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CASE STUDY
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Sudden spasms following gradual lordosis—the
stiff-person syndrome
Robin K Wilson and Beth B Murinson*
This article offers the opportunity to earn one
Category 1 credit toward the AMA Physician’s
Recognition Award.
THE CASE
A 28-year-old woman presented to a hospital emer-
gency room with intense lower back spasms in the
context of coughing during an upper respiratory
illness. The back spasms had become progressively
more painful over a period of 2 months, and were
associated with leg clonus, episodic lumbar hyper-
lordosis, preserved consciousness, and exacerba-
tion during stressful situations. Her parents, who
were physicians, noted that the spasms resem-
bled those associated with tetanus. Until 1 week
before her presentation, the patient had been
working in Southeast Asia, where she had initially
sought medical care. Her spasms had at that time
improved with oral diazepam 5 mg every 6 h as
required, and oral cyclobenzaprine 10 mg every
8 h as required.
During the patient’s evaluation in the emer-
gency room, her past hospital medical records
were reviewed, which revealed that the patient
had experienced progressive lower back prob-
lems for the past 6 years. While the patient had
been at college, she had participated in athletics,
but she had gradually developed lumbar stiff-
ness which prevented her from playing golf,
touching her toes, or sitting on the floor with
her legs crossed. A lumbar spine MRI scan had
been undertaken 2 years previously, and this
had demonstrated an increase in her lordosis but
no other abnormalities.
Until commencing treatment with inter-
mittent diazepam and cyclobenzaprine a few
weeks before her presentation, the patient had
not been taking any medications. She did not
smoke or use illegal drugs, and she rarely drank
alcohol. She had obtained a tattoo in Southeast
Asia 2 months before her presentation. She had
received standard childhood immunizations,
including tetanus vaccination. Her family history
revealed that her maternal grandmother had had
breast cancer and arthritis.
Background A 28-year-old woman presented to hospital after an episode
of severe lower back spasms that occurred during a stressful family
gathering. She had a history of progressive difficulty bending forward and
increasing lumbar lordosis.
Investigations Physical examination, spine MRI scan, abdominal
and pelvic ultrasound, electromyogram, nerve conduction studies,
cerebrospinal fluid analysis, breast examination, Pap smear,
transabdominal and endovaginal ultrasound.
Diagnosis Stiff-person syndrome with high titer of antibodies against
glutamic acid decarboxylase.
Treatment Benzodiazepines and intravenous immunoglobulins.
KEYWORDS antibodies, anxiety, glutamic acid decarboxylase,
lumbar lordosis, spasms
CME
RK Wilson is a fellow with the Johns Hopkins Adult Hydrocephalus
Program, and BB Murinson is Assistant Professor and Director of Pain
Education in Neurology, both at the Johns Hopkins School of Medicine,
Baltimore, MD, USA.
Correspondence:
*
Department of Neurology, 509 Pathology, 600 North Wolfe Street, Johns Hopkins Hospital,
Baltimore, MD 21287, USA
bmurins1@jhmi.edu
Received 6 February 2006 Accepted 19 May 2006
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doi:10.1038/ncpneuro0259
SUMMARY
AUGUST 2006 VOL 2 NO 8 NATURE CLINICAL PRACTICE NEUROLOGY 455
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CASE STUDY
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A systems review revealed that the patient had
intentionally lost 11 kg in weight over the past
year, and had been experiencing generalized
anxiety exacerbated by crowds, in addition to low
back pain and difficulty in walking. She had not
received treatment for her anxiety. She had expe-
rienced no fever, nausea, vomiting, night sweats,
appetite change, shortness of breath, bowel
or bladder incontinence, breast lumps, skin
changes, lymphadenopathy, headache, dizziness,
dysarthria, or swallowing difficulties.
On examination, the patient was a pleasant
young woman who was in moderate distress
secondary to her lower back spasms. Her vital
signs were normal, and she demonstrated
normal use of language, intellect and affect. Her
neck was supple without lymphadenopathy
or thyromegaly, her lungs were clear, and her
abdomen was muscular and firm but not tender.
Her cranial nerves were normal, and muscle bulk
and strength were very good. Her muscle tone
was mildly increased in the upper extremities
and significantly increased in the proximal lower
extremities and paraspinal muscles. Her arm
coordination was intact, but coordination was
limited by proximal muscle spasm in her legs.
Her reflexes were normal throughout, with flexor
plantar responses. Sensation was intact to light
touch, sharp stimuli, proprioception and vibra-
tion. Her gait was stiff, and she demonstrated
difficulty in bending at the waist and had marked
lumbar lordosis. Her toe, heel, and tandem walk
were stiff, but well coordinated.
MRI scans of the brain, and cervical, thoracic,
and lumbar spine with and without gado-
linium showed lumbar lordosis (Figure 1). An
abdominal and pelvic CT scan with oral and
intravenous contrast agents was normal. Nerve
conduction studies of the right sural sensory
nerve and right deep peroneal nerve were found
to be normal. An electromyogram (EMG) of the
paraspinal muscles at T6 and the right iliacus
performed after diazepam administration was
also found to be normal.
Laboratory testing revealed a normal CBC,
and comprehensive metabolic testing including
calcium and transaminase levels was also found
to be normal. Serum testing revealed normal
levels of thyroid-stimulating hormone and
glycated hemoglobin (HbA
1c
), and the glucose
tolerance test, rapid plasma reagin test, and tests
for HIV and human chorionic gonadotropin in
urine and serum were all negative. Cerebrospinal
fluid analysis revealed two white blood cells,
one red blood cell, normal glucose and protein
levels, no oligoclonal bands and no myelin basic
protein antibodies. The patient’s erythrocyte
sedimentation rate (ESR) was mildly elevated
at 35 mm/h. The anti nuclear antibody test
was positive at 1:320 with a nucleo lar pattern.
Anti-thyroglobulin antibodies were positive
at 1:160.
The patient was admitted to hospital, where
she responded to symptomatic treatment with
scheduled oral diazepam 5 mg every 6 h and oral
cyclobenzaprine 10 mg every 8 h as required.
After 6 days, the patient was discharged home
with an acceptable level of pain control, and the
ability to walk and climb stairs. As the diaze pam
had been causing an unacceptable level of
drowsiness, gradual alterations were made to her
medication regimen—her diazepam dose was
reduced to 2.5 mg in the morning and late after-
noon, with cyclobenzaprine 10 mg every 8 h and
ibuprofen 600 mg every 6 h if required. She was
also prescribed oral clonazepam 0.5 mg every
12 h as required as an alternative to diaze pam,
and a diazepam 5 mg rectal suppository for
treatment of severe spasm development.
Figure 1 MRI of the lumbosacral spine. Increased
lumbar lordosis is evident in the L3–S1 region.
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CASE STUDY
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A week after the patient was discharged,
the results of her glutamic acid decarboxylase
(GAD)-65 antibody level test arrived from Quest
Diagnostic Laboratory, and were found to be
markedly positive at 71,300 U/ml (normal value
<1.0 U/ml), supporting a diagnosis of GAD-
antibody-associated stiff-person syndrome
(GAD
+
SPS). The patient was followed up by
the gynecology service, and results from a Pap
smear, breast examination, transabdominal
and endovaginal ultrasound were found to be
normal. At a follow-up visit 6 months after
her initial presentation, she had developed no
evidence of an underlying neoplasm, but her
GAD antibody level had increased to 95,000 U/ml.
She had achieved excellent symptomatic control
with the use of diazepam 2.5 mg at 7:00 h and
19:00 h, clonazepam 0.5 mg at 10:30 h, and an
occasional extra dose of diazepam 2.5 mg as
required. She had resumed work and vigorous
exercise, but reported continued difficulty in
flexing at the waist and tying her shoes. She
had noticed a general decrease in her anxiety
level, but loud noises and stressful situations
still induced abrupt muscle spasms, primarily
involving her lower back. Intravenous immuno-
globulin infusion was recommended in order to
improve her symptoms further, but her insur-
ance carrier has been reluctant to cover the cost
of this treatment.
DISCUSSION OF DIAGNOSIS
In 1956, Moersch and Woltman described a
“beguiling enigma” posed by 14 unrelated
patients with muscular rigidity and episodic
spasms that principally involved the trunk and
proximal lower limbs.
1
Initially termed “stiff-
man syndrome,” the condition is now widely
referred to as stiff-person syndrome (SPS)—in
particular, because it affects twice as many
women as men.
2
SPS involves severe stiffness and
profound muscle spasms, and it is often linked
with autoantibodies against proteins involved
in neurotransmission.
The most common form of SPS is associated
with high levels of antibodies against GAD.
2,3
GAD is essential for synthesis of gamma-
aminobutyric acid (GABA), a key inhibitory
neurotransmitter in the brain and spinal cord.
Other immunological variants of SPS have
also been identified, but a diagnosis of SPS is
based on clinical criteria, rather than the results
of immunological testing (Box 1). The first
noticeable symptoms of GAD
+
SPS are typically
painful muscle spasms in response to emotional
stress or loud noises, and lumbar lordosis may
develop at this early stage. The patient will also
often experience stimulus-triggered falls and,
as in the present case, overwhelming anxiety.
4
These symptoms contribute to a difficulty in
crossing streets and a fear of open spaces, and
psychiatric referral is common. It is unclear
whether the anxiety and phobias arise because
of an antibody-related CNS process, or are
solely a reaction to situation-induced spasms.
The onset of GAD
+
SPS usually occurs in
middle age. Although not generally familial,
there is a single case report of a father and
daughter both with GAD
+
SPS.
5
Occasionally,
GAD
+
SPS can present as a focal variant, with
the spasms confined to one leg.
2
In one reported
case series, 80% of patients with GAD
+
SPS were
found to have additional autoimmune diseases
such as diabetes, thyroiditis, pernicious anemia,
and celiac disease;
6
there are also reports of
concomitant vitiligo and myasthenia.
7,8
Typically, patients with GAD
+
SPS exhibit
increased tone in the paraspinal muscles and
proximal lower extremity muscles, and contin-
uous motor unit activity will be present on an
EMG. As seen in the present case, however,
EMG activity is abolished by treatment
with diaze pam, and a significant number of
patients will therefore demonstrate ‘negative’
EMG results.
The majority of GAD
+
SPS patients either
already have diabetes, or will subsequently
develop the disease.
9
Pancreatic β-cells express
GAD, and many patients with autoimmune
Box 1 Criteria for glutamic acid decarboxylase
(GAD)-antibody-associated stiff-person
syndrome.
2
1 Prodrome of episodic aching stiffness involving
axial muscles
2 Progression to include stiffness of proximal
limbs
3 Painful spasm elicited by triggers
4 Increased lumbar lordosis
5 Normal sensation, motor function and intellect
6 Response to benzodiazepines
7 High levels of GAD antibodies
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diabetes produce low levels of GAD antibodies.
The GAD antibodies that are present in many
diabetics recognize a different epitope on the
GAD-65 protein and are present at lower levels
than the GAD antibodies in patients with SPS.
10
Clinically, the majority of patients with
GAD
+
SPS have concomitant diabetes, but
diabetics with GAD antibodies are unlikely to
have SPS. GAD antibodies are also associated
with several other rare neurological diseases
including progressive encephalomyelitis with
rigidity and myoclonus (PERM), Batten’s disease,
and cerebellar ataxia.
2,7
SPS can also develop as a result of para-
neoplasia. Although there are rare reports
of paraneoplastic GAD
+
SPS,
11
most para-
neoplastic presentations of the condition are
associated with antibodies to the synaptic
vesicle protein amphiphysin, and occur in
patients with breast cancer.
12
In contrast to
GAD
+
SPS, lumbar lordosis is not prominent
in patients with amphiphysin-associated SPS.
Amphiphysin antibodies, in combination with
other para neoplastic antibodies, have also
been implicated in syndromes such as lung-
cancer-associated encephalo myelitis with sensory
neuropathy.
13
Studies indicate that passive
transfer of amphiphysin antibodies induces
episodic stiffness, supporting a pathogenic role
for the antibodies.
14
DIFFERENTIAL DIAGNOSIS
In addition to GAD
+
SPS and other variants of
SPS, the differential diagnosis for severe back
spasms includes infectious, toxic, neoplastic,
vascular, genetic and autoimmune diseases
(Box 2).
2
Tetanus is an infection that can present as
fulminant trismus, with stiffness of the neck
and rigidity of the abdominal muscles.
15
It also
involves episodic spasms that last for several
minutes and can occur for a period of weeks.
Worldwide, tetanus causes over 800,000 deaths
per year—in the US, the annual incidence has
been reduced to less than 50 cases. Although the
spasms in the current patient partially resem-
bled tetanus, the long progressive history and
the exclusive involvement of the lumbar para-
spinal and lower limbs indicated that tetanus
was unlikely to be the cause. In addition,
almost all cases of tetanus occur in individuals
who have never received a tetanus vaccination
or who have not received a tetanus vaccine
booster in many decades. In a manner similar
to tetanus, strychnine poisoning can also cause
acute muscle spasms and back arching.
Neoplastic lesions that invade or compress
the paraspinal muscles and nerves can trigger
episodic muscle spasms and pain. An MRI scan
with and without contrast of the spine, and a
CT scan with oral and intravenous contrast of
the abdomen and pelvis can help to eliminate
this possibility. Inflammatory diseases that affect
the spine such as multiple sclerosis and myelitis
can induce painful back spasms—the presence
of normal cerebrospinal fluid and normal spinal
imaging, however, can help to eliminate these
etiologies. Spinal vascular malformations and
venous occlusion can also induce back pain
and spasms with either an acute or episodic
presentation. Typically, neurological signs and
symptoms suggestive of a spinal cord infarction
or compression will also be present on clinical
examination of the patient. Vascular abnormali-
ties can be revealed by an MRI scan, although a
spinal angiogram might also be necessary.
Hereditary hyperekplexia is characterized
by episodic spasms and generalized stiffness
triggered by emotional upset.
16
In a manner
similar to SPS, hyperekplexia
can lead to an
awkward, hesitating gait and anxiety. The most
common form occurs as the result of an auto-
somal dominant mutation in the gene coding
for a subunit of the glycine receptor. The disease
usually presents in infancy, although late-onset
Box 2 Differential diagnosis for severe
back spasms.
Infectious disease
Tetanus
Toxic disease
Strychnine poisoning
Neoplastic disease
Mass effect causing irritation to spinal nerves or
paraspinal muscles
Vascular disease
Spinal arteriovenous malformations
Intermittent venous congestion
Genetic disease
Hyperekplexia
Autoimmune disease
Isaacs’ syndrome
Spinal multiple sclerosis
Paraneoplasia
Myelitis
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variants have been described. Hyperekplexia
is not generally asso ciated with progressive
lumbar lordosis.
Finally, autoantibodies directed against
voltage-gated potassium channels can cause
acquired neuromyotonia or Isaacs’ syndrome,
17
with sweating, muscle cramps, and muscle
spasms involving the distal, proximal, and
cranial muscles. Axial muscles may also spasm,
resulting in abnormal posturing of the indi-
vidual. An EMG will demonstrate myokymic
and neuromyotonic discharges that are respon-
sive to neuromuscular blockade, but not to
centrally acting agents such as diazepam.
TREATMENT
Although benzodiazepines and baclofen provide
substantial symptomatic relief for patients with
SPS, treatment with these agents is limited by
adverse effects such as sedation, cognitive impair-
ment and short-term memory loss. Diazepam
and clonazepam are the most commonly used
benzodiazepines.
18
Diazepam can be titered in
divided doses ranging from 5–200 mg per day,
but most patients tolerate no more than 20–
40 mg per day. Many patients prefer clonazepam
in divided doses of between 2.5–18 mg per day.
Baclofen can be used alone or in conjunction
with a benzodiazepine, and divided doses ranging
from 5–60 mg per day should be increased grad-
ually. Carefully selected patients may benefit
from an intrathecal baclofen pump. Assuming
that the patient is able to tolerate these medica-
tions, they can all be continued indefinitely. It
should be stressed by the physician, however,
that abrupt cessation of benzodiazepines or
baclofen can cause life-threatening exacerbation
of symptoms.
Intravenous immunoglobulin has emerged
as an important therapy for GAD
+
SPS.
19
The
response to this treatment varies, but patients
can sustain improvement for up to 1 year. The
financial costs associated with intravenous
immunoglobulin treatment are substantial,
however, and these can limit the viability of the
treatment for patients. Plasmapheresis can also
lead to symptom remission when used in combi-
nation with steroids, but the benefits are short-
lived. Patients with amphiphysin-associated SPS
rarely respond to intravenous immunoglobulin,
although plasmapheresis followed by steroids
can be helpful. In these cases, the identification
and treatment of an underlying malignancy can
result in symptom remission.
CONCLUSION
The peculiar intermittent spasms, stimulus-
triggered falls, social phobia, and anxiety asso-
ciated with SPS can lead to the psychiatric referral
of patients displaying these symptoms rather
than to the correct diagnosis. Although SPS is
a rare syndrome, clinical awareness can lead to
accurate recognition, appropriate treatment,
and—if the patient has amphiphysin-associated
SPS—discovery of an unsuspected neoplasm.
References
1 Moersch FP and Woltman HW (1956) Progressive
fluctuating muscular rigidity and spasm (“stiff-man”
syndrome); report of a case and some observations in
13 other cases. Mayo Clin Proc 31: 421–427
2 Murinson BB (2004) Stiff-person syndrome.
Neurologist 10: 131–137
3 Murinson BB et al. (2004) Markedly elevated GAD
antibodies in SPS: effects of age and illness duration.
Neurology 63: 2146–2148
4 Ameli R et al. (2005) A neuropsychological assessment
of phobias in patients with stiff person syndrome.
Neurology 64: 1961–1963
5 Burns TM et al. (2003) Clinically disparate stiff-person
syndrome with GAD65 autoantibody in a father and
daughter. Neurology 61: 1291–1293
6 Dalakas MC et al. (2000) The clinical spectrum of
anti-GAD antibody-positive patients with stiff-person
syndrome. Neurology 55: 1531–1535
7 Meinck HM and Thompson PD (2002) Stiff man syndrome
and related conditions. Mov Disord 17: 853–866
8 Thomas S et al. (2005) Stiff person syndrome with
eye movement abnormality, myasthenia gravis, and
thymoma. J Neurol Neurosurg Psychiatry 76: 141–142
9 Solimena M et al. (1990) Autoantibodies to GABA-
ergic neurons and pancreatic beta cells in stiff-man
syndrome. N Engl J Med 322: 1555–1560
10 Raju R et al. (2005) Analysis of GAD65 autoantibodies
in Stiff-Person syndrome patients. J Immunol 175:
7755–7762
11 Schiff D et al. (2003) Anti-GAD antibody positive stiff-
limb syndrome in multiple myeloma. J Neurooncol 65:
173–175
12 Rosin L et al. (1998) Stiff-man syndrome in a woman
with breast cancer: an uncommon central nervous
system paraneoplastic syndrome. Neurology 50: 94–98
13 Saiz A et al. (1999) Anti-amphiphysin I antibodies in
patients with paraneoplastic neurological disorders
associated with small cell lung carcinoma. J Neurol
Neurosurg Psychiatry 66: 214–217
14 Sommer C et al. (2005) Paraneoplastic stiff-person
syndrome: passive transfer to rats by means of IgG
antibodies to amphiphysin. Lancet 365: 1406–1411
15 Rhee P et al. (2005) Tetanus and trauma: a review and
recommendations. J Trauma 58: 1082–1088
16 Khasani S et al. (2004) Hyperekplexia and stiff-man
syndrome: abnormal brainstem reflexes suggest
a physiological relationship. J Neurol Neurosurg
Psychiatry 75: 1265–1269
17 Arimura K et al. (2002) Isaacs’ syndrome as a
potassium channelopathy of the nerve. Muscle Nerve
(Suppl 11): S55–S58
18 Vasconcelos OM and Dalakas MC (2003) Stiff-person
syndrome. Curr Treat Options Neurol 5: 79–90
19 Dalakas MC (2005) The role of IVIg in the treatment
of patients with stiff person syndrome and other
neurological diseases associated with anti-GAD
antibodies. J Neurol 252 (Suppl 1): I19–I25
Competing interests
The authors declared
they have no competing
interests.
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