PAIN MEDICINE
Volume 10 • Number 3 • 2009
CASE REPORT
Stiff Limb Syndrome: End of Spectrum or A Separate Entity?
Usha K. Misra, DM, Pradeep K. Maurya, MD, Jayantee Kalita, DM, and Rakesh K. Gupta, MD
Department of Neurology and Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow,
India
ABSTRACT
Background. Stiff-person syndrome is a rare disorder characterized by rigidity of axial or limb
muscles with episodes of co-contraction of agonist and antagonist muscles during the spasms. In
some patients axial or limb involvement may predominate and may have unusual manifestations.
Design. Case report.
Setting. Tertiary care teaching hospital.
Patient. A 42-year-old farmer presented with seasonal occurrence of hiccup and vomiting during
summer months for the last 3 years. He had painful lower limb spasms lasting for 2–3 minutes every
10–15 minutes for the past 20 days. His neurological examination was normal, erythrocyte sedimentation rate (ESR) was 50 mm at 1st hour, and cerebrospinal fluid protein 78 mg/dL without
pleocytosis. Radiograph of chest, abdominal ultrasound, and craniospinal magnetic resonance
imaging were normal. The patient improved on diazepam.
Conclusion. Our patient is a forme fruste of stiff person syndrome with hiccups and vomiting due to
diaphragmatic spasm.
Key Words. Stiffman; Stiff Limb; Stiff Person Syndrome; Diazepam; Treatment; GAD Antibody
Introduction
S
tiff person syndrome is a rare disorder characterized by rigidity of axial or limb muscles
and episodes of co-contraction of agonist and
antagonist muscles during spasms as a result of
involuntary motor unit discharges at rest [1]. The
cause of stiff person syndrome is unknown but an
autoimmune mechanism is suggested because of
presence of antibodies against glutamic acid
decarboxylase (GAD) in 60% of patients [2].
There is B cell-mediated clonal production of
autoantibodies against presynaptic inhibitory
epitopes on the enzyme GAD in stiff person syn-
Reprint requests to: U. K. Misra, DM, Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical
Sciences, Raebareily Road, Lucknow—226014, India. Tel:
+91-0522-2668004; Fax: +91-0522-2668017; E-mail:
[email protected]; [email protected].
drome [3]. Anti-GAD antibody has also been
reported in other autoimmune disorders such as
diabetes mellitus [4], Hashimoto encephalopathy
[5], minimal change nephritic syndrome [6], and
adenocarcinoma of lung with anti-Ri antibodies
[7]. Moreover, stiff person syndrome responds
to immunomodulatory therapies such as corticosteroids, plasmapharesis, intravenous immunoglobulin (IVIg), and chemotherapy, suggesting
its autoimmune nature [8]. The role of gaminobutyric acid (GABA) in its pathogenesis is
supported by magnetic resonance (MR) spectroscopy showing reduced GABA-to-creatine ratio
and mild to moderate response to drugs that
enhance GABAergic transmission such as diazepam and baclofen [9].
Moersh and Woltman in 1956 reported 14
patients with stiff man syndrome seen over 32
years [10]. Subsequently, such cases were reported
© American Academy of Pain Medicine 1526-2375/09/$15.00/594 594–597
doi:10.1111/j.1526-4637.2009.00578.x
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Stiff Limb Syndrome
in both men and women and one study even
reported higher frequency in women (6 vs 14);
therefore, the term stiff person instead of stiff man
syndrome has been suggested [1]. Stiff person syndrome has been divided into three subgroups—
stiff trunk (man) syndrome, stiff limb syndrome,
and progressive encephalomyelitis with rigidity
and distinct clinical, electrophysiological, and
immunological features [11]. Whether these cases
represent the end of a spectrum or etiologically
distinct entities is an unanswered question. In the
available medical literature, we could not find
association of stiff limb syndrome with hiccup,
vomiting, and seasonal exacerbation of symptoms.
We report a patient with stiff limb syndrome with
unusual features and highlight the clinical, neurophysiologic, and MR spectroscopic findings.
Case Report
A 42-year-old farmer presented with history of
recurrent intractable hiccups and vomiting for 3
years. He had neither difficulty swallowing nor
nasal regurgitation. The hiccups had a seasonal
trend occurring during the summer, lasting for
2–3 months. This year, his hiccups were associated
with recurrent spontaneous painful spasm of the
lower limbs. During the attack, the patient tossed
and turned and even cried out because of painful
muscle spasm that lasted for 2–3 minutes. In
between the spasms, he was normal but did not
allow anyone to touch his legs because even a light
touch precipitated the painful spasm and awakened him from sleep. There was no history of
fever, exposure to any pesticide or toxin, or preceding physical exhaustion. No family member
was suffering from a similar illness.
On examination, the patient was conscious, oriented, and anxious. He rested with his legs stiff and
straight. His mental status and cranial nerves were
normal. Sensory examination revealed hyperesthesia in both legs without any sensory loss. There
were no extrapyramidal or cerebellar signs. The
lower limbs were stiff with normal muscle power.
The biceps, triceps, and knee reflexes were normal
and ankle reflexes were diminished. Plantar response was flexor bilaterally. His blood leukocyte
count was 6,000/mm3, hemoglobin 13.6 gm/dL,
ESR 50 mm at the end of first hour, fasting blood
sugar 72 mg/dL, serum sodium 142 meq/L, potassium 3.5 meq/L, creatinine 1.3 mg/dL, bilirubin
1 mg/dL, serum glutamate pyruvate transaminase
(SGPT) 84U/L, calcium 9.7 mg/dL (ionized
4.6 mg/dL), lactate 12 mg/dL, and creatine kinase
173 (MM-156) U/L. Arterial blood gas analysis
was normal. During the spasm, there was cocontraction of agonist and antagonist muscles of
the lower limbs that was apparent on surface electromyography. His electrocardiogram, radiograph
of chest, ultrasound abdomen, and magnetic resonance imaging of spine and brain were normal. MR
spectroscopy was performed on a 1.5 Tesla MR
system (Signa, General Electric Medical Systems,
Milwaukee, WI, USA). MR spectra were obtained
by using a water-suppressed localized single-voxel
stimulated-echo acquisition mode (STEAM) with
repetition time/echo time (TR/TE) = 3,000 ms/
20 ms. A voxel of 1.2 ¥ 1.2 ¥ 1.2 cm3 was located in
the bilateral precentral gyrus and subcortical white
matter including the leg area. The GABA-tocreatine ratio was 0.039 on right side and 0.000 on
left side on point-resolved spectroscopy. Using
STEAM, his GABA-to-creatine ratio was 0.075 on
the right side and 0.083 on the left side. Cerebrospinal fluid (CSF) revealed five lymphocytes/
mm3, normal sugar, and mildly elevated protein
(78 mg/dL). Anti-GAD antibody was negative in
CSF. Nerve conduction study and concentric
needle electromyography were performed during
the pain-free period. Peroneal motor nerve conduction velocity was 37 m/second, with compound
muscle action potential amplitude of 8 mv. Sural
nerve conduction velocity was 55 m/second and
sensory nerve action potential amplitude was
24.2 mv. The needle electromyography carried out
in tibialis anterior, gastrocnemius, and vastus lateralis revealed no spontaneous activity and motor
unit potentials were normal in shape and size with
normal interference pattern. Needle electromyography of diaphragmatic muscle was not possible.
The patient was treated with carbamazepine,
baclofen, domperidone, and tramadol without any
relief. His muscle spasm, however, responded to
diazepam 10 mg iv. Thereafter, he was prescribed
diazepam 25 mg per oral (PO) thrice daily, which
resulted in significant improvement in painful
spasm, vomiting, and hiccup. Frequency of spasm
was reduced to 1–2/day with marked reduction
in pain. At 6-month follow-up, the patient was
taking diazepam 12.5 mg PO thrice daily and was
asymptomatic.
Discussion
Our patient was diagnosed as stiff limb syndrome
because of lower limb rigidity, painful spasm,
co-contraction of lower limb muscles during
spasm without any other underlying cause, and
596
good response to diazepam [1]. Prompt response
to diazepam has been used to confirm the clinical
diagnosis of stiff man syndrome [9]. Stiff person
and stiff limb syndromes essentially are clinical
diagnoses. Anti-GAD antibodies are reported to
be positive in only 60% of patients [2,12]. In a
review of 23 stiff man syndrome cases, stiffman
(trunk) syndrome was found in eight, stiff limb
syndrome in 13, and two patients had encephalomyelitis with rigidity [11]. The stiff trunk syndrome patients had lumbar paraspinal and
abdominal rigidity with occasional proximal limb
muscle involvement resulting in hyperlordosis. In
these patients, upper and lower limbs were not
affected. A majority of these patients had antiGAD antibodies and additional autoimmune disorders. The patients with stiff trunk syndrome had
better outcomes compared with the stiff limb syndrome. The stiff limb syndrome in the 13 patients
was characterized by rigidity and painful spasms
that were restricted to distal lower limb muscles.
However, two of these patients also had truncal
rigidity and two had anti-GAD antibodies. Our
patient did not have truncal rigidity and anti-GAD
antibodies. The patients with stiff limb syndrome
did not have associated autoimmune disorders. In
our patient, antinuclear antibody, rheumatoid
factor, and antiparietal cell antibody were also
absent and he had no evidence of diabetes or any
other systemic disorders. Patients with stiff limb
syndrome are not generally associated with malignancy; breast and lung cancer were present in the
four reported cases and there is one reported case
with multiple myeloma [13]. Stiff limb syndrome,
unlike stiff person syndrome, generally responds
poorly to diazepam [14]; however, our patient
responded to moderate dose of diazepam. Although stiff trunk and stiff limb syndrome have
distinct differences and are reported as two distinct entities [11], there are overlapping features.
For example, one out of eight patients with stiff
trunk syndrome had involvement of an entire leg
in addition to paraspinal rigidity. Similarly, one
out of 13 patients with stiff limb syndrome had
early symmetric involvement of paraspinal
muscles, and in another, truncal rigidity appeared
1 year later [2].
Painful spasm in stiff man syndrome and stiff
limb syndrome are aggravated by tactile and
auditory stimuli or emotional stress. Increased
inhibition of the uninvolved upper extremity in
a patient with stiff limb syndrome has been
reported [4]. In our patient, the nerve conduction
studies were nearly normal. In a detailed neuro-
Misra et al.
physiological study of stiff man syndrome,
peripheral nerve conduction velocity was normal,
but transcranial motor stimulation revealed a distinct pattern in proximal lower limb muscles
consisting of markedly increased lower limb,
motor-evoked potential amplitude, reduced excitability threshold, and absent silent period. The
clinical and motor-evoked potential changes normalized on diazepam and baclofen treatment [15].
Head retraction reflex has been evaluated in stiff
man syndrome and related disorders, which is a
vestigial cutaneomuscular withdrawal reflex of the
face and is suppressed in healthy individuals. It is
elicited by gentle tap to the face or electrical
stimulation of the trigeminal nerve, and the
muscle contraction response is recorded by
surface electrodes from orbicularis oculi, trapezius, sternocleidomastoid, and paraspinal muscles
at mid-dorsal and lumbar areas. Mild to severe
contraction was observed in 17 out of 28 patients
with stiff man syndrome, 10 out of 20 patients
with progressive encephalomyelitis with rigidity
and myoclonus, but none of two patients with
stiff limb syndrome. Presence of head retraction
reflex suggests a nonspecific cutaneomuscular
brainstem reflex abnormality [16].
In our patient, hiccup and vomiting preceded
lower limb rigidity and spasm by 3 years. We feel
that hiccup and vomiting could be due to spasm of
the diaphragm. These symptoms along with lower
limb spasm responded to diazepam therapy.
Bulbar muscles can be involved in stiff person syndrome. Facial muscle involvement resulting in
masking of face was reported in 10 out of 12
patients. Rigidity of respiratory muscles can also
result in breathing difficulty that may be aggravated by anxiety and fear [9].
In stiffman syndrome, MR spectroscopy has
revealed reduced GABA-to-creatinine ratio suggesting reduction in GABA transmission. Moreover the therapeutic response to diazepam, a
GABA agonist, confirms the MR spectroscopic
finding.
We conclude that stiff limb syndrome is clinically distinct from stiff person syndrome but may
be similar pathophysiologically and in their
response to some therapeutic agents, and may
represent the end of spectrum of stiff person
syndrome.
Acknowledgment
We thank Rakesh K. Nigam for secretarial help.
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Stiff Limb Syndrome
References
1 Dalakas MC. ClInical symptomatology of stiffperson syndrome. In: Levy LM, moderator. The
stiff-person syndrome: An autoimmune disorder
affectIng neurotransmission of gammaamInobutyric
acid. Ann Intern Med 1999;131:522–30.
2 Meinck HM, Ricker K, Hulser PJ, Solimena M.
Stiff man syndrome: Neurophysiological findings in
eight patients. J Neurol 1995;242:134–42.
3 Espay AJ, Chen R. Rigidity and spasms from
autoimmune encephalomyelopathies: Stiff-person
syndrome. Muscle Nerve 2006;34:677–90.
4 Gürol ME, Ertas M, Hanagasi HA, Sahin HA,
Gürsoy G, Emre M. Stiff leg syndrome: Case
report. Mov Disord 2001;16:1189–93.
5 Calvet D, Touzé E, Delegue P, Bertherat J, Zuber
M. Stiff limb syndrome associated with Hashimoto’s
encephalopathy: Improvement after corticotherapy.
Rev Neurol (Paris) 2002;158:602–4.
6 Ergün I, Akbostanci MC, Canbakan B, et al.
Minimal change nephrotic syndrome with stiffperson syndrome: Is there a link? Am J Kidney Dis
2005;46:e11–4.
7 McCabe DJ, Turner NC, Chao D, et al. Paraneoplastic “stiff person syndrome” with metastatic
adenocarcinoma and anti-Ri antibodies. Neurology
2004;62(8):1402–4.
8 Lockman J, Burns TM. Stiff-person syndrome.
Curr Treat Options Neurol 2007;9:234–40.
9 Levy LM, Dalakas MC, Floeter MK. The stiffperson syndrome: An autoimmune disorder affect-
10
11
12
13
14
15
16
ing neurotransmission of gammaaminobutyric acid.
Ann Intern Med 1999;131:522–30.
Moersh FP, Woltman HW. Progressive fluctuating
muscular rigidity and spasm (“stiff-man” syndrome):
Report of a case and some observations in 13 other
cases. Mayo Clin Proc 1956;31:421–7.
Barker RA, Revesz T, Thom M, Marsden
CD, Brown P. Review of 23 patients affected
by the stiffman syndrome: Clinical subdivision
into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with
rigidity. J Neurol Neurosurg Psychiatry 1998;65:
633–40.
Solimena M, Folli F, Aparisi R, Pozza G, De
Camilli P. Autoantibodies to GABA-ergic neurons
and pancreatic beta cells in stiff-man syndrome. N
Engl J Med 1990;322:1555–60.
Schiff D, Dalmau J, Anti-Myers DJ. GAD antibody
positive stiff-limb syndrome in multiple myeloma.
J Neurooncol 2003;65:173–5.
Brown P, Marsden CD. The stiff man and stiff
man plus syndromes. J Neurol 1999;246:648–
52.
Logullo F, Di Bella P, Provinciali L. Motor
evoked potentials in a case of stiff-man syndrome: A
longitudinal study. Ital J Neurol Sci 1999;20:133–
8.
Berger C, Meinck HM. Head retraction reflex in
stiff-man syndrome and related disorders. Mov
Disord 2003;18:906–11.