Journal of the Neurological Sciences 314 (2012) 178–180

Contents lists available at SciVerse ScienceDirect

Journal of the Neurological Sciences
journal homepage: www.elsevier.com/locate/jns

Short communication

Callosal warning syndrome☆
Ramachandiran Nandhagopal a,⁎, Abdullah Al-Asmi a, William James Johnston b,
P.C. Jacob a, G.R. Arunodaya a
a
b

Unit of Neurology, Department of Medicine, College of Medicine and Health Sciences, P.O. Box. 35, SQU, Al-Khod, Zip 123, Muscat, Oman
Internal Medicine, Department of Medicine, College of Medicine and Health Sciences, P.O. Box. 35, SQU, Al-Khod, Zip 123, Muscat, Oman

a r t i c l e

i n f o

Article history:
Received 16 August 2011
Received in revised form 3 October 2011
Accepted 4 October 2011
Available online 8 November 2011
Keywords:
Disconnection syndrome
Callosal infarction
Stroke warning syndrome

a b s t r a c t
Objective: To report the clinical and imaging findings in a patient with an initial fluctuating disconnection
syndrome due to corpus callosal ischemia that ultimately culminated in infarction with persistent symptoms.
Case report: A 40-year-old, hypertensive, right-handed man presented with transient, stereotyped symptoms
of corpus callosal disconnection (intermanual conflict, apraxia, dysgraphia and construction difficulties in
his left hand). Serial magnetic resonance imaging scans demonstrated the ischemic nature of the initial fluctuating symptoms and later showed callosal infarction when the symptoms were persistent. Magnetic resonance angiogram did not reveal significant stenosis or occlusion of the internal carotid or proximal portion of
anterior cerebral arteries. Patient received standard treatment for ischemic stroke and at follow-up 1 month
later, had mild left hand apraxia, dysgraphia and construction difficulties.
Conclusion: The case highlights the unusual occurrence of crescendo transient ischemic attacks culminating in
infarction in the location of corpus callosum. We have termed this novel stroke syndrome as ‘callosal warning
syndrome’ as the temporal profile was quite indistinguishable from that of relatively well-known stroke
warning syndromes in the location of internal capsule and pontine tegmentum.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction

2. Case report

Stroke warning syndrome refers to a cerebrovascular syndrome
that is characterized by recurrent, stereotyped episodes of transient
neurological symptoms and signs leading up to infarction in the
corresponding anatomical site [1–4]. Based on the neuroanatomical location of the final infarction, the syndrome has been
given the corresponding name. For instance, when the recurrent
episodes of transient hemiparesis are followed by infarction in
the internal capsule, it is called capsular warning syndrome [1,2].
On the other hand, when the corresponding infarction heralded
by transient events occurs in the region of the pontine tegmentum,
it is termed as pontine warning syndrome [3,4]. In this communication we report on a novel stroke syndrome that is characterized
by initial fluctuating symptoms of corpus callosal disconnection
followed by an ischemic infarction in the same region. In keeping
with the naming convention, we have coined the term ‘callosal
warning syndrome’ for this particular stroke syndrome.

A 40-year-old, right-handed man with a history of heavy cigarette
smoking, hypertension and occurrence of stroke in his father, presented with recurrent episodes of symptoms dominated by intermanual conflict lasting for a few minutes. During these episodes, he
described that his left hand was clumsy and acted at cross-purpose
to the action of the right hand as, for instance, his left hand untucked
the shirt that was tucked by the right hand or unbuttoned the shirt
in conflict with the action of the right hand. He could not account
for the actions of his left hand that were ‘bizarre and weird’. This
symptom was not associated with reflexive grasping, groping, compulsive manipulation of objects, impaired consciousness, staring
spell, aura, automatism or tonic-clonic limb movements. However
these episodes were accompanied by dysarthria, whole body numbness and mild unsteadiness of walking. He denied history of
any other neurological symptoms or stroke in the past. Upon arrival
in the emergency room 5 h after the onset of his symptoms, his
blood pressure was 154/102 mm Hg. He demonstrated mild
left hand apraxia and dysgraphia and construction difficulties,
mild dysarthria, slightly broad-based gait and National Institute
of Health (NIH) stroke score of 2. He scored 30/30 on mini-mental
status examination (MMSE) and on Addenbrooke's cognitive examination (ACE-R), his general/total score was 95 [subscores: attention and
orientation — 18/18; memory — 26/26; fluency — 10/14; language —
26/26 and visuospatial function — 15/16]. Initial CT brain showed old

☆ All the authors have contributed to the study design, analysis and intellectual
contents.
⁎ Corresponding author at: College of Medicine and Health Sciences, P.O. Box. 35,
SQU, Al-Khod, Zip 123, Muscat, Oman. Tel.: + 968 24143404; fax: + 968 2441 3419.
E-mail address: rnandagopal@yahoo.com (R. Nandhagopal).
0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2011.10.007

R. Nandhagopal et al. / Journal of the Neurological Sciences 314 (2012) 178–180

Fig. 1. Diffusion weighted axial MRI (DWI) brain demonstrating small foci of restricted
diffusion [hyperintense lesions on DWI, b1000 (panel A) and hypointense lesions on
apparent diffusion coefficient (ADC) map (panel B)] suggestive of acute small infarction
in bilateral parietal parasagittal areas.

lacunes in bilateral basal ganglia and right thalamus but there were
no new infarcts. MRI brain revealed additional few, scattered, small,
new infarcts in the parietal parasagittal region bilaterally and right
centrum semiovale posteriorly (Fig. 1). There was no lesion in the corpus callosum on fluid attenuated inversion recovery MRI, diffusion
weighted sequence and apparent coefficient map (Fig. 2, upper
panel). MR angiogram of extracranial carotid arteries, circle of Willis
and intracranial arteries did not reveal any significant stenotic/occlusive
lesions or vascular malformation. Trans-thoracic echocardiography was
normal. His blood tests including peripheral smear, arterial blood gas,
urea, creatinine, glucose and lipids were unremarkable. He received
treatment with aspirin and amlodipine (his usual antihypertensive
medication). During 24 h of observation in the hospital, he had no
further occurrence of transient symptoms or persistent signs. He was
discharged on antiplatelet, statin and antihypertensive medication
with advice to stop smoking and to return for review immediately if
there was further recurrence of symptoms. Meanwhile we had arranged an out-patient appointment for appraising the pending results
of vasculitis panel and thrombophilia work-up.
Seventy-two hours after the initial hospital visit, he presented with
increasing frequency of the same symptoms. On arrival, his blood pressure was 130/78 mm Hg. His MMSE and ACE-R scores and NIH stroke
scale score remained the same. He demonstrated persistent apraxic errors in his left hand while pantomiming to verbal commands and left
arm dysgraphia and construction difficulties, apart from the other

179

clinical finding of slightly broad-based gait with mildly impaired tandem
walking. There were no primary sensori-motor deficits, unilateral verbal
anosmia, tactile anomia, hemi-alexia, double hemianopsia or extinction
or neglect on double simultaneous sensory testing and line bisection
test. Repeat MRI brain showed acute infarction (Fig. 2, lower panel)
in the body of corpus callosum (sparing the rostrum, genu and splenium), in addition to the small, acute infarcts in bilateral parietal parasagittal regions and right centrum semiovale as mentioned above. MR
angiogram did not reveal any occlusive lesions of the intracranial arteries including anterior cerebral arteries and extracranial carotid arteries
or vascular malformation. Trans-esophageal echocardiography and
ECG did not reveal any cardiac source of embolism. There were no epileptiform discharges on EEG. Anti-nuclear antibody, anti-cardiolipin
and anti-β2 glycoprotein antibodies and anti-neutrophil cytoplasmic
antibodies, HIV and syphilis serologies were non-reactive/in the normal
range. During the eight day stay in the hospital, he had persistent left
arm apraxia and dysgraphia and construction difficulties while other
symptoms viz. intermanual conflict, dysarthria, numbness and gait
problems improved significantly. At neurological follow-up 1 month,
3 months and 6 months later, he had mild left arm apraxia and dysgraphia and construction difficulties. MRI brain obtained 1 month after the
ictus showed the same callosal infarction (Fig. 3).
3. Discussion
Our patient had recurrent, transient episodes of callosal disconnection syndrome in the form of alien limb sign (with intermanual
conflict), left hand apraxia and dysgraphia and construction difficulties initially. Later, he developed persistent but incomplete syndrome
with unilateral hand apraxia, dysgraphia and construction difficulties.
The etiological spectrum of callosal lesions in adults includes vascular
processes (infarction, arterio-venous malformation, aneurysmal
hemorrhage, Susac's syndrome), demyelinating diseases (multiple
sclerosis, progressive multifocal leukoencephalopathy, Marchiafava–
Bignami disease, acute disseminated encephalomyelitis), tumors
(lipoma, gliobastoma multiforme, lymphoma), trauma (diffuse axonal
injury), encephalopathy with reversible splenial lesion (viral and parasitic infections, toxic-metabolic disorders, anticonvulsant withdrawal
and high altitude cerebral edema) and surgical procedures (shunting
for long-standing hydrocephalus, callosotomy for refractory epilepsy)
[5,6]. These competing diagnoses, other than ischemic stroke, were
ruled out in the present case in the absence of appropriate clinical
and imaging evidence. Interestingly the initially fluctuating transient

Fig. 2. Upper panel. MRI brain [axial DWI, b1000 (panels A, C), ADC map (panels B, D) and sagittal T1 weighted image (panel E)] performed within 24 h of onset of initial symptoms
of callosal disconnection. There is no abnormal signal intensity or infarction in the region of corpus callosum. Lower panel. MRI brain [axial DWI, b1000 (panels F, H), ADC map
(panels G, I) and sagittal T1 weighted image (panel J, arrow depicts the hypointensity/infarction)] obtained one week after the initial symptoms shows acute infarction involving
the body of corpus callosum.

180

R. Nandhagopal et al. / Journal of the Neurological Sciences 314 (2012) 178–180

Fig. 3. MRI brain [sagittal T2 weighted image (panels A and B)] obtained 1 month after
the ictus demonstrates established infarction involving the body of corpus callosum.

symptoms were not accompanied by corresponding lesion/infarction in
the corpus callosum on the diffusion weighted MRI and apparent diffusion coefficient map obtained within 24 h of onset of symptoms (Fig. 2,
upper panel), while the subsequent brain MRI (performed one week
after the initial symptoms) revealed the characteristic callosal infarction (Fig. 2, lower panel) when the symptoms were persistent. As diffusion-weighted MRI is quite sensitive to depicting infarction within
hours of ischemic symptoms [7], the temporal course of clinicoimaging findings suggest that there was initial symptomatic callosal
ischemia culminating in infarction in the subsequent days. The accompanying small, scattered, acute extra-callosal lesions in the distribution of anterior cerebral arteries or anterior-middle cerebral border
zone area (distal vascular field) also favored ischemic infarction over
hyperacute demyelination or tumor as the underlying causative
mechanism.
The corpus callosum is supplied by three main arteries viz. anterior
communicating artery, distal anterior cerebral artery and distal posterior cerebral artery [8]. The anterior portion of the corpus callosum
(rostrum and genu) is usually supplied by the subcallosal and
medial callosal branches of the anterior communicating artery. The
pericallosal branch of the distal anterior cerebral artery often provides blood supply to the body, whereas the splenium derives its vascular supply, most often, from the splenial or posterior pericallosal
branch of the distal posterior cerebral artery. As in our patient, infarction of the callosal body (and or rostrum and genu) could present
with the disconnection syndrome as mentioned above [9–13]. In
contrast, splenial infarction accompanying occipitotemporal lesion
of the dominant hemisphere due to posterior cerebral arterial occlusion usually presents with alexia without agraphia [14]. This form of
pure alexia arises from the disconnection of the non-dominant occipital lobe from the language area and was not observed in our patient in whom the splenium was spared (Fig. 3). The crescendo
transient ischemic attacks involving the callosal body culminating
in ischemic infarction and persistent symptoms were in keeping
with the temporal profile of warning syndromes that has been described for capsular and pontine tegmental strokes [1–4]. The predominant pathophysiologic mechanisms underlying these stroke
warning syndromes include hemodynamic compromise of penetrating arterial branch and peri-infarct depolarization [1,2]. Consistent with this mechanism of branch vessel occlusion, there were no
stenotic or occlusive lesions in the proximal portion of anterior cerebral
or extracranial carotid arteries on serial MR angiograms in our patient
who had vascular risk factors such as hypertension and heavy cigarette
smoking. To the best of our knowledge, callosal warning syndrome presenting with callosal disconnection syndrome has not been reported
earlier, although there are case reports of disconnection syndrome
due to established infarction or hemorrhage involving part or whole
length of the callosum [9–13].

Regarding the symptoms of disconnection syndrome, alien limb
phenomenon has been attributed to the failure of supervisory attentional system to inhibit inappropriate motor routines [15]. The transient nature of this symptom in our patient could be due to
potentially reversible ischemia of the genu and rostrum as this
part of the callosum was spared at the time of ultimate infarction.
The callosal apraxia and dysgraphia could result from the disconnection of the right motor association area from the left hemisphere. The
stereotyped, transient episodes of stroke warning syndrome could
be mistaken for seizures, paroxysmal symptoms of multiple sclerosis,
recurrent hypoglycemic spells and migraine aura. Recognizing the ischemic basis of this syndrome has clinical relevance as this would
avoid diagnostic uncertainty. From a therapeutic perspective, this
syndrome could pose considerable challenges for decisions regarding
intravenous thrombolytic therapy in the emergency room, where the
patients present with transient symptoms that appear to improve
within the therapeutic time window only to be left with persistent
symptoms and established infarction later.
In conclusion, we provide the first account of callosal warning syndrome, a rare stroke syndrome that manifests with a flurry of episodes
of transient symptoms dominated by the findings of callosal disconnection due to callosal ischemia initially. Later, the symptomatic ischemia culminates in callosal infarction with persistent neurological
signs. This novel stroke syndrome adds to the growing list of wellknown stroke warning syndromes that have been described in the location of the internal capsule and pontine tegmentum.
References
[1] Donnan GA, O'Malley HM, Quang L, Hurley S, Bladin PF. The capsular warning
syndrome: pathogenesis and clinical features. Neurology 1993;43(5):957–62.
[2] Staaf G, Geijer B, Lindgren A, Norrving B. Diffusion-weighted MRI findings in
patients with capsular warning syndrome. Cerebrovasc Dis 2004;17(1):1–8.
[3] Oliveira-Filho J, Ay H, Koroshetz WJ, Buonanno FS. Localization of clinical syndromes
using DWI: two examples of the “capsular” warning syndrome. J Neuroimaging
2001;11(1):44–7.
[4] Muengtaweepongsa S, Singh NN, Cruz-Flores S. Pontine warning syndrome: case
series and review of literature. J Stroke Cerebrovasc Dis 2010;19(5):353–6.
[5] Bourekas EC, Varakis K, Bruns D, Christoforidis GA, Baujan M, Slone HW, et al.
Lesions of the corpus callosum: MR imaging and differential considerations in
adults and children. AJR Am J Roentgenol 2002;179(1):251–7.
[6] Garcia-Monco JC, Cortina IE, Ferreira E, Martínez A, Ruiz L, Cabrera A, et al. Reversible
splenial lesion syndrome (RESLES): what's in a name? J Neuroimaging 2011;21(2):
e1–14.
[7] Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke
Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia;
Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular
Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The
American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009;40(6):2276–93.
[8] Ture U, Yasargil MG, Krisht AF. The arteries of the corpus callosum: a microsurgical
anatomic study. Neurosurgery 1996;39(6):1075–84.
[9] Chan JL, Ross ED. Alien hand syndrome: influence of neglect on the clinical presentation of frontal and callosal variants. Cortex 1997;33(2):287–99.
[10] Leiguarda R, Starkstein S, Berthier M. Anterior callosal haemorrhage. A partial
interhemispheric disconnection syndrome. Brain 1989;112(Pt 4):1019–37.
[11] Lausberg H, Gottert R, Munssinger U, Boegner F, Marx P. Callosal disconnection
syndrome in a left-handed patient due to infarction of the total length of the
corpus callosum. Neuropsychologia 1999;37(3):253–65.
[12] Giroud M, Dumas R. Clinical and topographical range of callosal infarction: a clinical and radiological correlation study. J Neurol Neurosurg Psychiatry 1995;59(3):
238–42.
[13] Suwanwela NC, Leelacheavasit N. Isolated corpus callosal infarction secondary to
pericallosal artery disease presenting as alien hand syndrome. J Neurol Neurosurg
Psychiatry 2002;72(4):533–6.
[14] Martin A. Shades of Dejerine — forging a causal link between the visual word form
area and reading. Neuron 2006;50(2):173–5.
[15] Spence SA. Alien motor phenomena: a window on to agency. Cogn Neuropsychiatry
2002;7(3):211–20.