Brief communication

Satoyoshi’s syndrome related muscle spasms: Functional study

Spasmes musculaires en rapport avec un syndrome de Satoyoshi :etude fonctionnelle

J.M. Pardal-Fernandez a,*, J. Solera-Santos b, I. Iniesta-Lopez c, M. Rodrıguez-Vazquez d

aClinical Neurophysiologist, School of Medicine, UCLM, Unit of clinical electromyography, Department of Neurophysiology, University General

Hospital, c/Hermanos Falco s/n, 02006, Albacete, SpainbDepartement of Internal Medicine, School of Medicine, UCLM, Chief of Department of Internal Medicine, University General Hospital,

c/Hermanos Falco s/n, 02006, Albacete, SpaincDepartment of Neurology, The Walton Centre NHS Foundation Trust, University General Hospital, Lower Lane, Liverpool, Merseyside L9 7LJ,

United KingdomdDepartment of Dermatology, University General Hospital, c/Hermanos Falco s/n, 02006, Albacete, Spain

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i n f o a r t i c l e

Article history:

Received 24 October 2010

Received in revised form

12 March 2011

Accepted 22 June 2011

Published online 17 November 2011

Keywords :

Satoyoshi syndrome

Komuragaeri disease

Muscular spasm

Transcraneal magnetic stimulation

H-reflex

Paired pulses paradigm

Mots cles :

Syndrome de Satoyoshi

maladie de Komuragaeri

Spasme musculaire

Stimulation magnetique

transcranienne

Reflexe H

Paradigme des impulsions appariees

a b s t r a c t

Satoyoshi syndrome is a rare disease presumed to be immunologically mediated, charac-

terized by muscle spasms, alopecia and diarrhea. We describe the case of a female in whom

the muscle spasms were the predominant feature and we analyze the changes in cortical

and in spinal excitability under the paired pulses paradigm. Hyperexcitability was present in

the H-reflex study, thus suggesting that the spinal cord is the structure most likely

responsible for the spasms. This is the first reported case in Spain.

# 2011 Elsevier Masson SAS. All rights reserved.

r e s u m e

Le syndrome de Sataoyoshi est une maladie rare probablement d’origine immunologique

caracterisee par des spasmes musculaires, une alopecie et une diarrhee. Nous presentons un

nouveau cas chez une femme souffrant de spasmes musculaires comme symptomatologie

principale. Nous avons analyse l’excitabilite corticale et spinale utilisant le paradigme des

impulsions appariees. D’apres l’hyperexcitabilite observee lors de l’etude du reflexe H, une

dysfonction medullaire est probablement a l’origine des spasmes musculaires. Cela est le

premier cas espagnol.

# 2011 Elsevier Masson SAS. Tous droits reserves.

* Corresponding author.

Available online at

www.sciencedirect.com

E-mail address : josempardal@yahoo.es (J.M. Pardal-Fernandez).

0035-3787/$ – see front matter # 2011 Elsevier Masson SAS. Tous droits reserves.doi:10.1016/j.neurol.2011.06.004

r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 2 9 1 – 2 9 5292

Fig. 1 – Graphic of magnetic transcraneal stimulation

results. X-axis: conditioned responses; ISIs (interstimul

interval), milliseconds (ms). Y-axis: amplitude (mV) of

unconditioned and conditioned responses.

Resultats de la stimulation magnetique transcranienne.

Abscisses : reponses conditionnees ; ISIs (interstimul interval),

millisecondes (ms). Ordonnees : amplitude (mV) des reponses

conditionnees et non conditionnees.

1. Introduction

Satoyoshi syndrome (SS), also known as ‘‘Komuragaeri’’

disease, is a rare progressive multisystemic disease of unknown

etiology presumed to be immunologically mediated. SS is

characterized (Satoyoshi and Yamada, 1967; Satoyoshi, 1978,

Ikeda et al., 1998) by painful muscle spasms (MS), alopecia,

diarrhea, endocrinopathy with amenorrhea, skeletal abnorma-

lities and autoimmune diseases (Satoh et al., 1983; Yamagata

et al., 1991). However, the pathophysiological basis of SS related

MS remains unknown. MS can interfere significantly and even

be disabling when severe. Clinical as well as neurophysiological

findings suggest that MS originate from the central nervous

system, more likely from spinal cord (Kujirai et al., 1993). In this

paper, we describe the first Spanish case reported yet of SS, and

study the cortical and spinal excitability in an attempt to

understand the underlying mechanisms.

2. Case report

A 19-year-old Caucasian woman with no relevant family

history was referred to us for severe MS. She had previously

been diagnosed with SS based on her alopecia, diarrhea,

developmental delay (weight 38 kg, height 140 cm, BMI

19.3 kg/m2), skeletal abnormalities, amenorrhea and MS,

and had previously been unsuccessfully tried on gabapentin

and carbamazepine. MS involved the thorax, the back and all

four limbs, in a bilateral asymmetric way, and were signifi-

cantly interfering with her daily activities. They were triggered

by stress or exercise and improved after several hours of

bedtime rest. MRI of the CNS axis as well as a full cell count,

biochemistry profile and microbiological investigations in

both, plasma and CSF, were unremarkable.

Serum antiglutamate decarboxilase antibodies (anti-GAD)

were tested seven times before and after treatment. Values

ranged from 0.1 to 1.11 U/mL. In only one instance were they

found weakly positive prior to treatment (1.11 U/mL – for a

reference range of less than 0.9 U/mL). Acetylcholine receptor

antibodies (Anti-Ach) were determined 5 times, testing

positive in all between 6.82 and 11.5 nmol/L (reference range

less than 0.15). However, no clinical or neurophysiological

evidence to support a diagnosis of myasthenia gravis was

found. Serum antinuclear antibodies (ANA), anti-Ro, anti-La,

anti-Jo, anti-RNP, anti-Sm, anti-Scl79, anti parietal cell anti-

bodies, anti-IgG and anti-GM1 were all negative.

3. Materials and methods

Nerve conduction studies (NCS) and needle electromyogram

(EMG) were carried out on the lower limbs. Transcraneal

magnetic stimulation (TMS) over the motor cortex with single

and paired pulses (PP) (Ridding et al., 1995; Ziemann et al.,

1996) was also undertaken and the H-Reflex recovery curve

(HRrc) (Panizza et al., 1990; Aminoff, 1998), were both recorded

from the soleus muscle. The EMG background noise was

monitored by acoustic feedback. All the exams took place in a

quiet, relaxing environment in penumbra with the patient in a

supine position. Motor evoked potentials (MEPs) were ampli-

fied using a SynergyR electromyograph (CareFusion Co. USA).

Magnetic shocks were delivered with a Magstim 200 stimu-

lator (the Magstim Co. Ltd, UK). TMS was performed with a

circular coil on the scalp two centimetres anterior to the vertex

(the center over it), which corresponded to the primary motor

area of the soleus muscle. The intracortical inhibition (ICI) and

intracortical facilitation (ICF) were delivered in accordance

with the PP paradigm, in which two magnetic stimulators are

connected through a Bistim module. The intervals between

the stimuli (ISI) were 1, 2, 4, 15, 20 and 25 ms. For each ISI, eight

responses were recorded. The HRrc obtained for ISIs were 30,

60, 70, 100, 120, 200, 300, 400, 500 and 1000 ms. Amplitude of

the conditioned MEPs recorded at each ISI was averaged.

These values were compared to the amplitude of unconditio-

ned MEPs (including percentage). At least, six consecutive

recordings, taken 10 s apart, were done for each interval, with

no changes of amplitude left to chance.

4. Results

Single pulse MTS, NCS and EMG were all found to be normal.

Cortical excitability tests and HRrc results are highlighted on

Fig. 1. HRrc studies revealed a significant absence of inhibition

with ISI above 250 ms (Figs. 1, 2 and 3) and less pronounced

with ISIs 50 to 70 ms. At follow up within the first few months

of sustained immunosupression, with prednisone 40 mg per

day and methotrexate 7.5 mg per week, no changes were seen,

despite reducing the frequency and the intensity of the MS. A

considerable clinical improvement was seen after a year of

ongoing treatment, while the HRs were normalized (Fig. 1).

Fig. 2 – Graphic of H-Reflex results. X-axis: conditioned

responses; ISIs (interstimul interval), miliseconds (ms).

Y-axis: amplitude (mV) of unconditioned and conditioned

responses.

Resultats de l’etude du reflexe H. Abscisses : reponses

conditionnees ; ISIs (interstimul interval), millisecondes (ms).

Ordonnees : amplitude (mV) des reponses conditionnees et non

conditionnees.

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Conditioned responses measuring the inhibitory SICI (1/

4 ms) interval as well as the facilitator ICF (7–20 ms) interval in

MTS studies prior to and after treatment where all found to be

normal. MEP amplitude in relation to the responses in the pre-

and post-treatment MTS studies, the conditioned responses

for the inhibitory interval SICI (1–4 ms), and the facilitator ICF

(7–20 ms) interval were all normal. MEP amplitudes in relation

to the unconditioned response did not show any significant

changes using different ISIS (Table 1 and Fig. 1).

Fig. 3 – Left: MTS paired pulses study. First unconditioned MEP (m

9 ms, respectively. The corrected MEPs became suppressed with

pulses study. Top, conditioned MEPs, ISIs 60, 70 and 120 ms. B

H-wave amplitudes of conditioned MEPs were consistently grea

(hyperexcitability).

Gauche : etude des impulsions appariees. Potentiels moteur evoques

ISIs 2,4, 6, 9 ms. Les MEP corriges sont supprimes lors d’ISIs de 2 et 4

conditionnes, ISIs 60, 70 et 120 ms. Bas : suppression de l’impulsio

conditionnees sont constamment elevees. Stimulation moteur impor

On the contrary, MEP amplitudes in the H-reflex pre- and

post-treatment studies did show clear changes, particularly

involving the inhibitory interval of 250 to 400 ms, in which

MEPs were multiplied by five times after treatment (Table 1

and Fig. 2).

5. Discussion

Since the first description by Satoyoshi and Yamada (1967),

only 50 cases have been reported thus far. Additional findings

have been observed and hence included as part of SS,

particularly dermatological (Oyama et al., 1999; Wisuthsare-

wong et al., 2001), serological (Matsuura et al., 2007; Drost et al.,

2004), therapeutic (Endo et al., 2003; Heger et al., 2006), and

more recently, neurological (Drost et al., 2006).

In the SS case we have reported the most significant finding

was the hyperexcitability as shown by the HRrc in the context

of frequent MS. An ISI inhibitory interval of more than 250 ms

before treatment showed MEPs well above the expected

amplitude as a result of the excessive recruitment of motor

units. Following treatment, amplitudes declined up to five

times compared with the pre-treatment. As Drost et al. (Drost

et al., 2006) have suggested these findings could be somewhat

related to failure of the inhibitory mechanisms of the alpha

spinal motor neurons.

MS are characterized by a sudden unexpected and painful

muscular activity (Miller and Layzer, 2005) resulting from

uncontrolled contraction of a group of muscles, usually in

segmental distribution.

In this first case of Satoyoshi’s syndrome reported in Spain

thus far, we found a significant alteration in the inhibition

interval of HRrc within the ISIs of 300 to 500 ms and less

pronounced within those of 70 ms or less.

The level of neuronal excitability determines the motor

output. The MTS with PP are considered to be useful markers

of the cortical motor excitability (Peurala et al., 2008). ISIs of 1

otor evoked potential). Down conditioned MEPs, ISIs 2, 4, 6,

ISIs 2 and 4 ms (normal situation). Right: H-Reflex paired

ottom, paired pulse suppression (ISIs 300 and 400 ms).

t. There was an important enhanced motor output

(MEP) non conditionnes. Respectivement MEP deconditionnes,

ms (situation normale). Droite : etude du reflexe H. Haut : MEP

n (ISIs 300 and 400 ms). Les amplitudes de l’onde H des MEP

tante (hyperexcitabilite).

Table 1 – Mean values of neurophysiological parameters of patient (soleus muscle).Valeurs significatives des parametres neurophysiologiques du patient (muscle soleaire).

Pre-treatment Post-treatment

EMT H-REFLEX EMT H-REFLEX

Unconditioned MEP (mV) TMS 3588 3996

RMT (% output stimulator) 32 38

SICI 2 ms (%) 12.55 11.95

SICI 4 ms (%) 41.56 40.25

ICF 7 ms (%) 125.61 119.55

ICF 10 ms (%) 159.92 171.80

ICF 20 ms (%) 188.83 191.90

Unconditioned MEP (mV) H-Reflex 3996 4195

ISI 60 ms (%) 19.85 18.80

ISI 70 ms (%) 76.11 29.90

ISI 120 ms (%) 95.23 92.50

ISI 300 ms (%) 125.66 43.50

ISI 400 msg (%) 169.61 26.60

(%) Amplitude of conditioned MEP (expressed as % of unconditioned MEP); ms: miliseconds; MEP: motor evoked potential; RMT: rest motor

treshold; ICI: intracortical inhibition; ICF: intracortical facilitation; ISI: interstimul interval.

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to 4 ms causes an enhanced GABA-A mediated intracortical

inhibition, while ISIs of 7 to 30 ms has the opposite effect

(facilitation). The HRrc have similar considerations. The ISIs of

40 to 70 and 200 to 1000 ms are inhibitory, while the ISIs of 70 to

200 are excitatory.

Prolonged immunosuppression resulted in a significant

clinical improvement particularly during the first few months

and especially for MS control. Neurophysiological follow ups

using the HRrc also showed a gradual improvement until they

became normal after a year.

Based on the clinical findings and electromyographic

features found in one case of SS, Drost et al. (2006) have

proposed a spinal disinhibition to explain the MS. In this sense,

our findings support this theory and suggest the existence of a

target within the spinal modulation structures, probably

interneurons, accounting for the underlying pathophysiology

of SS. In our case, we were unable to identify any inflammatory

markers involved. It is also noteworthy that the clinical

response obtained with GABAergic agents, such as gabapentine

to which the patient had been long exposed, was poor.

To conclude, and taking into account the few cases

reported to date where this motor phenomena have been

investigated, in our view the spinal cord is directly involved in

the generation of SS related MS as a result of disinhibition,

causing an excessive motor output from the lower motor

neurons.

Disclosure of interest

The authors declare that they have no conflicts of interest

concerning this article.

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