r e v c o l o m b r e u m a t o l . 2 0 2 0;2 7(2):130–134
www.elsevier.es/rcreuma
Case report
Stiff person syndrome, clinical case presentation
and treatment update夽
Fernando González Trujillo a,∗ , Karen Parra Cortes b , Guillermo Barrios Arrazola c ,
Juan Guillermo Zapata Jaramillo d
a
Neurología Clínica, Centro Integral del Cáncer, Clínica de Occidente, Santiago de Cali, Colombia
Departamento de Investigación y Educación, Fundación Universitaria San Martín, Clínica de Occidente, Santiago de Cali, Colombia
c Neurología Clínica, Clínica de Occidente, Santiago de Cali, Colombia
d Medicina Física y Rehabilitación, Clínica de Occidente, Santiago de Cali, Colombia
b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Stiff person syndrome affects the central nervous system. Relevant clinical signs are stiff-
Received 21 October 2018
ness, muscle spasms, increased sensitivity with external stimuli that increase muscle
Accepted 25 February 2019
contractions. Women are affected twice to three times more, in comparation with the
Available online 7 June 2020
men. There are characteristic clinical and electrophysiological type markers. The etiology is
associated with mediation by antibodies and may be the expression of a paraneoplastic syn-
Keywords:
drome. Pharmacological treatment is focused on muscle relaxant-type medications, drugs
Syndrome
with immunomodulatory or immunosuppressive mechanism. In addition, complementary
Stiff person
rehabilitation treatment is required.
Antibodies
Paraneoplastic
Immunotherapy
The purpose of the group is to make the description of the clinical case that is relevant
due to the low frequency of presentation and to carry out an update of the topic.
© 2020 Published by Elsevier España, S.L.U. on behalf of Asociación Colombiana de
Reumatologı́a.
Plasmapheresis
Síndrome de persona rígida, presentación de un caso clínico y actualidad
en el tratamiento
r e s u m e n
Palabras clave:
El síndrome de persona rígida afecta el sistema nervioso central. Los signos clínicos rele-
Síndrome
vantes son la rigidez, los espasmos musculares y sensibilidad incrementada a los estímulos
Persona rígida
externos, que inducen las contracciones musculares. Las mujeres son afectadas de 2 a 3
Anticuerpos
veces más con relación a los hombres. Hay marcadores de tipo clínico y electrofisiológico car-
Paraneoplásico
acterísticos. La etiología se asocia con la mediación por anticuerpos y puede ser la expresión
PII of original article: S0121-8123(19)30044-1
夽
Please cite this article as: González Trujillo F, Parra Cortes K, Barrios Arrazola G, Zapata Jaramillo JG. Síndrome de persona rígida,
presentación de un caso clínico y actualidad en el tratamiento. Rev Colomb Reumatol. 2020;27:130–134.
∗
Corresponding author.
E-mail address: fernando.gonzaleztrujillo@gmail.com (F. González Trujillo).
2444-4405/© 2020 Published by Elsevier España, S.L.U. on behalf of Asociación Colombiana de Reumatologı́a.
r e v c o l o m b r e u m a t o l . 2 0 2 0;2 7(2):130–134
131
Inmunoterapia
de un síndrome paraneoplásico. El tratamiento farmacológico se realiza con medicamentos
Plasmaféresis
relajantes musculares y medicamentos con mecanismo inmunomodulador o inmunosupresor. Adicionalmente, se requiere un plan complementario de rehabilitación.
El propósito del grupo es hacer una descripción del caso clínico, que consideramos es
relevante por su baja frecuencia de presentación y realizar una actualización sobre el tema.
© 2020 Publicado por Elsevier España, S.L.U. en nombre de Asociación Colombiana de
Reumatologı́a.
Introduction
The stiff person syndrome (SPS) is a disease affecting the
central nervous system and manifests with stiffness, muscle
spasms, and increased sensitivity to external stimuli that further deteriorate the contractions. There are distinctive clinical
and electrophysiological markers such as the simultaneous
contraction of agonistic and antagonistic muscles, the involuntary and continuous motor unit firing at rest.1–4
The reports submitted indicate a prevalence of 1–2 cases
per million per year. The mean age at presentation varies
between 20 and 50 years, women are more frequently affected
in a proportion of 2–3 times more than men.3,4
The goal is to make a clinical case description that we feel
is relevant on account of the low frequency of presentation
and do an update on the topic.
Clinical case
This is a female patient who presented with varying symptomatology back in 2012, including “electric shock” type pain
in the extremities, in addition to involuntary facial movements, difficulty to articulate words, distal weakness of the
lower limbs associated to stiffness, focal painful muscle
contractions of several muscle groups that worsened with
environmental stimuli; subsequently, the effect became generalized up to the development of lack of motor coordination,
slow gait, and marked feeling of fatigue. The physical examination revealed severe dysarthria, hypotonic tongue with
limited protrusion, head tremor, bilateral dysmetria and ataxic
gait. In accordance with the presentation of the clinical characteristics, a probable diagnosis of SPS was considered, and
hence the relevant tests were prescribed in order to elucidate
the potential etiology (Table 1). The metabolic profile tests, as
well as infection screening, nutritional, occult neoplasm and
immunology analyses were all reported as normal. The presence of anti-glutamic acid decarboxylase antibody (GAD) was
specifically screened for, and the report was negative.
The comprehensive management of the patient included
symptomatic pharmacological therapy with buspirone,
levodopa–carbidopa, pregabalin and a rehabilitation plan
with speech therapy for improving swallowing and voice,
physical therapy with emphasis on hydrotherapy for improved
mobility and independence.
The 2-year follow-up showed a progressive loss of independence to carry out the activities of daily living and increased
compromise of gait, which required the prescription of a
wheel chair. By the year 2017 the clinical condition further deteriorated and the patient had to be permanently
assisted to conduct the basic activities of daily living until
she was finally hospitalized. On this occasion, the physical
examination revealed an alert patient, with severe dysarthria
and naming difficulty; the patient could not hold her head
up or keep her balance in the sitting position. The muscle examination revealed exacerbated myotendinous reflexes,
hypertrophic hypertonic muscle groups, with involuntary contractions, sustained muscle spasms and extreme difficulty for
relaxation, causing significant pain.
The case was studied by the group of treating physicians,
with the following findings:
1. A constant and slowly progressive evolution throughout
the years of the disease, progressing toward functional disability.
2. The clinic showed stiffness, generalized and painful muscle spasms exacerbated by environmental impacts.
3. The electrodiagnostic studies recorded continuous involuntary activity, with no evidence of peripheral nervous
system involvement.
4. Absence of cachexia or any other signs of malnutrition.
5. The haemato-oncology team conducted paraclinical extension studies for occult neoplasms, including bone marrow
biopsy, flow cytometry for immature forms of lymphocytes which was negative; the immunoglobulin serum
levels measured were normal, making it unlikely to diagnose cancer or paraneoplastic syndrome. Consequently,
the antineuronal autoantibodies profile was not considered
a requirement.
The conclusion was that the clinical condition of the
patient was probably consistent with SPS of probable autoimmune etiology.
The studies were updated (Table 2) and the etiological
therapy suggested was plasmapheresis and complementary
symptomatic treatment with baclofen. The patient remained
hospitalized until completion of 10 plasmaphereses, evidencing a clinical improvement after the seventh exchange
procedure. This improvement materialized as a reduction in
dysarthria, less muscle spasms and improved muscle tone,
which improved the patient’s mobility and trunk control.
Additionally, low vitamin-D levels were documented, but
despite supplementation, there was no evidence of improvement in muscle stiffness upon normalization of the vitamin-D
levels. The patient was discharged with pharmacological
therapy based on baclofen, buspirone, levodopa–carbidopa,
pregabalin, vitamin-D and a rehabilitation program with
132
r e v c o l o m b r e u m a t o l . 2 0 2 0;2 7(2):130–134
Table 1 – Extension studies.
Cerebral
Brain spectroscopy
Spine
Functional language
Electroencephalogram
Echocardiogram
Repetitive muscular
stimulation test
4 extremities nerve conduction
studies
Small hypersensitivity areas with non-specific white matter punctiform signals.
Spectral pattern alteration identified, with increased concentrations of glycine or myoinositol found on
the same spectral position (3.56) at the level of the right basal ganglion, with no further abnormalities in
the spectral patterns or in the relationships of the metabolites assessed.
Mild osteochondritis-type changes in the cervical spine, central osteophyte at C3–C4 which partially
obliterates the anterior subarachnoid space; additional findings were identified at the level of T7–T8 and
T8–T9.
Left language dominance with very mild activation with different types of paradigms. Presence of motor
activation of the tongue usually localized in the bilateral precentral gyrus. No alterations of the tracts
studied and the t1 volume study did not show any evidence of atrophic changes.
Normal
Normal
With no electrophysiological evidence of presynaptic or postsynaptic disorder of the neuromuscular
junction.
Motor and sensitive nerve conduction in the 4 extremities (medial, ulnar, tibial, fibular and sural)
resulting in latencies, amplitudes and conduction velocities within the normal limits.
Table 2 – Electromyography.
Side
Muscle
Nerve
Root
Right
Right
Right
Right
Right
Right
Right
Right
Left
Left
Left
Left
First dorsal interosseous
Abductor pollicis brevis
Biceps
Triceps
Tibial anterior
Gastrocnemius
Rectus femoris
Femoral biceps
Tibialis anterior
Gastrocnemius
Recto femoral
Femoral Biceps
Ulnar
Median
Cutaneous muscle
Radial
Dp Br peroneal
Tibial
Femoral
Sciatic
Dp Br peroneal
Tibial
Femoral
Sciatic
C8-T1
C8-T1
C5-6
C6-7-8
L4-5
S1-2
L2-4
L5-S1
L4-5
S1-2
L2-4
L5-S1
Recruitment
Pattern of interference
Reduced
Reduced
Normal
Normal
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
50%
25%
75%
Normal
25%
25%
50%
50%
50%
25%
50%
50%
The needle electromyography showed sustained, irregular and paroxysmal involuntary muscle activity of multiple muscle groups with impossibility to accomplish rest or absolute relaxation, with absent signs of membrane instability and of neuromyotonic discharges.
Bold letter: highlights the abnormal findings of the electromyography study.
speech therapy for improving swallowing, and dysarthria, and
to improve the patient’s ability to communicate. Additionally, she was prescribed physical and occupational therapy to
maintain the articular rage of movement, modulate muscle
tone, improve balance, coordination and motor control.
Finally, the decision was made to discontinue plasmapheresis and continue outpatient treatment with rituximab.
This decision was supported by the positive reports discussed
in the medical literature, the easy dosing and administration
of the product. The patient was administered an IV infusion
with 1000 mg and an additional dose after 15 days. The regimen was repeated over the next 4 months, and in total she
has received 3 cycles. Clinical follow-up was conducted. In
contrast to the clinical condition reported in 2017, the patient
improved in terms of the intensity of the axial and cervical
muscle spasms that caused significant dysphagia, the sitting balance and independence in daily life activities also
improved, and she was able to move around with a walker
and therefore she now enjoys a better quality of life.
Discussion
The etiology of SPS is associated with antibody mediation that,
when combined with antigens, result in functional block of
the neuronal synapses – in the brain and spinal cord – that
use gamma aminobutyric acid (GABA)1 as neurotransmitter.
The best reported antibodies are: anti-GAD antibodies – glutamic acid decarboxylase (GAD) autoantibody – antiglycine
alfa 1 (anti-GlyR) antibodies, antianphiphysin antibodies and
gephyrin.1 The synthesis to produce GABA has 2 isoforms: the
antibody formation against the GAD65 isoform which is the
most frequently reported in patients with SPS, localized in the
presynaptic terminal and anchors in a reversible manner onto
the membranous synaptic vesicles. The pathogenic effect of
the anti-GAD65 antibodies is uncertain, due to the intracellular localization of the antigen which hinders antibody action
and expresses with different clinical syndromes.1–3 The antiGAD antibodies are not specific for SPS, since up to 1% of the
normal population assessed expresses them, are positive in up
to 5% in different neurological syndromes such as: cerebellar
ataxia, limbic encephalitis with myoclonus and temporal lobe
epilepsy.1,2 The clinical severity of the disease is unrelated to
the level of antibody titers measured in serum and in the CSF;
there are reports of patients who develop a severe disease with
low titers and vice versa, whilst others who have the disease
have negative serum titers.1,5
Antianphiphysine and anti-gephyrin antibodies – synaptic proteins – are expressed in paraneoplastic syndromes
associated with breast and ovarian tumors, small-cell lung
r e v c o l o m b r e u m a t o l . 2 0 2 0;2 7(2):130–134
cancer, renal cell carcinoma, thyroid carcinoma, colon
cancer, thymoma, Hodgkin’s and non-Hodgkin lymphoma,
colangiocarcinoma.1,3 In SPS, as in the paraneoplastic syndromes, a defective endocytosis of the transmitter develops
caused by the antibody.1 In the case of SPS in cancer patients,
a direct pathological mechanism of the antibodies is suggested, which was shown in laboratory experiments with
mice that were infused with specific antianphyphysine antibodies, which developed a clinical syndrome, with abnormal
electromyography studies and positive central nervous system antibodies.1 T and B-cells involvement is not clear. The
assumption is that the microglial cells and B-cells function as
T-lymphocyte antigen presenting cells (GAD65 antigen), hence
perpetuating their impact on the central nervous system, and
B-cells are linked to the generation of oligoclonal populations
of antibodies.3,5
Genetically speaking, different genes of the major histocompatibility complex (MHC) are expressed in SPS –
particularly the DQB1*0201 and DRB1 alleles of CMH II.1,3
The clinical presentation of the disease was classified in
subtypes, as follows3,4,6 :
Classical type SPS
SPS variants
Focal o segmented
SPS with spasms
Variant of progressive encephalomyelitis with stiffness and
myoclonus.
• SPS with ataxia, epilepsy, etc.
• Paraneoplastic variant
•
•
•
•
•
The progressive encephalomyelitis variant with stiffness
and myoclonus, affects people between 50 and 60 years old,
with an insidious onset and evolution with a pattern of remission and relapse; there is brain stem dysfunction, signs of
dysautonomia, and is related to anti-glycine alfa 1r (anti-GlyR)
antibodies.3
For the SPS diagnosis – classical variant – the criteria submitted are3,6–8 :
• Inexpressive facies with stiffness of the axial muscles and
extremities, predominantly in the abdominal and thoracolumbar paravertebral muscles which cause a constant
hyperlordosis-like deformity, with difficult breathing due to
the involvement of the thoracic muscles.
• Painful muscle spasms caused by environmental stimuli
such as noise, emotional and tactile stresses. The spasms
are intermittent and similar to those present in tetany, last
several minutes and may result in bone fractures or joint
dislocations.
• The electromyogram shows continuous motor activity in
the agonistic and antagonistic muscles.
• Compromise due to other neurological diseases should be
ruled out.
• Positive anti-GAD65 or antianphiphysine serum antibodies.
• Clinical improvement with benzodiazepines.
Fatigue in patients can be accounted for by the presynaptic
defect at the neuromuscular junction as shown by electrophysiological studies.9
133
SPA should be differentiated from pathologies compromising both the pyramidal and the extra-pyramidal
system, for instance: anti-N-methyl-d-aspartate (NMDA)
receptor encephalitis, limbic encephalitis, refractory epilepsy,
myelopathies, dystonia, spinocerebellar degeneration, primary lateral sclerosis, neuromyotonia, tetanus, myasthenia
gravis, type I diabetes (in 35% of the cases coexists with the
syndrome), autoimmune thyroiditis, Graves’ disease, polyendocrine autoimmune syndrome, vitiligo, retinopathy and
autoimmune scleritis, lupus, pernicious anemia and celiac
disease.1–3
The diagnostic methods include brain and spinal cord
MRI, electromyography with the above described findings and
electroencephalograms.1–4 A complete test screening should
be conducted to cover the above-mentioned broad differential
spectrum. In case of patients suspicious of the paraneoplastic variant, the Anti-Ma, Anti-Yo, Anti-Hu, antianphiphysine
and gephyrin paraneoplastic antibodies shall be measured, as
well as the anti-acetylcholine receptor, anti-glycine receptor,
anti-GABA receptor, anti-GAD receptor.10
The treatment is addressed in accordance with the positivity of the antibody identified as positive; there is evidence
of patients with positive antibodies against the GABA receptor
which respond better to immunoglobulin. The anphiphysine
positive patients respond better to steroids, plasmapheresis, and primary cancer treatment; the anti-GAD positive
responded well to immunoglobulins, diazepam, clonazepam,
whilst the anti-GlyR alfa 1 positives have improved results
with immunotherapies.8
With regards to the SPS pathogenesis, the following therapies are available3,4,7 :
• GABAergic medications: benzodiazepines, botulin toxin,
intrathecal baclofen with average results. In order to modulate symptoms, other options such as gabapentin, tiagabine,
valproate, levetiracetam, are suggested.7,8
• Medications with immunomodulatory o immunosuppressive effects. The best reports include:
◦ Prednisone.
◦ Plasmapheresis: Dra. Pagano et al. reported their
experience with a group of 9 patients treated with
plasmapheresis who had worsened with first line therapies; 78% reported a mild clinical improvement and 56%
experienced a significant improvement, with good tolerance to treatment. The study by Johns Hopkins Institute
found positive results with plasmapheresis in 56% of the
patients included; other papers report that therapy is well
tolerated with just 4–75% of adverse events.7,8
◦ Intravenous immunoglobulin: the European Federation
of Neurological Societies indicated its administration in
case of non-responders to first line therapies, at a dose of
2 g/kg weight; a significant improvement of stiffness and
a reduction of GAD autoantibodies were reported.8
◦ Monoclonal antibodies against B type receptor cd20+
lymphocyte cells, such as rituximab. The trials so
far conducted emphasize good tolerance, long clinical
remissions with improved spasms and muscle stiffness; however, the titers of circulating antibodies drop
and the overall benefit is poor, probably on account
of the antibody-mediated resistance mechanisms, the
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T-cells mediated immune activity rather than mediated
by B-cells or auto-antibodies. Doses ranging from 350 to
375 mg–m2 are administered every 7–14 days, or weekly,
for 4 weeks.8 In GAD+ cases experiencing relapses, additional doses between months 6–8 of the initial infusion
have been reported to be beneficial.1,5,8
Pregnant patients with SPS should avoid benzodiazepine
therapy during the first trimester because of the risk of teratogenicity; the use of baclofen is preferred. Benzodiazepines
may be administered during the last trimesters, monitoring
the risk of sedation, respiratory depression and fetal hypotony.
Labor may be assisted with regional anesthesia and pain
should be under control to avoid muscle spasms. There is
no consensus in terms of the route of delivery – vaginal or
cesarean section.11
Conclusion
The SPS is an infrequent condition with a broad range of differential diagnoses; comprehensive screening tests shall be
performed, assessing the presence of antibodies to establish
differences between a primary or secondary immune event
associated with a paraneoplastic syndrome.
The treatment comprises symptomatic management and
should include regimens with immunosuppressors and
immunomodulators.
The clinical case herein discussed was considered to be
relevant for publication on account of the low frequency of
occurrence of this pathology, and in order to highlight the good
clinical response and conspicuous quality of life improvement
of the patient with plasmapheresis and monoclonal antibody
treatment with rituximab.
Financing
No financial contributions were received.
Conflict of interests
None declared.
Acknowledgements
We would like to acknowledge Dr. Jorge Karim Assis, director of the Department of Research and Education, Clínica de
Occidente S.A., and his team, for allowing us access to the
institutional medical records in order to conduct this study.
Likewise, we acknowledge Prof. Adriana P. Henao Galindo,
copy editor, for her contribution in reviewing this article.
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