Cerebellum (2014) 13:787–790
DOI 10.1007/s12311-014-0587-y
CASE REPORT
Cerebrotendinous Xanthomatosis: The Effectiveness
of High-Dose Piracetam for the Treatment of Cerebellar
and Sensorial Ataxia
Ugur Uygunoglu & Aysegul Gunduz & Sukriye F Menku &
Basak Yilmaz & Esra Hatipoglu & Cengiz Yalcinkaya &
Sabahattin Saip & Hulya Apaydin
Published online: 2 August 2014
# Springer Science+Business Media New York 2014
Introduction
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal
recessive metabolic disease that is based in a deficiency of
sterol 27-hydroxylase, which leads to the storage of
cholestanol and cholesterol in the lenses, central nervous
system and tendons [1, 2]. The most common neurological
manifestations of CTX include pyramidal signs, cerebellar
ataxia, cognitive impairment, dysphagia, dysarthria and pe-
ripheral neuropathy [3]. Brain magnetic resonance imaging
(MRI) usually reveals cerebral atrophy and T2 signal changes
in the dentate nucleus and, less commonly, in the spinal cord
and basal ganglia [4].
Chenodeoxycholic acid (CDCA) effectively treats the
symptoms of CTX via a reduction in the synthesis and plasma
levels of cholestanol [3]. Although the effects of CDCA on the
progression of CTX have been explicitly described, the value
of treating the ongoing symptoms of CTX using pharmaco-
therapies remains controversial [5–7]. For example, adult
CTX patients may undergo long-term treatment with CDCA
alone or in combination with inhibitors of hydroxy-3-methyl-
glutaryl-coenzyme A (HMG-CoA) reductase [8]. Similarly,
high-dose parenteral piracetam is effective in some definite
and probable cases of hereditary spinocerebellar ataxia (SCA)
[9, 10]. Here, we report the effectiveness of high-dose intra-
venous piracetam for the treatment of ataxia in two cases of
CTX.
U. Uygunoglu : A. Gunduz (*) : S. F. Menku : B. Yilmaz :
C. Yalcinkaya : S. Saip : H. Apaydin
Department of Neurology, Cerrahpasa School of Medicine, Istanbul
University, K.M. Pasa, 34098 Istanbul, Turkey
e-mail: draysegulgunduz@yahoo.com
E. Hatipoglu
Department of Internal Medicine, Cerrahpasa School of Medicine,
Istanbul University, Istanbul, Turkey
Patients and Methods
Patient 1
A 30-year-old female presented to our clinic with
truncal ataxia that had begun to develop in her early
teens and which had been rapidly progressing over the
past 3 years. She had previously undergone surgeries to
treat bilateral juvenile-onset cataracts and to remove a
tumour-like enlargement in her Achilles tendon that was
subsequently diagnosed as a xanthoma. Her immediate
family was composed of five individuals from the mid-
dle part of Turkey and included the patient, her consan-
guineous parents (first cousins) and two siblings. The
siblings were healthy and there was no similar family
history.
A neurological examination revealed truncal ataxia, pyra-
midal findings that were prominent in the lower extremities
and a loss of the sense of vibration distal to the patella. Brain
and spinal MRI scans revealed increased signal intensities in
the bilateral basal ganglia, bilateral dentate nucleus, pons,
medulla oblongata and the posterior and lateral columns of
the spinal cord (Fig. 1).
Patient 2
A 32-year-old male presented to our outpatient clinic with
complaints of walking impairments that had progressed over
the last 2 years. At 2 years old, the patient was diagnosed with
epilepsy that was attributed to premature delivery and had
been successfully treated with antiepileptic drugs. He had
undergone surgery for bilateral cataracts 3 years prior to his
admission and he had a biopsy performed on an enlarged
Achilles tendon that was diagnosed as a xanthoma. A neuro-
logical examination revealed truncal ataxia, pyramidal signs
788 Cerebellum (2014) 13:787–790

Fig. 1 a An axial T2-weighted

fast-spin echo (FSE) image of the A B
cerebellum reveals bilateral
symmetrical hyperintensities in
the cerebellar white matter
adjacent to the dentate nuclei
(circle). b An axial T2-weighted
FSE image of the upper cervical
spine shows increased signal
intensities in both dorsal (arrow)
and lateral (stars) columns along
the entire course of the tracts

that were prominent in the lower extremities, and nonprogres-
sive cognitive impairment. A brain MRI scan showed in-
creased T2 signal intensities in the bilateral and symmetrical
white matter of the cerebellum (Fig. 2).
The clinical and radiological findings of both patients and
their histories of juvenile cataracts and tendon xanthomas
suggested a diagnosis of CTX. Thus, a cardiac examination
was performed, and the levels of total serum cholesterol, low-
density lipoprotein (LDL) cholesterol, high-density lipopro-
tein (HDL) cholesterol and triglycerides were analysed. The
cardiac examinations were unremarkable, but the laboratory
tests revealed that patient 1 had a total cholesterol level of
156 mg/dL, an LDL level of 96 mg/dL, an HDL level of
39 mg/dL and a triglyceride level of 106 mg/dL, while patient
2 had a total cholesterol level of 197 mg/dL, an LDL level of
144 mg/dL, an HDL level of 31 mg/dL and a triglyceride level
of 114 mg/dL. Both patients exhibited osteopenia and were
put on an oral regimen of daily calcium carbonate (2,500 mg/
day) and monthly vitamin D3 (300,000 IU). A mutation
analysis performed using the blood of patient 1 detected a
homozygous mutation of CYP27A1, but patient 2 did not give
his consent for a genetic analysis.
The present study was approved by the Local Ethical
Committee, and the patients and their families provided in-
formed consent.
Methods
Both patients were given daily intravenous injections of pir-
acetam (15 g/day in 100 cm3 of 5 % dextrose solution) that
were divided into three doses per day. The total dose gradually
increased every 3 days until it reached 24 g/day. The entire
treatment period comprised 10 days, after which concurrent
treatment with CDCA was initiated. Pre- and post-infusion
evaluations included a complete blood count, an analysis of
serum electrolytes, and liver and renal function tests.
The presence of ataxia was subjectively and objectively
evaluated. The subjective assessments included the observa-
tions of the patients and their families, while the objective
assessments included evaluations at baseline, end-of-study
and a follow-up examination 3 months after the treatment
period. The objective assessments included neurological

Fig. 2 a An axial fluid-

attenuated inversion recovery
(FLAIR) image of the cerebellum
reveals bilateral and symmetrical
T2 hyperintensities of the
cerebellar white matter (arrows).
b A sagittal T1-weighted image of
the ankle reveals a gross
intermediate-hypointense signal
intensity mass in the Achilles
tendon (star) that is correlated
with a xanthoma
Cerebellum (2014) 13:787–790
examinations and the Scale for the Assessment and Rating of
Ataxia (SARA), which is a clinician-rated assessment of
cerebellar ataxia. Both patients continued daily treatment with
2.4 g of oral piracetam following the treatment period.
Results
The administration of high-dose parenteral piracetam reduced
subjective feelings of imbalance in both patients, and they
declared that they felt more secure during the maintenance of a
stance and gait. At baseline, both patients required assistance
during gait, whereas during the end-of-study neurological
examinations, both patients exhibited reduced disability, im-
proved tandem gait and the ability to maintain their stance
while the feet were adjacent. At baseline, the total SARA
scores for patients 1 and 2 were 14 and 21, respectively, but
these scores had decreased to 8 and 16, respectively, at the
end-of-study evaluation. At the 3-month follow-up examina-
tion, the total SARA scores remained at 8 and 16. There were
no clinical side effects or abnormalities in laboratory tests.
Discussion
The neurological symptoms associated with CTX can be
attributed to the deposition of cholestanol and cholesterol in
related neural structures [1, 2]. Long-term therapy with CDCA
mainly prevents the progression of these neurological symp-
toms and even their development if initiated sufficiently early.
However, patients 1 and 2 were not diagnosed with CTX for
more than 15 years after the initial development of their
symptoms as teenagers (especially patient 1); thus, CDCA
was not administered until adulthood in both cases. The
subsequent truncal ataxia was disabling for both patients.
Although changes in the dorsal column are known to be
involved in ataxia and patient 1 experienced a loss of the sense
of vibration, she also exhibited cerebellar involvement as
demonstrated by the increased signal intensities in the dentate
nuclei (Fig. 1).
Table 1 Studies using piracetam in patients with ataxia
Author, year Aetiology Dose Duration
Vural et al., 2003 Cerebellar ataxia 60 g/day 14 days
n=1 with cerebellar
cortical atrophy
De Rosa et al., 2006 SCA2 12–18 mg/day 3 months
n=1
Ince Gunal et al., 2008 SCA (one definite 60 g/day 14 days
n=8 SCA2)
789
Piracetam (2-oxo pyrrolidone) is a cyclic derivative
of gamma-aminobutyric acid that has been used as a
nootropic drug [11]. It was first approved in Europe in
the early 1970s for the treatment of vertigo and age-
related disorders [12]. The underlying mechanisms of
piracetam are thought to include enhanced cell energy
and metabolism, glucose utilisation and membrane flu-
idity as well as the positive modulation of AMPA-
sensitive ionotropic glutamate receptors [13]. Although
the precise mechanisms of action for piracetam are not
fully understood, this drug has been successful for the
treatment of cognitive disorders, cortical myoclonus and
vertigo [14]. Piracetam also results in modest improve-
ments of posture and gait in patients with a suspected
diagnosis of hereditary SCA [9, 10], but it does not
ameliorate speech or oculomotor disorders. However,
there was a dramatic recovery when these studies eval-
uated the symptomatic effects of piracetam on truncal
ataxia. In these two studies, only one patient had a
definite diagnosis of hereditary SCA type 2 (SCA2)
[9]. Piracetam and levetiracetam have been also used
to treat other types of hereditary ataxia cases with a
definite diagnosis, specifically SCA2, SCA15 and frag-
ile X syndrome [15–17]. However, these studies did not
specify the effects of these drugs on ataxia. Table 1
summarises previous reports using piracetam.
Ince Gunal et al. [9] administered three divided doses
of 30 g of piracetam (in 100 cm3 of 5 % dextrose
solution) for 3 days, then 45 g for 3 days and then
60 g over the last 8 days to eight patients. An additional
patient with cerebellar ataxia, but whose diagnosis was not
genetically confirmed, also benefited from the same doses
of piracetam [10]. Although high doses were administered
in the present two cases, the findings suggest that a daily
dose of 24 g is as effective as a daily dose of 45 g. In
fact, a daily dose of 24 g may be preferable due to a
decreased risk of side effects, which can include anxiety,
insomnia, drowsiness and agitation [11]. There were no
side effects in either of the cases described here following
treatment with intravenous piracetam.
Route of Assessment Results
administration
IV Neurological examination Effective improvement
of gait
IV Videotaped examination Effective reduction
of myoclonus of myoclonus
IV International Cooperative Effective
Ataxia Rating Scale improvement of
(ICARS) posture and gait
790
Conclusion
CTX is a rare autosomal recessive metabolic disease of which
the most disabling neurological symptom is cerebellar ataxia.
However, the early detection and prompt treatment of CTX
can reduce the progression and even the development of this
disease. When long-term therapy with CDCA is initiated for
the treatment of CTX, piracetam may be co-administered for
the symptomatic relief of cerebellar ataxia.
Conflict of Interest None of the authors have received financial sup-
port or funding over the preceding 12 months, regardless of the relation-
ship to the current manuscript.
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