Metab Brain Dis (2010) 25:155–159
DOI 10.1007/s11011-010-9192-z

ORIGINAL PAPER

Split-brain syndrome after hepatic transplantation:
a tacrolimus-related vasculitis?
Sara Montagnese & Sami Schiff & Carlo Poci &
Pamela Iannizzi & Anna Biancardi & Renzo Manara &
Chiara Briani & Daniela Mapelli & Giuseppe Realdi &
Piero Amodio

Received: 1 June 2009 / Accepted: 13 January 2010 / Published online: 5 May 2010
# Springer Science+Business Media, LLC 2010

Abstract An unusual case of inter-haemispheric disconnection syndrome occurring in a patient who had undergone
hepatic transplantation is presented. The underlying disorder,
at first wrongly interpreted as encephalitis, was found to be
severe, diffuse cerebral vasculitis. The hypothesis that
treatment with tacrolimus might have caused, or at least
favoured the vascular damage is discussed.
Keywords Cirrhosis . Hepatitis C . Transplantation .
Tacrolimus . Corpus callosum . Split-brain . Vasculitis
Abbreviations
HCV
hepatitis C virus
ITT
inter-haemispheric transmission time
MELD model end stage liver disease
MRI
magnetic resonance imaging
OLTx
orthotopic hepatic transplantation

S. Montagnese and S. Schiff contributed equally
S. Montagnese : S. Schiff : A. Biancardi : P. Amodio (*)
Department of Clinical and Experimental Medicine,
University of Padova,
Via Giustiniani, 2,
35128 Padova, Italy
e-mail: piero.amodio@unipd.it
C. Poci : G. Realdi
Department of Medicine and Surgery, University of Padova,
Padova, Italy
P. Iannizzi : D. Mapelli
Department of General Psychology, University of Padova,
Padova, Italy
R. Manara : C. Briani
Department of Neurosciences, University of Padova,
Padova, Italy

Introduction
Split-brain is the term used to describe the clinical
consequences of a complete or partial section of the corpus
callosum, the main brain structure that allows information
transfer between the two haemispheres. The syndrome has
been reported after ischaemic/haemorrhagic vascular accidents (Berlucchi and Aglioti 1999; Marzi et al. 1991) and
the elective section of the corpus callosum was also utilised
as a therapeutic measure to contain the generalization of
seizures from one haemisphere to the other in treatmentresistant epilepsy (Wilson et al. 1977). Corpus callosum
damage has also been related to alcohol misuse, although
mostly as a post-mortem (Marchiafava and Bignami 1903)
or an imaging (Hommer et al. 1996) rather than a clinical
finding.
Crucial elements for the diagnosis of split-brain syndrome are: i) left hand tactile agnosia, or the inability to
recognize objects placed in the left hand in the eyes-closed
condition, since this function requires information transfer
from the right sensory cortex to the left parietal associative
cortex, and ii) prolonged inter-haemispheric transmission
time (ITT), as measured by the difference between left/right
hand reaction times to lateralised stimuli (Mooshagian et al.
2009). As a consequence, also the early sensory evoked
potential components produced in response to a visual
stimulus presented to one visual haemifield segregate
within the stimulated, contra-lateral haemisphere, since
the damage stops these components from spreading contralaterally. In contrast, the later components, such as the
P300, spread to both haemispheres, suggesting that
information related to late stimulus processing is transferred via alternative inter-haemispheric pathways, such as
the anterior commissure and/or the superior colliculus
(Yovel et al. 2003).

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Case history
A 53-year-old male was referred to our centre 22 months after
orthotopic hepatic transplantation (OLTx) with worsening
neuropsychiatric performance.
He had been diagnosed with hepatitis C virus (HCV)related cirrhosis at the age of 36. He was a non-insulin
dependent diabetic and had an otherwise unremarkable
medical history. He had never misused alcohol and was
completely abstinent since the diagnosis of cirrhosis. At the
age of 48 he had undergone trans-jugular intra-hepatic
portal-systemic shunt because of diuretic-resistant ascites.
The procedure had been well tolerated and he had not
developed overt nor minimal hepatic encephalopathy
(normal psychometric performance and electroencephalogram (Amodio et al. 1999)). He had subsequently been
transplanted at the age of 51, when he was classified as
Child-Pugh class C/10 (Pugh et al. 1973) and Model End
Stage Liver Disease (MELD) 14 (Kamath et al. 2001).
Eighteen months after OLTx, he had started to develop
disorientation in time, anxiety, bizarre behaviour, fatigue,
insomnia, mild left haemiparesis, followed by severe
frontal-temporal headache and vomiting. He had been
admitted into a local district hospital and treated with
prednisone on a presumptive diagnosis of viral encephalitis,
with no benefit. Meanwhile, he had also developed severe
systemic hypertension.
When we first reviewed him, he reported that his left
hand performed actions that were somehow ‘independent’
of his will and of those of the right hand (i.e. attempting to
close a door with his right hand whilst opening it with his
left hand). In addition, he complained of gait disturbance.
On clinical examination he was vigilant, cooperative,
orientated in time and space, with apparently normal mood
and nutrition status. No lung, cardiac or abdominal
abnormalities were detected. Mild pitting oedema was
present bilaterally. Neurological examination revealed a
remarkable lack of motor coordination, a mild deficit of the
Fig. 1 Performance of the
patient in the drawing copying
section of the Mini Mental State
Examination (overlapping
pentagons; a), the drawing
copying section of the Brief
Neuropsychological Examination (a house; b) and the free
drawing section of the Brief
Neuropsychological Examination (daisy with stem and
leaf; c). The patient shows a
piecemeal, fragmented approach
and seems to miss the overall
picture and the aim of the
construction task

Metab Brain Dis (2010) 25:155–159

inferior branch of the left VII cranial nerve and a mild
strength reduction in both the upper and the lower left limb.
Laboratory exams revealed microcytic anaemia (haemoglobin 7.3 g/dL; erythrocyte mean cellular volume 76 fL),
renal impairment (creatinine 509 µmol/L, urea 31 mmol/L),
massive proteinuria (5 g/day), good glycemic control
(glycaeted haemoglobin 6.0%), traces of cryoglobulin;
smooth muscle antibodies were positive at low titre,
rheumatoid factor and anti-neutrophil cytoplasmic antibodies were negative. Tacrolimus plasma levels were
adequate at 4.2 µg/L.
A complete neuropsychological examination was performed. The Mini Mental State Examination (Folstein et al.
1975) was abnormal with a score of 22/30 (reference range
≥ 24/30), while the Brief Neuropsychological Examination
(Mondini et al. 2003) showed that short/long term verbal
memory, attention, working memory, executive function
and language (comprehension, visual naming, verbal
fluency) were substantially preserved. In contrast, severe
constructional apraxia, or the inability to draw with/without
a model, was detected (Fig. 1). Eyes-closed, left hand
tactile anomia was also observed: while all 13 threedimensional objects presented to the right hand were
correctly named, only five of those presented to the left
hand were correctly named. In addition, the patient
exhibited lateralised ideational apraxia, being unable to
make a ‘military knot’ or to cross himself with his left arm.
Split-brain syndrome was therefore suspected and the ITT
measured utilising a simple lateralized reaction time task,
according to Poffenberger (Poffenberger 1912). The ITT was
prolonged at 37 ms (reference range ≤ 4–10 ms) (Fig. 2),
confirming the clinical suspicion. To further characterize the
disorder, visual event-related potentials were measured under
the same task. The evoked components P1 and N1 were
significantly larger contra- compared to ipsi-laterally (contraP1: 3.6±0.4 µV; ipsi-P1: 2.6±0.3 µV; F [1,9]=39.0, p<
0.0001) (contra-N1: -4.9±0.2 µV; ipsi-N1: −2.9±0.2) µV;
F [1,9]=160.6, p<0.0001) (Fig. 3).

Metab Brain Dis (2010) 25:155–159

157

Reaction time (ms)

510
500
490
480

a

470

b

460
450

Right hand

440
430

Left hand
Left

Right

Visual field
Fig. 2 The interaction between hand-position and stimulus-position in
the Poffenberger task. Reaction times are faster for the uncrossed
responses (same hand- and stimulus-position) compared to the crossed
(different hand- and stimulus-position). The average of the crosseduncrossed difference [(a+b)/2], or inter-haemispheric transmission
time, was prolonged at about 37 ms (reference range ≤ 4–10 ms)

Both acute encephalitis and cerebral vasculitis were
considered as potential causes for the observed clinical
syndrome.
Cerebral magnetic resonance imaging (MRI) was performed, which documented frontal para-saggital abnormalities extending to the gyrus cinguli and involving the
posterior part of the corpus callosum, potentially consistent
with both diagnostic hypotheses. Cerebrospinal fluid was
examined: no biochemical abnormities were detected and
microbiological investigations were negative for bacteria,
fungi and viruses, with the exception of HCV-RNA. This
might have been related to blood contamination but quasispecies determination was not obtained.
At this stage, the hypothesis of viral encephalitis was
abandoned and that of vasculitis pursued with an angioMRI scan. This showed signs of cerebral vasculitis with
Fig. 3 The voltage distribution
across the scalp of the P1 and
N1 responses evoked by stimuli
presented in the right/left visual
fields. The responses are considerably attenuated in the haemisphere ipsi-lateral to the
stimulus position due to the
lesion in the corpus callosum

multifocal, impressive narrowing of the main cerebral
arteries. A tacrolimus-related vasculitis was suspected and
thus tacrolimus was stopped and replaced with mycophenolate mofetil, cyclophosphamide and methylprednisolone.
However, the clinical condition worsened further and after
10 days the patient was dysarthric, dysphagic and the left
haemisyndrome had become more obvious. A second
cerebral MRI was performed, which showed a further
ischemic right lesion within the pons, while the previously
detected lesions had evolved into atrophic-degenerative
areas. The corpus callosum was heavily involved (Fig. 4).
The diagnosis of cerebral arteritis was eventually confirmed
by angiography (Fig. 5). Treatment with mycophenolate
mofetil, cyclophosphamide and methylprednisolone was
continued. However, both the renal failure and the
neurological syndrome worsened and the patient selfdischarged and died at home after a few days, with severe
renal impairment and coma. The relatives did not consent to
post-mortem examination.

Discussion
To our knowledge, this is the first time that a split-brain
syndrome is reported after OLTx. The patient developed
systemic hypertension, progressive renal impairment with
proteinuria and, finally, inter-haemispheric disconnection.
Although histopathological confirmation was not available,
there is sufficient evidence to support the hypothesis that a
vasculitis involving at least the kidneys and the brain was the
most likely cause for transplant failure and, ultimately, death.
Fatal cerebral vasculitis was reported during treatment
with tacrolimus in a diabetic patient who had been trans-

Voltage distribution of the early visual evoked potentials

158

Metab Brain Dis (2010) 25:155–159

Fig. 4 Cerebral magnetic resonance: T2 axial and sagittal
images showing diffuse involvement of the corpus
callosum

planted for hepatitis B and C cirrhosis (Pizzolato et al.
1998). In this individual, the brain lesions were characterised by neutrophilic infiltration of the walls of the small
cortical arteries and perivascular spaces; recent thrombi
were detected in the vessels with ensuing focal foci of
cortical necrosis (Pizzolato et al. 1998). Fatal cardiac failure
due to severe large/small coronary arteritis was also
reported after treatment with high doses of tacrolimus in a
child who had undergone liver/bowel transplantation
(Atkison et al. 1997).
Tacrolimus is also known to accelerate the progression
of other vascular diseases (Morioka et al. 1999), probably
by limiting nitric oxide production (Diaz-Ruiz et al. 2005)
and thus causing a reduction in the ratio between vasodilating substances and endothelin. Interestingly, the vascular effects of tacrolimus seem to be more common at
relatively low doses rather than at immunosuppressant
doses, at least in the animal models (Ochiai et al. 1993).
In our patient, who had HCV infection and whose graft
showed HCV-related hepatitis, tacrolimus might have
caused a vasculitis or possibly worsened/accelerated an
HCV-related vasculitis (Hartge et al. 2006). Within the
context of HCV infection, the most common vasculitis is

related to mixed cryoglobulinemia. However, its clinical
presentation is generally limited to cutaneous purpura and
arthralgia (Cacoub et al. 2001; Dammacco et al. 2001). A
different, more severe type of HCV/cryoglobulinemiarelated vasculitis shares some clinical features with periarteritis nodosa: it has an acute onset and it is associated
with poor general conditions, severe multifocal sensorimotor mono-neuropathy, high blood pressure and central
nervous system or gastro-intestinal involvement (Cacoub et
al. 2001). The presence of renal impairment, high cryocrit
and complement activation represent negative prognostic
factors (Ramos-Casals et al. 2006). Our patient had renal
impairment, but very low cryoglobulin levels, probably
indicating that an additional factor, most likely treatment
with tacrolimus, might have contributed. Based on these
considerations, the choice of replacing tacrolimus with an
immunosuppressive regimen including mycophenolate
mofetil, cyclophosphamide and methylprednisolone seemed
reasonable, but was made at a fairly late stage and did not
prove beneficial.
The current understanding of the pathophysiology and
the management of vasculitis in transplanted patients is
limited and further research is needed.

Fig. 5 Digital subtraction cerebral angiography showing severe
stenosis of the intracranial segment of the right carotid artery (black
arrow) and minor alterations of the lumen of the right middle cerebral
artery (black arrowhead). There were also severe perfusion defects
within the territories of the right anterior cerebral artery, which were

supplied by anastomotic lepto-meningeal collaterals (white arrows);
multiple stenoses were apparent along the basilar artery (white
arrowheads) and the intracranial segments of the vertebral arteries.
Cerebral veins and sinuses were unremarkable (not shown)

Metab Brain Dis (2010) 25:155–159
Conflict of interest Nothing to declare.

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