] However, up to our knowledge, our case with RESLES in association with deep anemia
is unique expanding the spectrum of RESLES.
Another interesting point was that the diffusion-restricted lesions also involved
bilateral corona radiate and hippocampus in addition to the splenium. Classically,
the extracallosal lesions are not expected to occur in RESLES.[5] However, recent reports remark on the presence of extracallosal lesions frequently
in patients with RESLES.[4]
[6] Zhang et al reported extracallosal lesions in four of their eight patients with
RESLES and they discussed that these lesions may be associated with unfavorable prognosis.[4] Contrasting with this observation, the prognosis of our patient was excellent, such
that she recovered completely in a few days following transfusion therapy.
A crucial hypothesis regarding the pathogenesis of a reversible diffusion-restricted
lesion in RESLES is the excitotoxic mechanisms that do not lead to brain ischemia.[7] In excitotoxic edema, glutamate is the main agent inducing edema and it occurs predominantly
in glial cells and myelinic sheaths.[7] This involvement pattern protects axons from intracellular edema and irreversible
neuronal damage.[7] The neuronal somata make up less than 1% of the corpus callosum whereas it is mainly
composed of axons and glial cells[8] which may be responsible from the specific vulnerability of this region in RESLES.
The corona radiata also involve white matter connections without neuronal somata,
however, we know that the hippocampus is comprised primarily of pyramidal cells. On
the other hand, the pyramidal layers of the hippocampus are tightly packed with glutamatergic
neurons that have a low firing threshold[9] supporting the view of glutamate-associated excitotoxic mechanisms. Of note, in
our patient, the most probable etiological agent was deep iron deficiency anemia which
is interestingly shown to lead marked functional alterations in both excitatory and
inhibitory neurotransmitter receptors.[10] However, these hypotheses are all warranted to be clarified in future studies including
a large number of patients. We think that the illustration of these rare patients
may provide contributions regarding our understanding of the mechanisms of RESLES
also without extracallosal lesions. Finally, the clinical awareness of this entity
is critical for optimal diagnosis and avoiding unnecessary interventions.
