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Hereditary Neuronal Intranuclear Inclusion Disease With Autonomic Failure and Cerebellar Degeneration
Raffaella Zannolli, MD;
Sid Gilman, MD, FRCP;
Simone Rossi, MD;
Nila Volpi, MD;
Andrea Bernini, MD;
Paolo Galluzzi, MD;
Daniela Galimberti, MD;
Lucia Pucci, PhD;
Alfonso D'Ambrosio, MD;
Guido Morgese, MD;
Fabio Giannini, MD
Arch Neurol. 2002;59:1319-1326.
ABSTRACT
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Background Neuronal intranuclear inclusion disease (NIID), a multiple-system degeneration,
occurs usually as a sporadic disorder with onset in childhood. The disease
has been found in monozygotic twins and in siblings. In 2 previously described
families, the disorder has affected 2 generations.
Objective To investigate the clinical, anatomical, and electrophysiological characteristics
of NIID that affect the central nervous system and the central and peripheral
components of the autonomic nervous system in 2 successive generations of
a family.
Design Case report.
Setting Tertiary care hospital.
Patients A 53-year old woman and her sons, aged 28 and 25 years. Symptoms began
in childhood in 2 of the 3 cases, and consisted of urinary and fecal incontinence,
erectile dysfunction in the men, and recurrent orthostatic hypotension.
Methods We used results of clinical neurological evaluations; cranial magnetic
resonance imaging; skeletal muscle and sphincter electromyography (EMG); peripheral
nerve conduction and bulbocavernosus reflex studies; autonomic function tests;
brainstem, visual, somatosensory, and motor evoked potentials; auditory and
vestibular testing; metabolic and molecular genetic testing; and muscle and
rectal biopsy with immunohistochemistry.
Results We found variable degrees of ocular dysmetria in 2 cases, ataxic dysarthria
and limb ataxia in 1, and hyperreflexia in 2. Magnetic resonance imaging revealed
cerebellar atrophy in all 3 cases and diffuse cerebral cortical atrophy in
1. Results of peripheral nerve conduction studies were normal. Sphincter EMG
findings were abnormal in 2 of the 3 cases, and results of autonomic function
tests were abnormal in the same 2. The EMG in 1 case revealed a chronic neurogenic
pattern in the distal limb muscles. Metabolic and molecular genetic testing
revealed no abnormal findings. Results of the muscle biopsy were negative,
but results of the rectal biopsy revealed eosinophilic ubiquitinated intranuclear
inclusions in neurons.
Conclusion Transmission of NIID in 2 generations presenting with autonomic failure
and cerebellar ataxia was hereditary.
INTRODUCTION
A PROGRESSIVE neurodegenerative disorder, neuronal intranuclear inclusion
disease (NIID), usually begins clinically in childhood,1-17
although adult18-20
and late-life21 onset have been reported. Although
NIID appears principally as a sporadic disease, it has been reported in monozygotic
twins2, 6, 20 and in
siblings.18, 22-23
Hereditary transmission, possibly autosomal dominant, occurs rarely.20, 23-24 Distinctive neuropathological
changes characterize the disease and consist of eosinophilic ubiquitinated
intranuclear inclusions in neurons of the peripheral, central, and autonomic
nervous system and neuronal loss in multiple systems.20
The inclusions contain expanded polyglutamine tracts.25-27
The disease frequently appears clinically as multiple-system degeneration
with the dominant features of ataxia, spasticity, parkinsonism, and intellectual
impairment. It can also present as a visceral neuropathy.22, 24
We herein describe a family with NIID in 3 members of 2 generations. Unlike
the previously described families in whom NIID affected 2 generations, autonomic
failure, cerebellar degeneration, and subtle signs of corticospinal tract
involvement developed in this family. The diagnosis was made on the basis
of results of a rectal biopsy in 1 of the cases.
PATIENTS AND METHODS
All 3 family members underwent evaluation including a history, medical
and neurological examinations, and the special diagnostic tests listed subsequently.
AUDITORY AND VESTIBULAR TESTS
The tests, previously described,28 included
observations of nystagmus, smooth pursuit movements, saccadic movements, optokinetic
nystagmus, responses to caloric stimulation, and pure tone audiometry.
IMAGING AND ELECTRODIAGNOSTIC STUDIES
We used cranial magnetic resonance imaging (MRI) at 0.5 and 1.5 T and
included T1- and T2-weighted images in the coronal and sagittal planes. We
obtained electromyograms (EMGs) of several muscles (ie, brachial biceps, first
dorsal interosseous muscle of the hand, rectus femoris, tibialis anterior,
and orbicularis oris) to examine the shape and size of motor unit action potentials
and the interference pattern. We examined the external anal sphincter (EAS)
and pudendal-nerve terminal motor latency (PNTML) using standard techniques.29-31 Using standard surface
techniques, we investigated sensory nerve action potentials; conduction velocities
of the median, ulnar, and sural nerves; compound muscle action potentials;
motor conduction velocities; and distal latencies in the median, ulnar, tibial,
and common peroneal nerves.32 We also applied
standard approaches to examine the median, tibial, and pudendal-nerve somatosensory
evoked potentials33; the sacral bulbocavernosus
reflex32; brainstem auditory evoked potentials;
and visual evoked potentials. We evaluated corticospinal tract function with
motor evoked potentials to transcranial magnetic stimulation.34
AUTONOMIC NERVOUS SYSTEM TESTING
We studied the sympathetic skin response (SSR) using standard methods
in both hands and both feet in all 3 subjects and in the penes of the 2 men.35 We obtained 3 or 4 recordings of the SSR from each
site (palm, sole, and penis) and selected as representative the 2 SSRs with
the clearest reproducibility and lowest variability. The latency was obtained
at the first deflection and the amplitude as the baseline to the first peak.
The SSR was considered absent if no consistent voltage change occurred at
a sensitivity of 50 µV after 3 trials at a slightly painful intensity.
We recorded the electrocardiographic R-R interval with standard techniques
at rest, during deep breathing, during movement from the lying to the standing
position, and during the Valsalva maneuver.36
We measured blood pressure after 2 minutes in the recumbent position and 3
minutes after standing, and we recorded the time course of blood pressure
variations for 24 hours using standard techniques.
MUSCLE BIOPSY
We performed an open biopsy on the right vastus lateralis muscle of
patient 1.
For light microscopic examination, standard histological and histochemical
stains (hematoxylin-eosin, modified Gomori trichrome, myofibrillar adenosine
triphosphatase [pH, 9.4], and, after acid preincubation [pH, 4.35 and 4.63],
periodic acid–Schiff, oil red O, acid phosphatase, nicotinamide adenine
dinucleotide [reduced form]–tetrazolium reductase, succinic dehydrogenase,
cytochrome-c oxidase, myoadenilate deaminase, and
phosphofructokinase) were performed on cryostat sections 10 µm thick.
Ultrathin sections from blocks routinely embedded in epoxy resin (Fluka; Sigma-Aldrich
Corp, St Louis, Mo) were also examined in transmission electron microscopy
(Philips CM10; Philips, Eindhoven, the Netherlands).
RECTAL BIOPSY
We performed a rectal biopsy under local anesthesia on patient 1. A
block was longitudinally cut, and a full-length specimen was fixed in buffered
formalin and embedded in paraffin. Serial 8-µm-thick sections were stained
with hematoxylin-eosin. Immunohistochemistry was performed on 5-µm-thick
sections from the paraffin-embedded block following preestablished protocols37; sections were incubated overnight in a 1:1000 dilution
of a polyclonal rabbit antiubiquitin antibody (DAKO, Glostrup, Denmark) and
successively in a 1:200 dilution of goat anti–rabbit IgG conjugated
to peroxidase (Sigma-Aldrich Corp). Immunolocalization was revealed by means
of the chromogen diaminobenzidine (Sigma-Aldrich Corp). Sections were counterstained
with hematoxylin. For transmission electron microscopy, specimens were fixed
in 2.5% glutaraldehyde–4% paraformaldehyde in cacodylate buffer and
routinely processed. Immunohistochemistry slides and semithin sections, after
toluidine blue staining, were examined with a light microscope (Zeiss Axioplan;
Carl Zeiss, Oberkochen, Germany). Ultrathin sections were contrasted with
lead citrate and uranyl acetate and observed with an electron microscope (Philips
CM10; Philips).
RESULTS
Table 1 summarizes the principal
clinical features and the results of the investigations of the 3 patients
examined.
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Clinical Characteristics and Results of Examinations
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PATIENT 1
A 28-year old man was referred to the University of Siena, Siena, Italy,
with a long-term history of abnormally frequent intestinal evacuations with
more or less fluid stools and soiling of his underclothing. In childhood,
when it started, the problem was attributed to food intolerance, and in adolescence,
to irritable bowel syndrome. At that time, investigations revealed no food
intolerance, intestinal maldigestion or malabsorption, or bacterial or parasitic
pathogens. Additional studies included blood smear; measurement of serum electrolyte,
serum urea nitrogen, creatinine, calcium, phosphorus, albumin, and total protein
levels; a search for specific nutritional deficiency (iron, vitamin B12, folic acid, and vitamin E); testing for antibodies to gliadin and
antimysium; and a sweat test.38 His present
complaints included 2 to 3 daily evacuations of loose stools associated with
mild incontinence, resulting in chronic soiling and occasional fecal incontinence.
He also complained of urinary urgency. He reported erectile dysfunction and
lack of morning erections from adolescence to the present. He experienced
difficulty with balance, coordination, and strength in his legs since his
second decade of life. He also experienced repeated light-headedness when
moving from the lying to the standing position. As a consequence of these
symptoms, he stopped participating in sports as a teenager and restricted
his social activities. The family history was positive for similar symptoms
in his mother and his older brother. His father was asymptomatic, and there
were no other siblings in the family. On general physical examination, no
abnormalities were found except for weak contraction of the EAS. Results of
a neurological examination revealed normal cognitive function. Although full,
extraocular movements showed overshoot dysmetria and slow pursuit movements.
Speech was slow with an ataxic dysarthria. The gait was wide based and ataxic,
with irregular size and directions of individual steps and difficulty turning
without loss of balance. Arm and hand movements were mildly ataxic, and handwriting
was consistent with ataxia. The legs were mildly weak and ataxic in attempts
at coordinated movement. No parkinsonian features were detected. The deep-tendon
reflexes were increased, but no clonus was found and the plantar responses
were flexor.
Cranial MRI revealed atrophy of the cerebellar hemispheres (Figure 1, patient 1, A and B). The electroencephalogram
revealed normal findings. An H-reflex could be recorded from the foot muscles
at rest, which is an abnormal finding suggestive of subclinical corticospinal
tract dysfunction. No evidence was found of a somatic peripheral neuropathy,
but the EMG of the EAS revealed evidence of denervation consisting of abundant
spontaneous activity at rest and a reduced interference pattern. The pudendal
compound muscle action potential was reduced in amplitude despite a normal
PNTML, and the bulbocavernosus reflex was absent. The R-R interval variability,
SSR, and results of 24-hour blood pressure monitoring were normal. Results
of multimodal evoked potentials tests were also within normal limits. Cytogenetic
analysis with G-banding at a 550-band resolution revealed a normal 46,XY karyotype.
Results of molecular analyses for the spinocerebellar ataxia (SCA1, SCA2, SCA3,
and SCA7) and the Friedreich ataxia genes were negative.
Results of a muscle biopsy revealed no myopathic or neurogenic changes and
no histochemical or ultrastructural evidence of a mitochondrial disease. Results
of rectal biopsy revealed sparse eosinophilic intranuclear inclusions in neurons,
mainly in the myenteric plexus. Inclusions were immunoreactive to ubiquitin
and consisted of fine filaments (Figure 2).
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Figure 1. Cranial magnetic resonance imaging.
A, Midline sagittal T1-weighted image. B, Coronal T2-weighted image. Atrophy
of the cerebellar hemispheres is evident in patients 1 (a 28-year-old man)
and 2 (the 53-year-old mother of patients 1 and 3) and subtle in patient 3
(the 25-year-old brother of patient 1 and son of patient 2). Vermal atrophy
is seen in patient 2. Diffuse cerebral cortical atrophy is seen in patient
3. Images for patients 1 and 2 are 1.5 T; for patient 3, 0.5 T.
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Figure 2. Rectal biopsy findings in patient
1. A and B, Ganglia cells from superficial myenteric plexus. Round intranuclear
inclusions, surrounded by a thin clear halo, distinctly eosinophilic and demarcated
from chromatin (arrows), are seen. A faintly visible nucleolus is seen close
to the eosinophilic inclusion (asterisk) (hematoxylin-eosin, orignal magnification
x1000). C and D, Ubiquitin staining of inclusions (inset) diffuses to
the nucleus (arrows and asterisk) (antiubiquitin immunoperoxidase, original
magnification x1000). E, Semithin section. Hyaline appearance of the
inclusion (arrow) is seen, close to the nucleolus (asterisk) (toluidine blue,
original magnification x1000). F, Nuclear inclusion (arrows) consisting
of intermingled fine filaments, most of which transversally sectioned, with
no defined spatial array. Bar indicates 1 µm (transmission electron
microscopy, original magnification x10 500).
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PATIENT 2
A woman aged 53 years was the mother of patients 1 and 3. She complained
of recurrent syncopal episodes with momentary loss of consciousness, usually
induced by moving from the lying to the standing position. These episodes
began when she was about 20 years of age and had increased in frequency in
recent years. She had been aware of generalized hypohidrosis for most of her
adult life. She had experienced mild fecal incontinence consisting of chronic
soiling and urgency of defecation for many years. She also complained of frequent
urination and incomplete voiding during the same period.
Results of a general physical examination disclosed no abnormalities
except for a weak EAS contraction. Results of a neurological examination revealed
normal cognition, speech, and cranial nerve functions. Extraocular movements
were normal. Results of the motor system examination were also entirely normal,
with no ataxia or parkinsonian features. The deep-tendon reflexes were diffusely
hyperactive, but without clonus and with flexor plantar responses. Cranial
MRI revealed atrophy of the cerebellar vermis and hemispheres (Figure 1, patient 2, A and B). She refused to undergo electroencephalography.
The EMG showed a chronic neurogenic pattern in the distal muscles of the upper
and lower limbs. Although results of motor and sensory nerve conduction studies
were normal, the findings suggested a mild subclinical motor axonal peripheral
neuropathy. The EMG of the EAS revealed abnormal spontaneous activity at rest
(fibrillations and positive wave potentials) and a reduced interference pattern,
indicating denervation. Moreover, the pudendal compound muscle action potential
was reduced in amplitude, despite a normal PNTML. The SSR was abnormal, with
reduced amplitude and delayed response from the sole of the right foot and
absent responses from other limbs. Results of the R-R interval variability
study were normal. Blood pressure monitoring for 24 hours showed continuous
but asymptomatic hypotension, without variations of circadian rhythm (mean
daytime systolic and diastolic blood pressure, 102.8 and 69.5 mm Hg, respectively;
mean nighttime values, 100.8 and 67.0 mm Hg, respectively). During the physical
examination, the blood pressure in the supine position was 105/70 mm Hg and
85/60 mm Hg 3 minutes after standing. Results of the multimodal evoked potentials
tests were within normal limits. Cytogenetic analysis with G-banding at the
550-band resolution revealed a normal 46,XX karyotype.
PATIENT 3
A 25-year old man had a history of intermittent fecal and urinary incontinence
and episodic erectile failure that began sometime in adolescence. He also
reported mild light-headedness on moving from the lying to the standing position.
He had noted joint laxity for many years.
Results of a general physical examination revealed marked hypotonia
and joint laxity of the limbs. Results of a digital rectal examination showed
weak contraction of the EAS. On neurological examination, cognitive function
was intact. Results of oculomotor testing showed overshoot dysmetria and slow
pursuit movements. No abnormalities were detected in speech or in other cranial
nerve functions. Examination of the motor system revealed no abnormalities,
and the deep-tendon reflexes were normal, with flexor plantar responses.
Cranial MRI showed subtle cerebellar hemisphere atrophy and diffuse
cerebral cortical atrophy (Figure 1,
patient 3, A and B). The electroencephalogram was normal. The EMG of the limb
musculature showed no abnormality, and no clinical or electrophysiological
evidence of a peripheral neuropathy was found. Despite the weak EAS contraction
on digital examination, EMG of the EAS, amplitude of the pudendal motor response,
and PNTML were normal. The bulbocavernosus reflex, however, showed a markedly
delayed response (58.2 milliseconds; normal, <42.5 milliseconds).39 The cortical component of the pudendal somatosensory
evoked potential was also markedly delayed (45.6 milliseconds; normal, <41.2
milliseconds).40 Results of autonomic function
tests all were within normal limits, but the 24-hour blood pressure monitoring
showed some asymptomatic episodes in which the blood pressure declined to
78/55 mm Hg. The multimodal evoked potentials were normal. Cytogenetic analysis
with G-banding at 550-band resolution revealed a normal 46,XY karyotype.
COMMENT
We present, to our knowledge, the first report of 2 successive generations
of a family with NIID that affected the central nervous system and the central
and peripheral components of the autonomic nervous system. This report is
also the second of central nervous system NIID that affected 2 successive
generations of a family. In the first report,20
neurogenic weakness developed in female monozygotic twins in adult life, followed
by cerebellar ataxia, dysarthria, and death after 20 years. An identical illness
developed in 2 adult sons of 1 twin. In another family, NIID affected 2 generations
with a visceral neuropathy manifested as chronic idiopathic intestinal pseudo-obstruction,
and results of rectal biopsy established the diagnosis.23-24
The remaining reports of NIID concern sporadic cases except for occasional
cases involving monozygotic twins2, 6
or siblings.18, 22
We describe herein 3 members of a family affected by a neurological
disorder involving multiple systems that began in the first or second decade
of life and progressed slowly. Autonomic disorders appeared first, consisting
of fecal and urinary incontinence of varying degrees, accompanied by postural
hypotension and hypohidrosis in 1 case and erectile dysfunction in both male
members. In 1 family member, cerebellar dysfunction affected speech, oculomotor
function, and limb coordination, and structural imaging revealed widespread
cerebellar atrophy. The other 2 members also had widespread cerebellar atrophy,
but with only minor clinical manifestations in 1 of the 2, consisting principally
of mildly abnormal extraocular movements. Hyperreflexia with normal plantar
responses in 2 of the members suggested mild corticospinal involvement in
addition to the autonomic and cerebellar involvement, and mild weakness of
the lower extremity in patient 1 probably resulted from corticospinal disease.
Laboratory investigations confirmed the clinical impressions and added
new information. The EMG of the EAS revealed a neurogenic pattern in 2 of
the 3 cases, indicating denervation. Moreover, in both of these cases, the
pudendal compound muscle action potential was reduced in amplitude, despite
a normal PNTML. These findings indicate degeneration of the Onuf nucleus,
which is located in the anterior horn of sacral segments 2, 3, and 4 and supplies
the striated sphincter muscles by way of the pudendal nerves. In one son,
the bulbocavernosus reflex was absent, and in the second it was delayed, providing
further evidence of autonomic failure and demonstrating the neurogenic basis
of the erectile dysfunction.
In patient 2, who had a history of hypohidrosis, the SSR was abnormal
in the limbs. The SSR serves as an index of peripheral autonomic nerve activity,
especially for sudomotor function of postganglionic unmyelinated sympathetic
fibers.41 In this same patient, the EMG revealed
a chronic neurogenic pattern in the distal limb muscles, suggesting a subclinical
motor axonal peripheral neuropathy. In 2 family members, hyperreflexia suggested
corticospinal tract involvement, and in 1 of these (patient 1), an H-reflex
could be recorded from the foot muscles at rest, providing further evidence
of corticospinal involvement. Since motor evoked potentials to transcranial
magnetic stimulation, which reflect the functionality of the fastest corticospinal
fibers,34 were normal, the hyperreflexia probably
resulted from dysfunction of small myelinated fibers of the corticospinal
tracts.42
All 3 family members complained of orthostatic light-headedness, but
measurements of orthostatic changes in blood pressure revealed orthostatic
hypotension only in patient 2. Moreover, 24-hour blood pressure monitoring
demonstrated only asymptomatic hypotensive episodes in 2 family members.
Although no history of a similar disorder in previous generations could
be ascertained, the 3 affected members of this family provide further evidence
of an inherited form of NIID, possibly by means of autosomal dominant inheritance.
In the previously described family with NIID of the central nervous system20 and the previously described family with visceral
NIID,23-24 only 2 generations
were affected, and the transmission was considered to be autosomal dominant.
The absence of similar disorders in previous generations in all 3 families
suggests the possibility of a spontaneous mutation in the gene responsible
for NIID. Such a mutation could also account for the previous reports of NIID
affecting monozygotic twins2, 6
and siblings.18, 22
Achieving a correct diagnosis of the disorder in this family proved
challenging and triggered an extensive diagnostic evaluation. The rectal biopsy
was the only method that allowed the correct diagnosis to be made in a living
patient. The constellation of symptoms in these cases bore some similarity
to a previously described multiple-system degeneration resulting from the SCA1 gene.43 In the patients
in this previous report, a cerebellar ataxia accompanied by autonomic insufficiency,
dystonia, and peripheral neuropathy developed. The onset was much later in
life than in the current cases, however, and the autonomic failure was not
as severe. Moreover, results of genetic testing for the SCA1 gene (and also for the SCA2, SCA3, and SCA7 genes) were negative in the
present family. This family's disease also bears some clinical resemblance
to familial amyloidotic polyneuropathy associated with cerebellar ataxia and
signs of corticospinal tract dysfunction.44-45
This diagnosis was ruled out in the present cases by results of the peripheral
nerve studies, which provided no evidence of an overt somatic polyneuropathy.
Familial dysautonomia, the Riley-Day syndrome, results from a genetic disorder
mapped to chromosome 9q31-q33.46-47
This autosomal recessive disorder affects the Ashkenazi Jewish population,
causing developmental loss of neurons from the sensory and autonomic nervous
system. The mode of inheritance, ethnic background, and absence of sensory
abnormalities made this diagnosis unlikely in the present family. A mitochrondrial
DNA mutation presented another possibility, in that a familial multiple-system
degeneration has been reported in association with such a mutation.48 In the reported cases, however, parkinsonism dominated
the clinical presentation, and the other disorders included dysarthria, areflexia
or hyperreflexia, spasticity, ataxia, ptosis, progressive external ophthalmoplegia,
and an abnormal muscle biopsy finding. Autonomic failure with urinary and
fecal incontinence and postural hypotension were not found. An autosomal dominant
orthostatic hypotensive disorder has been mapped to chromosome 18q.49 In those family members, the symptoms consisted of
light-headedness on standing, which could worsen to syncope, along with palpitations
and blue-purple ankle discoloration. Accompanying these symptoms, the systolic
blood pressure markedly declined, the diastolic blood pressure rose, and a
tachycardia developed. The symptoms did not include urinary, sexual, or fecal
disorders, as in the present family.
In conclusion, the study of clinical, pathological, and electrophysiological
features of NIID in a family presenting with fecal incontinence, autonomic
failure, and cerebellar ataxia suggests a hereditary transmission of this
condition.
AUTHOR INFORMATION
Accepted for publication December 4, 2001.
Author contributions: Study concept and design (Drs Zannolli, Rossi, Bernini, Galimberti, Pucci, D'Ambrosio,
Morgese, and Giannini); acquistion of data (Drs Zannolli,
Rossi, Volpi, Bernini, Galluzzi, Galimberti, Pucci, D'Ambrosio, Morgese, and
Giannini); analysis and interpretation of data (Drs
Zannolli, Gilman, Rossi, Bernini, Galimberti, Pucci, D'Ambrosio, Morgese,
and Giannini); drafting of the manuscript (Drs Zannolli,
Rossi, Volpi, Bernini, Galluzzi, Galimberti, Pucci, D'Ambrosio, Morgese, and
Giannini); critical revision of the manuscript for important intellectual
content (Drs Zannolli, Gilman, Rossi, Volpi, Bernini, Galluzzi,
Galimberti, Pucci, D'Ambrosio, Morgese, and Giannini); obtained funding (Drs Zannolli and Morgese); administrative, technical,
and material support (Drs Zannolli, Rossi, Volpi, Bernini,
Galluzzi, Galimberti, Pucci, D'Ambrosio, Morgese, and Giannini); and
study supervision (Drs Zannolli, Gilman, Morgese, and Giannini).
Corresponding author and reprints: Raffaella Zannolli, MD, Department
of Pediatrics, Obstetrics, and Reproductive Medicine, Section of Pediatrics,
Policlinico Le Scotte, University of Siena, Siena, Italy (telephone: 390 577
586514; fax: 390 577 586143; e-mail: zannolli{at}unisi.it).
From the Department of Pediatrics, Obstetrics, and Reproductive Medicine,
Section of Pediatrics (Drs Zannolli, Galimberti, Pucci, D'Ambrosio, and Morgese),
Department of Surgery (Dr Bernini), and Department of Neuroscience, Section
of Neurology (Drs Rossi and Giannini), Policlinico Le Scotte, and the Department
of Anatomical and Biomedical Sciences (Dr Volpi), University of Siena, and
the Neuroradiology Unit, Azienda Ospedaliera Senese, Policlinico Le Scotte
(Dr Galluzzi), Siena, Italy; and the Department of Neurology, University of
Michigan, Ann Arbor (Dr Gilman).
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