Reversible splenial lesion syndrome in neuroleptic malignant syndrome
1 Imaging Department, Universiti Putra Malaysia, Malaysia
2 Radiology Department, Hospital Kuala Lumpur , Malaysia
3 Neurology Department, Hospital Kuala Lumpur , Malaysia
4 Radiology Department, Universiti Kebangsaan Malaysia, Malaysia
Background: Reversible focal lesions in the
splenium of the corpus callosum (SCC) or reversible splenial lesion syndrome
are rare and little is known about their pathophysiology.
Case summary: The authors describe a case of a
65-year-old female who presented with fever, abnormal behaviour and mild
hypernatremia. She was on neuropsychiatric treatment for bipolar disorder but
denied any history of seizure. After an extensive workout to exclude infection,
a clinical diagnosis of neuroleptic malignant syndrome (NMS) was made. Initial
magnetic resonance imaging (MRI) of the brain showed a lesion in the SCC
characterized by high-signal intensity on T2-weighted and FLAIR sequences with
reduced signal intensity on T1-weighted sequence. Diffuse weighted imaging
(DWI) showed restricted diffusion. There was no enhancement following
Gadolinium administration. The follow-up MRI 8 weeks later showed complete
resolution of the SCC lesion.
Conclusion: While the pathophysiology of reversible
SCC lesions is still unclear, this case highlights the need to consider NMS in
the differential diagnosis of reversible splenial lesion of the corpus
callosum. � 2009 Biomedical Imaging and Intervention Journal. All rights
Keywords: corpus callosum, reversible splenial, neuroleptic
Reversible focal lesions in the splenium of the corpus
callosum (SCC) or reversible splenial lesion syndrome are rare and have only
been described in recent years. It has been reported in a few cases of mild
encephalitis and encephalopathy caused by various infective agents and has also
been reported in less than 40 epilepsy patients on antiepileptic treatment. The
underlying pathophysiology of these lesions still remains unclear and to this
date, various postulations have been put forward as the probable cause. The
authors present a case of this rare finding in a patient with NMS who was on
neuropsychiatric treatment for bipolar disorder.
A 32-year-old woman presented with a 1-week history of
fever, abnormal behaviour and refusal to eat and talk. She was a known case of
bipolar disorder and was on multiple neuropsychiatric drugs: clomazapine 10 mg
daily, lithium carbonate 300 mg (morning dose) and 600 mg (nocturnal dose),
lorazepam 1 mg bd and 1.5 mg nocturnal dose prn and benzhexol 4 mg tds. On
examination, she was conscious, flushed and able to open eyes spontaneously.
Her pupils were equally reactive. There was no neck stiffness. Motor examination
showed increased tone and brisk reflexes, more on the left side while the power
was reduced to 3/5 in the upper limbs. She also had tremors on the right side.
Plantar reflexes presented bilaterally.
Laboratory investigation showed leucocytosis with predominant
neutrophilia and normal platelet and hemoglobin counts. Liver function test
showed mild elevation of the alanine transaminase and alkaline phosphatase.
Renal profile showed raised sodium level (161 mmol/l). Creatine phosphokinase
(CPK) was markedly raised (537 U/l). Lumbar puncture was done and the opening
pressure was raised (35 cm H2O). Cerebrospinal fluid examination did
not show any presence of white cells. Ziehl-Nielsen stain, Gram stain and
Indian ink stain were all negative. The levels of glucose and proteins were
within normal limits. Hemophilus influenza B, Streptococcus
pneumoniae, Neisseria meningitides or Streptococcus group B antigens
were not detected in the cerebrospinal fluid.
CT scan of the brain showed a slightly swollen and hypodense
splenium of the corpus callosum. Subsequent brain MRI showed swollen splenium
of corpus callosum and appeared hypointense on T1-weighted image, hyperintense
on T2-weighted image and FLAIR. Restriction in diffusion was observed in the
DWI with decreased ADC values (Figure 1). No enhancement was noted on
Her CPK level showed an up-going trend from the time of
admission. It reached the maximum level of 1213 U/l on the 4th day
of admission and correspondingly, she was noted to be more aggressive verbally.
She was empirically treated for possible CNS infection with intravenous
ceftriaxone 1 g twice daily and C-Penicillin 2 megaunit 6-hourly. She was also
put on a rehydration regime in view of the rising CPK levels and hypernatremia.
Her temperature returned to normal and both CPK and sodium
levels came down to 417 U/l and 156 mmol/l, respectively. Upon discharge, there
was only minimal cog-wheel rigidity. She was otherwise well and able to talk
and eat as usual. A follow-up MRI done 8 weeks after discharge showed complete
resolution of the splenial lesion (Figure 2). In view of the clinical history
and presentation as well as the laboratory findings, a clinical diagnosis of
neuroleptic malignant syndrome was made.
Reversible splenial lesion of the corpus callosum has only
been described in recent years and has been reported in only a few patients to
date. The majority of reported cases have been found in patients with epilepsy
undergoing antiepileptic treatment [1-4]. In these cases, different
pathophysiologic hypotheses have been put forward as the possible etiology and
among them are the transient effects of anti-epileptic drugs on
arginine-vasopressin and its function in fluid balance systems in a condition
of vitamin deficiency , reversible demyelination related to anti-epileptic
drug toxicity  and transient focal oedema due to transcallosal seizure
spread in secondary generalized seizures .
Another recently described clinicoradiological syndrome is
the finding of a solitary reversible SCC lesion associated with mild
encephalitis or encephalopathy [5-7]. Various causative agents have been
attributed to this findings including influenza A, mumps virus, adenovirus,
rotavirus, varicella-zoster virus, Escherichia coli, measles and Salmonella
In both these groups, the consistent finding is the
similar signal characteristics of the SCC lesions on MRI. All lesions
demonstrate hypointense signal on T1 and hyperintense signal on T2 and FLAIR
sequences. Restricted diffusion was also seen in all cases that underwent DWI
sequence. None of these lesions showed enhancement following gadolinium
administration and complete resolution of the SCC lesion was seen in all
patients on follow-up MRI.
In the group of patients with encephalitis/encephalopathy,
complete resolution was seen on repeat imaging performed three days to two
months following the abnormal study, regardless of the different causative
agent. All reported cases had a mild clinical course with complete recovery
seen within a month after onset of neurological symptoms. None of the patients
developed permanent neurological sequelae.
In the patient described in this case report, both
seizures and encephalitis were excluded. Thorough blood and cerebrospinal fluid
examinations were also negative for encephalitis/encephalopathy. The diagnosis
of NMS was made based on the positive history of neuropychiatric treatment as
well as the clinical presentation and laboratory findings.
NMS is a relatively rare but potentially fatal side effect
of antipsychotic medications, which was first described by Delay et al in 1960
during early trials of haloperidol. The incidence of NMS ranges between 0.02%
to 3.23% of psychiatric patients receiving neuropsychiatric treatment. Clinically,
it is characterized by an abnormal mental status, hyperthermia, �lead-pipe�
rigidity, akinesia or dystonia, autonomic instability, rhabdomyolysis,
myoclonus, coarse tremors and cogwheeling. Common laboratory findings of NMS
include increased CPK due to rhabdomyolysis, leukocytosis and myoglobinuria
[8-12]. Some of these features were present in this patient and the authors
believe this could be the cause for the reversible splenial lesion on MRI.
Another possibility that needs to be considered in this
patient is hypernatremia. Maeda M et al reported a case of reversible splenial
lesion in a patient with hypernatremia . However, in this patient, there
were also additional parenchymal lesions located symmetrically in the
temporo-occipital lobes, which were not reversible and became more extensive in
the follow-up MRI. This patient eventually developed osmotic myelinolysis and
had a poor outcome. Although the clinical outcome in this patient was more
favourable and there were no additional parenchymal lesions on MRI,
hypernatremia as the cause for the reversible splenial lesion could not be
The underlying pathophysiology of NMS is still poorly
understood but it is thought to be caused by central and peripheral
dopaminergic blockade that results in muscle rigidity, core temperature
elevation and hypermetabolism. Virtually all classes of drugs that block the D2-receptors
have been associated with NMS and it was found to be more frequent in patients
receiving increasing and newly introduced doses of neuroleptic medication,
medications given via intramuscular route, patients requiring physical
restraints, patients suffering from mental disorders or retardation and those
receiving a higher total dose of treatment . Other risk factors include
poor oral intake, dehydration, exhaustion, agitation and elevated temperature.
There are no specific neuroimaging features associated
with NMS. CT Scan and MRI are usually done in patients with NMS to exclude
other structural lesions or infections that may give rise to similar clinical
presentation. Abnormalities in the corpus callosum have been reported in a
patient with neuropsychiatric lupus with psychosis . However, in this
particular case, the patient also has history of seizures. The authors also
concluded that the location of the lesion in the SCC associated with pure
psychotic disorders raises the possibility that such a lesion may be sufficient
to produce acute behavioral changes and psychotic features in certain patients.
To date, there has not been any reported case of
reversible lesion of the SCC that is associated with NMS. Establishing a
hypothesis for the precise etiology of the SCC lesion in this patient is
difficult. The authors postulate that the lesion itself may be associated with
the acute behavioral changes found in this patient. They also highlight the
possibility of including NMS as one of the differential diagnosis of reversible
splenial lesion of the corpus callosum.
Figure 1 MRI imaging of the brain on admission with (a) axial T2-weighted, (b) axial FLAIR, (c) axial DWI and (d) corresponding ADC map. An ovoid lesion is seen at the centre of the splenium of the corpus callosum, hyperintense on T2 and FLAIR with markedly restricted diffusion and decreased ADC values.
Figure 2 Follow up MR imaging performed 8 weeks after discharge with (a) axial FLAIR, (b) sagittal T2-weighted and (c) axial ADC map showing complete resolution of the SCC lesion and normalization of ADC values.
Polster T, Hoppe M, Ebner A. Transient lesion in the splenium of the corpus callosum: three further cases in epileptic patients and a pathophysiological hypothesis. J Neurol Neurosurg Psychiatry 2001; 70(4):459-63.
Kim SS, Chang KH, Kim ST et al. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? AJNR Am J Neuroradiol 1999; 20(1):125-9.
Oster J, Doherty C, Grant PE et al. Diffusion-weighted imaging abnormalities in the splenium after seizures. Epilepsia 2003; 44(6):852-4.
Prilipko O, Delavelle J, Lazeyras F et al. Reversible cytotoxic edema in the splenium of the corpus callosum related to antiepileptic treatment: report of two cases and literature review. Epilepsia 2005; 46(10):1633-6.
Tada H, Takanashi J, Barkovich AJ et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004; 63(10):1854-8.
Yeh IB, Tan LC, Sitoh YY. Reversible splenial lesion in clinically mild encephalitis. Singapore Med J 2005; 46(12):726-30.
Kobata R, Tsukahara H, Nakai A et al. Transient MR signal changes in the splenium of the corpus callosum in rotavirus encephalopathy: value of diffusion-weighted imaging. J Comput Assist Tomogr 2002; 26(5):825-8.
Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998; 49(9):1163-72.
Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000; 85(1):129-35.
Caroff SN, Mann SC, Campbell EC. Neuroleptic malignant syndrome. Adverse Drug React Bull 2001; 209:799-802.
Hall RC, Appleby B, Hall RC. Atypical neuroleptic malignant syndrome presenting as fever of unknown origin in the elderly. South Med J 2005; 98(1):114-7.
Viejo LF, Morales V, Punal P et al. Risk factors in neuroleptic malignant syndrome. A case-control study. Acta Psychiatr Scand 2003; 107(1):45-9.
Maeda M, Tsukahara H, Terada H et al. Reversible splenial lesion with restricted diffusion in a wide spectrum of diseases and conditions. J Neuroradiol 2006; 33(4):229-36.
Fogel B, Cardenas D, Ovbiagele B. Magnetic resonance imaging abnormalities in the corpus callosum of a patient with neuropsychiatric lupus. Neurologist 2006; 12(5):271-3.
|Received 5 February 2009; received in revised form 3 May
2009, accepted 15 July 2009
Correspondence: Radiology Department, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Kuala Lumpur, Malaysia. Tel.: +603-9145 6211; Fax: +603-9173 7307; E-mail: firstname.lastname@example.org (Ahmad Sobri Muda).
Please cite as: Al-Edrus SA, Norzaini R, Chua R, Puvanarajah SD, Shuguna M, Muda S,
Reversible splenial lesion syndrome in neuroleptic malignant syndrome, Biomed Imaging Interv J 2009; 5(4):e24