CLINICAL/SCIENTIFIC NOTES
Legend to the Video
Several spells of painful tonic spasm affecting the right side,
with hand predominance. The electroencephalogram was normal during these spells.

References
1. Demirkian M, Jankovic J. Paroxysmal dyskinesias: clinical features
and classification. Ann Neurol 1995;38:571–579.
2. Sethi K. Paroxysmal dyskinesias. In: Jankovic J, Tolosa E, editors.
Parkinson’s disease and movement disorders. Baltimore: Williams
and Wilkins; 1998. p 701–709.
3. Camac A, Greene P, Khandji A. Paroxysmal kinesigenic dystonic
choreoathetosis associated with a thalamic infarct. Mov Disord
1990;5:235–238.
4. Berger JR, Sheramata WA, Melamed E. Paroxysmal dystonia as the
initial manifestation of multiple sclerosis. Arch Neurol 1984;41:
747–750.
5. Fontoura P, Vale J, Guimaraes J. Symptomatic paroxysmal
hemidystonia due to a demyelinating subthalamic lesion. Eur J Neurol 2000;7:559 –562.
6. Tranchant C, Bhatia KP, Marsden CD. Movement disorders in
multiple sclerosis. Mov Disord 1995;10;418 – 423.
7. Burguera JA, Catalá J, Casanova B. Thalamic demyelination and
paroxysmal dystonia in multiple sclerosis. Mov Disord 1991;6:379 –
381.
8. Achiron A, Barak Y. Multiple sclerosis. From probable to definite
diagnosis. Arch Neurol 2000;57:974 –979.
9. McDonald I, Compston A, Edan G, Goodkin D, Hartung HP, Lublin
FD, McFarland HF, Paty DW, Polman CH, Reingold SC, SandbergWollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the
diagnosis of multiple sclerosis. Ann Neurol 2002;50:121–127.

1403

relationship, with the observed association providing evidence
for an anatomic substrate for PLM. © 2003 Movement Disorder Society
Key words: periodic leg movement (PLM); stroke; pons
Periodic limb movements during sleep are characterized by
recurrent episodes of repetitive, stereotyped limb movements
predominantly occurring in the legs.1 They recur approximately
every 30 seconds. They consist of dorsiflexion of the ankle and
toes and flexion of the hip and knee. They usually last approximately 1.1 to 2.8 seconds. They occur in clusters while the
subject is lying down or sleeping, primarily in non–rapid eye
movement sleep.
Such periodic leg movements (PLM) can be found in normal
individuals over 30 years of age and occur in 29% of those over
50 years of age.2 Almost all patients with restless leg syndrome
(RLS), whatever the cause, also have PLM during sleep.3 PLM
with RLS has been reported to be associated with peripheral
neuropathy, uremia, anemia, gastric surgery, chronic pulmonary disease, and chronic myelopathy.3–5 PLM without RLS
has been reported in stiff-man syndrome, Issac’s syndrome,
Huntington’s disease, and amyotrophic lateral sclerosis.5,6
However, it is difficult to say whether these reports indicate a
causal relationship between PLM and these conditions, and the
locus of generator is still unknown. In addition, their association with strokes has not been described previously. Here, we
describe 2 patients who suffered a pontine infarction, with the
subsequent onset of PLM.

Case Reports
Case 1

Periodic Limb Movement During Sleep
Developed After Pontine Lesion
Joong-Seok Kim, MD, Sang-Bong Lee, MD,
Soung-Kyeong Park, MD, Si-Ryung Han, MD,
Yeong-In Kim, MD, and Kwang-Soo Lee, MD*
Department of Neurology, College of Medicine, The Catholic
University of Korea, Seoul, Korea

Abstract: We describe 2 patients who suffered a pontine
infarction and subsequently developed periodic leg movement
(PLM). The temporal relationship between a stroke and subsequent PLM, as well as the absence of sleep-related disorders in
patients’ histories, favors the argument of a cause-and-effect

A videotape accompanies this article.
*Correspondence to: Dr. Kwang-Soo Lee, Department of Neurology,
Kangnam St. Mary Hospital, #505, Banpodong, Seochogu, Seoul,
137-701, Korea. E-mail: ks1007@cmc.cuk.ac.kr
Received 8 January 20023; Revised 7 April 2003; Accepted 23 April
2003

A 62-year-old, right-handed woman was admitted to our
hospital complaining of an abnormal movement in her right
foot and toes while sleeping. This movement had started approximately 1 month before her admission, when it was discovered she also had a transient ischemic attack, which manifested as a transient right hemiparesis. She had a 5-year history
of hypertension, which was well controlled by diet and exercise
therapy. There was no personal or family history of neurological diseases.
Her general and neurological examinations were unremarkable, with no extrapyramidal signs. On video monitoring during
sleep, a mixture of repetitive dorsiflexion of the ankle, subsequent jerking of the knee and hip were observed. These involuntary movements occurred periodically, at 25- to 50-second
intervals (see Video, Segment 1).
A brain magnetic resonance imaging (MRI), obtained 1 day
after her admission, showed a small infarct in the left middle
pons (Fig. 1). There were no other brainstem, cerebellar, or
supratentorial lesions. After 50 mg of levodopa was started, the
patient and her family reported an almost complete resolution
of the involuntary movement during sleep.

Case 2
A 53-year-old right-handed man, previously in good health,
was admitted to our hospital with a 5-hour history of hemiparesis of the right side. There was no personal or family history
of medical or neurological diseases. He also denied any history
of sleep disorders.

Movement Disorders, Vol. 18, No. 11, 2003

1404

CLINICAL/SCIENTIFIC NOTES

On examination, he was alert and oriented, with a blood
pressure of 160/90 mm Hg, a regular heart beat of 85 beats/
minute, and a temperature of 36.9°C. Physical and neurological
examination demonstrated no pathological findings. A brain
MRI, obtained on the day of admission showed an area of
infarction in the left mid-pons (Fig. 2).
Two days after admission, his caregiver reported an abnormal movement of his right leg during sleep. These involuntary
movements consisted of repetitive rapid dorsiflexion of the
right ankle, which recurred every 15 to 25 seconds (see Video,
Segment 2). A small dose of a dopamine agonist (0.15 mg of
pergolide mesylate) led to a marked improvement within a
week.

Discussion
Although the anatomical structure responsible for the PLM/
RLS remains unclear, several reports have described anatomical substrates related to PLM/RLS. Through electrophysiological studies, an association between the dysfunction of the
brainstem level and PLM has been strongly advocated.7 Recently, on the basis of the findings from functional MRI in
idiopathic PLM/RLS patients, Bucher and colleagues indicated
that the red nucleus and brainstem are involved in the generation of PLM in patients with RLS, and the cerebellum and
thalamus play a role in the generation of sensory leg discomfort.8 Additionally, it has been suggested that a lesion in the
brainstem was related to the development of secondary PLM.9
The underlying neurophysiological mechanisms are unknown,
but the results of neurophysiological and radiological studies
have revealed increasing evidence of the involvement of brainstem generators in the pathogenesis of PLM/RLS.
However, central nervous system generators, by themselves,
do not sufficiently explain PLM/RLS. It was assumed previ-

FIG. 1. Axial T2-weighted magnetic resonance imaging scan of Patient 1. The infarction is seen adjacent to the left pontine reticular
formation.

Movement Disorders, Vol. 18, No. 11, 2003

FIG. 2. Axial T2-weighted brain magnetic resonance imaging scan
shows a small ischemic lesion in the left paramedian at the middle
pontine level.

ously that diencephalospinal dopaminergic pathways might explain the beneficial effects of dopaminergic treatment in patients with PLM/RLS and the decrease of dopamine D2
receptor binding in the striatum.10 –12 In addition, several reports have described the involvement of lumbosacral generators in the development of PLM, as they have been observed in
patients with a spinal cord lesion.13–16
Our 2 patients both experienced PLM during sleep, after
ischemia involving the pons. There is a possibility that PLM are
only coincidental findings in patients with a pontine ischemic
lesion. However, the temporal relationship between a stroke
and subsequent PLM, as well as the absence of a previous
history of neurological and sleep disorders in our patients,
favors the argument of a cause-and-effect relationship and
against the simple coincidental occurrence.
Reticular formations in the brainstem directly influence the
sleep–wake cycle in the transition from wake to sleep and the
onset of rapid eye movement sleep.17 The disinhibition phenomena with reticulospinal excitatory responses in PLM/RLS
patients may lead to a pathological recruitment in propriospinal
or spinal jerks.18
In our cases, the lesions were located near the pontine
reticular formation. The destructive lesion of the pons with
PLM may reflect the disinhibition effects of the reticular formation on spinal pathways. In addition, the therapeutic responses to dopamine or dopamine agonist in our patients suggest that the dopaminergic paths were involved in the
pathogenesis of PLM. From a clinical viewpoint, the occurrence of PLM in our 2 patients, after a pontine infarct, provides
support for these symptoms having a biological and neuroanatomical substrate.

Legends to the Video
Segment 1. Patient 1 shows a mixture of repetitive dorsiflexion of the ankle and subsequent jerking of the knee and hip.

CLINICAL/SCIENTIFIC NOTES
These involuntary movements occurred periodically at 25- to
50-second intervals, with durations of 1 to 2 seconds. The
patient is snoring throughout the recording.
Segment 2. Patient 2 shows repetitive rapid dorsiflexion of
the right ankle during sleep. The involuntary movements recurred every 15 to 25 seconds, with durations of 0.5 to 1
second.

References
1. American Sleep Disorders Association. The international classification of sleep disorders: diagnostic and coding manual. Lawrence,
Kansas: Allen Press; 1990. p 65– 68.
2. Bixler EO, Kales A, Vela-Bueno A, Jacoby JA, Scarone S, Soldatos CR. Nocturnal myoclonus and nocturnal myoclonic activity
in the normal population. Res Commun Chem Pathol Pharmacol
1982;36:129 –140.
3. Stiasny K, Oertel WH, Trenkwalder C. Clinical symptomatology
and treatment of restless legs syndrome and periodic limb movement disorder. Sleep Med Rev 2002;6:253–265.
4. Allen RP, Earley CJ. Restless legs syndrome: a review of clinical
and pathophysiological features. J Clin Neurophysiol 2001;18:
128 –147.
5. Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Nocturnal myoclonus and restless legs syndrome. Adv Neurol 1986;43:295–307.
6. Martinelli P, Pazzaglia P, Montagna P, Coccagna G, Rizzuto N,
Simonati S, Lugaresi E. Stiff-man syndrome associated with nocturnal myoclonus and epilepsy. J Neurol Neurosurg Psychiatry
1978;41:458 – 462.
7. Wechsler LR, Stakes JW, Shahani BT, Busis NA. Periodic leg
movement of sleep (nocturnal myoclonus): an electrophysiological
study. Ann Neurol 1986;19:168 –173.
8. Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C.
Cerebral generators involved in the pathogenesis of the restless
legs syndrome. Ann Neurol 1997;41:639 – 645.
9. Ferini-Strambi L, Filippi M, Martinelli V, Oldani A, Rovaris M,
Zucconi M, Comi G, Smirne S. Nocturnal sleep study in multiple
sclerosis: correlations with clinical and brain magnetic resonance
imaging findings. J Neurol Sci 1994;125:194 –197.
10. Lang AE. Restless leg syndrome and Parkinson’s disease: insights
into pathophysiology. Clin Neuropharmacol 1987;10:476 – 478.
11. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function
in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies. Neurology 1999;52:932–937.
12. Staedt J, Stoppe G, Kogler A, Riemann H, Hajak G, Munz DL,
Emrich D, Ruther E. Nocturnal myoclonus syndrome (periodic
movements in sleep) related to central dopamine D2-receptor alteration. Eur Arch Psychiatry Clin Neurosci 1995;245:8 –10.
13. Yokota T, Hirose K, Tanabe H, Tsukagoshi H. Sleep-related periodic leg movements (nocturnal myoclonus) due to spinal cord
lesion. J Neurol Sci 1991;104:13–18.
14. Dickel MJ, Renfrow SD, Moore PT, Berry RB. Rapid eye movement sleep periodic leg movements in patients with spinal cord
injury. Sleep 1994;17:733–738.
15. Lee MS, Choi YC, Lee SH, Lee SB. Sleep-related periodic leg
movements associated with spinal cord lesions. Mov Disord 1996;
11:719 –722.
16. de Mello MT, Poyares DL, Tufik S. Treatment of periodic leg
movements with a dopaminergic agonist in subjects with total
spinal cord lesions. Spinal Cord 1999;37:634 – 637.
17. McCarley RW. Neurophysiology of sleep: basic mechanisms underlying control of wakefulness and sleep. In: Chokroverty S,
editor. Sleep disorders medicine-basic science, technical considerations and clinical aspects. Boston: Butterworth-Heinemann; 1995.
p 17–36.
18. Chokroverty S, Walters A, Zimmerman T, Picone M. Propriospinal myoclonus: a neurophysiologic analysis. Neurology
1992;42:1591–1595.

1405

Adult-Onset Niemann-Pick Type C Disease:
A Clinical, Neuroimaging, and
Molecular Genetic Study
Carla Battisti, MD,1 Patrizla Tarugi, PhD,2
Maria Teresa Dotti, MD,1 Nicola De Stefano, MD,1
Angelo Vattimo, MD,3 Francesea Chierichetti, MD,4
Sebastiano Calandra, MD,2 and Antonio Federico, MD1*
1

Department of Neurological and Behavioural Sciences,
University of Siena, Siena, Italy
2
Department of Biomedical Sciences, University of Modena
and Reggio Emilia, Modina, Italy
3
Unit of Nuclear Medicine, University of Siena, Siena, Italy
4
Departments of Nuclear Medicin and Radiology,
Castelfranco Hospital, Castelfranco Veneto, Treviso, Italy
Abstract: We report on a patient with adult-onset NiemannPick type C (NPC) disease, carrying the mutations P1007 and
I1061T in the NPC1 gene, presenting with marked psychiatric
changes followed by dystonia and cognitive impairment. Filipin staining, single photon emission computed tomography
perfusional, positron emission tomography metabolic, conventional magnetic resonance imaging, and magnetic resonance
spectroscopy findings suggested a pathophysiological correlation with phenotype expression. This case expands the clinical
and genetic spectrum of the rare adult-onset NPC disease
phenotype © 2003 Movement Disorder Society
Key words: NPC1; adult-onset; neuroimaging studies
Niemann-Pick type C disease (NPC) is an autosomal recessive
neurovisceral lipid storage disorder. Its frequency in the general
population has been estimated at 1:100,000 live births. The
phenotype of NPC (MIM 257220) is remarkably variable,
including an acute, rapidly lethal form presenting at birth; an
infantile and childhood form, presenting as a severe progressive
disease leading to death in the second or third decade of life; an
adolescent form, generally associated with a less aggressive
phenotype. A rare adult-onset form with a slowly progressive
course has been described in approximately 5% of patients.
Recent biochemical data indicate three different metabolic defects: (1) sequestration of low density lipoprotein (LDL) -cholesterol in lysosomes, (2) premature pathological presence of
cholesterol in trans-Golgi cisternae, and (3) altered intracellular
sterols traffic.1
Two complementation groups have been identified: (1) the
NPC1 complementation group (⬎90% of patients) carrying
mutations in the NPC1 gene(18q11), which encodes a protein
containing 13 transmembrane domains and a sterol-sensing

*Correspondence to: Dr. Antonio Federico, Unit of Neurometabolic
Diseases, Policlinico Le Scotte,Viale Bracci 2, 53100 Siena, Italy.
E-mail: federico@unisi.it
Received 28 December 2002; Revised 8 May 2003; Accepted 21
May 2003

Movement Disorders, Vol. 18, No. 11, 2003