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Decreased cerebrospinal fluid levels of substance P in patients with Rett syndrome.

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According to the experience of our patients, a fishing
chair with a sitting height of 38 cm gives an adequate
BP increment, is comfortable to sit on, and is relatively
cheap (it costs approximately 8 US dollars).
Decreased Cerebrospinal
Fluid Levels of Substance p
in Patients with
Rett Syndrome
This study was granted by the Prinses Beatriw Fonds (96FS01).
Toyojiro Matsuishi, MD,* Shinichiro Nagamitsu, MD,'
Yushiro Yamashita, MD,* Yoshihiko Murakami, MD,*
Akihiko Kimura, MD,*t Tetsuo Sakai, MD,$
Hiroshi Shoji, MD,§ Hirohisa Kato, MD,*
and Alan K. Pert$'
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To clarify the mechanism of brain and spinal cord impairment in Rett syndrome (RS), we measured the cerebrospinal fluid (CSF) levels of substance P in 20 patients
with RS including 16 childhood patients and 4 adult patients. Findings were compared with those obtained in
age-matched controls and diseased controls. The CSF
level of substance P was significantly lower in patients
with RS compared with controls. The alteration in the
CSF level of substance P may be related to the neurological impairment, especially autonomic dysfunction, and
neuropathological involvement of dorsal root ganglia and
peripheral nerve observed in RS.
Matsuishi T, Nagamitsu S, Yamashita Y, Murakami Y,
Kimura A, Sakai T, Shoji H, Kato H, Percy AK.
Decreased cerebrospinal fluid levels of substance P
in patients with Rett syndrome.
Ann Neurol 1997;42:978-981
Rett syndrome (RS) is a neurodevelopmental disorder
of unknown cause characterized by normal early psychomotor development followed by the loss of psychomotor and acquired purposeful hand skills and the
onset of stereotyped movement of the hands and gait
disturbance [ 11. The condition is clinically peculiar and
a diagnostic mystery that lacks biological markers [ 1,
The neuropeptide substance P is an important neurotransmitter or neuromodulator in the peripheral as
well as the central nervous system (CNS) [3-51. It has
been implicated in both psychiatric and neurological
From the *Department of Pediatrics and Child Health and SFirst
Department (Neurology) of Internal Medicine, Kurume University
School of Medicine, and $Department of Neurology, National
Chikugo Hospital, Fukuoka, and tAshikita Institution for the
Handicapped, Kuniamoto, Japan; and "Department of Pediatrics,
Division of Neurology, University of Alabama at Birmingham, AL.
Received Apr 3, 1997, and in revised form JuI 14. Accepted for
publication Aug 8, 1997.
Address correspondence to Dr Matsuishi, Department of Pediatrics
and Child Health, Kurume University School of Medicine, 67
Asahi-machi, Kurunie City, Japan 830.
Copyright .O 1997 by the American Neurological Association
disorders [ 3 , 4, 6, 71. Its pattern of distribution suggests various roles in sensory fibers, especially those for
pain and autonomic and extrapyramidal functions.
However, the role of substance P in patients with RS
has not been investigated. The cerebrospinal fluid
(CSF) concentration of substance P reflects brain and
spinal cord concentrations [4, 61. We compared CSF
levels of substance P in patients with RS and control
subjects and disease controls.
ratories, Belmont, CA), which showed no cross-reactivity
with either neurokinin A or neurokinin B. The CSF substance P levels were measured as described previously [4, 61.
W e evaluated the correlation between the level of substance P and the clinical symptoms and signs, including clinical stage, the presence of seizures, medication use (anticonvulsants), self-abuse, and the breathing abnormalities of
hyperventilation and/or apnea (see Table 1). We also compared the CSF levels of substance P in patients with RS and
childhood and adult diseased controls, including 7 patients
with mental retardation (MR) ( 5 boys and 2 girls; mean age,
5.0 2 2.4 years), 4 patients with epilepsy ( 2 boys and 2 girls;
mean age, 6.3 t 4.2 years), 3 patients with Guillain-Bard
syndrome (GBS) ( 1 boy and 2 girls; mean age, 4.4 ? 1.5
years), 14 patients with Parkinson disease (PD) (7 men and
7 women; mean age, 62.1 F 9.7 years), and 9 patients with
multiple system atrophy (MSA) (4 men and 5 women; mean
age, 61.6 F 7.8 years) (Table 2).
Data are summarized as mean 2 SD values. For statistical
analysis, we used analysis of variance. If the data differences
were significant, we then applied the Student's t test for
comparing group means. A p value of less than 0.05 was
considered significant.
Patients and Methods
A clinical diagnosis of RS was confirmed in 20 patients according to the Rett Syndrome Diagnostic Criteria Work
Group [1]. The 20 patients included 16 childhood patients
(mean age, 5.1
2.8 years) and 4 adult patients (mean age,
27.8 F 5.0 years) (Table 1 ) . The diagnosis of RS was confirmed at the age of 5 years, because the diagnosis of RS is
considered tentative until 2 to 5 years. The childhood controls included 1 1 patients without neurological disease (mean
age, 5.9 2 2.6 years), and the 17 adult controls included 7
patients with gynecological disease, 6 patients with urological
disease, and 4 patients with orthopedic disease, all without
neurological diseases (mean age, 33.2 t 8.4 years). All had
normal -CSF findings for standard parameters. CSF specimens were obtained with the written informed consent of
the subjects' parents or subjects' themselves. The mean CSF
levels of substance P in childhood patients with RS and adult
Datients with RS were comuared with those of age-matched
Lonrrols. Substance P immkoreactivity was detzrmined by
radioimmunoassay (RIA) using a highly specific antisubstance P serum (catalog no. RAS 7451; Peninsula Labo-
There was no significant difference in the levels of subStance I' according to sex among the age-matched 'Ont d s and disease controls, respectively. The CSF levels
of substance P in the controls did not change from 2
to 12 years and then decreased gradually, reaching a
plateau at the age of 20 years (data not shown). There-
Tnble 1. Clinical Characteristics and CSF Levels of Substnnce P in Patients with Rett Syndrome
Patient No.
Substance P (fmol/L)
Age (yr)
Mean 2 SD
4.2 5 1.7b
2.6 F 2.4'
Dara are mean 2 SD values. Patients 1 to 16 are childhood patients with RS; Patients 17 to 20 are adult patients with RS.
"Stage of RS was made according to the Rert Syndrome Diagnostic Criteria Work Group.
= 0.03, adult RS vs adult controls; Student's t test.
' p < 0.0001, childhood RS vs childhood controls; ' p
CSF = cerebrospinal fluid; RS = Rett syndrome; HV = hyperventilation; - = absent;
= present.
Brief Communication: Matsuishi et al: Rett Syndrome
Table 2. CSF Levels of Substance P in Childhood Patients
with Rett Syndrome, Adult Patients with Rett Syndrome,
Childhood Control, Mental Retardation, Epilepsy, GuillainBarre‘ Syndrome, Adult Control, Parkinson i Disease,and
Multiple System Atrophy
Substance P
Childhood control
Childhood RS
Mental retardation
Adult control
Adult RS
5.9 ? 2.6
5.1 2 2.8
5.0 t 2.4
6.3 5 4.2
4.4 t 1.5
33.2 t 8.4
27.8 t 5.0
62.1 t 9.7
61.6 t 7.8
8.3 Z 0.9
2 l.Pb
11.0 i 3.1
8.3 t 3.3
8.0 2 0.8
7.0 Z 1.1
2.6 -+ 2.4‘
5.9 t 1.4
5.8 i 1.5
n = number of the patients.
“p < 0,0001, childhood RS vs childhood controls; ‘p = 0.04, childhood RS vs mental retardation; “p = 0.03, adult RS vs adult controls; Student’s t test.
CSF = cerebrospinal fluid; RS = Rett syndrome; GRS = GuillainB a d syndrome; PD = Parkinson’s disease; MSA = multiple system atrophy.
fore, we used the two different age groups as controls.
The assay results of 16 patients with RS of ages less
than 12 years are categorized as childhood patients
with RS, and those of more than 20 years are categorized as adult patients with RS (Table 1). The CSF
substance P levels of the patients with stage I1 RS (n =
7)(age, 3.0 t 0.7 years), patients with stage 111 (n =
7) (age, 5.5
1.8 years), and patients with stage IV
(n = 6) (age, 22.1 t 9.7 years) were 4.7 t 1.8, 3.9 ?
1.8, and 3.0 5 2.0 fmollml, respectively (data not
shown). The CSF levels of substance P were not significantly different by clinical stage. The mean CSF
levels of substance P by group are shown in Table 2.
The CSF level (mean -C SD) of substance P in RS was
significantly lower than that of controls and M R ( p <
0.0001 and p = 0.04, respectively), in childhood patients with RS, being 50% o€ control values, and, in
adult patients with RS, being 370/6 of the adult control
value ( p = 0.03). There was no significant correlation
between the substance P level and clinical symptoms
and signs or drug treatment in RS. The mean CSF
levels of substance P in patients with MR, epilepsy,
and GBS were not significantly different from those in
controls lacking neurological disease. The mean CSF
levels of substance P in patients with PD or MSA were
lower than the control levels (see Table 2). However,
they did not differ significantly.
Substance P activity is associated with dopaminergic
neurons in the substantia nigra and the striatum, the
Annals of Neurology
Vol 42
No 6
December 1997
central autonomic nuclei, the dorsal root ganglia, and
the peripheral autonomic ganglia 14, 5 , 71. Previous
studies have shown that CSF levels of substance P are
decreased in patients with Machado-Joseph disease [4],
with congenital sensory neuropathy with anhidrosis
[GI, and with peripheral neuropathy and autonomic
dysfunction [7],
suggesting that substance P in the
lumbar CSF is derived from the spinal cord, nerve
roots, or dorsal root ganglia [4,6 , 71. The CSF level of
substance P had not been previously evaluated in patients with RS. The present study showed a pronounced decrease in such levels in patients with RS
compared with controls, even in the youngest children
(ages 2-3 years). Thus, the reductions are already identifiable in the early phases of the disease process and
are not age dependent.
Previous neuropathological studies have observed decreased melanin content of the zona compacta nigra in
the CNS [8] and axonopathy of the peripheral nerve in
patients with RS [8, 91. Degeneration and loss of spinal ganglion nerve cells, in addition to gliosis of both
the white and the gray matter of the spinal cord, have
also been observed [8, 101. Auditory brainstem response and somatosensory evoked potential studies in
RS demonstrated dysfunction of the dorsal column system and showed impairment of the conduction time
with slowing along the brainstem and the spinal cord
[l I]. Progressive limb muscle weakness and muscle atrophy were observed in patients with RS, which suggests lower motor neuron involvement [ I , 101. These
changes in the dorsal root ganglia and columns suggest
that lesions in the sensory systems may contribute to
disorders of gait and motor control [8]. The clinical
signs of autonomic dysfunction, including small and
cold feet, are important supportive signs of RS [I].
We also measured the CSF levels of substance P in
patients with MR, epilepsy, and GBS, because patients
with RS have MR, and some have epilepsy. The mean
CSF levels of substance P in patients with MR, epilepsy, and GBS were not significantly different from
those of the childhood controls without neurological
diseases. The CSF levels of substance P in patients with
GBS, in whom the peripheral nerves and spinal roots
are affected, were not decreased.
We previously demonstrated that CSF levels of substance P in patients with PD did not differ significantly
from levels in controls, which suggested that supraspinal substance P neurons contribute little to the level of
substance P in lumbar CSF [4].
Low CSF levels of substance P in patients with MSA have been reported and
were considered to be associated with autonomic dysfunction [7].
The decreased CSF level of substance P
observed in patients with RS may reflect a decreased
concentration of this substance in spinal neurons, perhaps linked to the involvement of the peripheral
nerves, or of the dorsal root ganglia and posterior col-
umns previously observed in this disease. As noted
above, no consistent biological marker has been established for RS. If confirmed at other centers, measurement of CSF levels of substance P could be useful in
this regard.
This research was supported in part by Grant 6A-1 for Nervous and
Mental Disorders from the Ministry of Health and Welfare, Japan.
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Brief Communication: Matsuishi et al: Rett Syndrome
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