Cureus 0012 00000011995

Download as pdf or txt
Download as pdf or txt
You are on page 1of 9

Open Access Review

Article DOI: 10.7759/cureus.11995

Stiff-Person Syndrome: A Treatment Update and


New Directions
Juan Fernando Ortiz 1 , Mohammad R. Ghani 1 , Álvaro Morillo Cox 2 , Willians Tambo 3 , Farah Bashir 4 ,
Martín Wirth 3 , Gustavo Moya 5

1. Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA 2. Medicine, Universidad
San Francisco de Quito, Quito, ECU 3. Neurology, Universidad San Francisco de Quito, Quito, ECU 4. Internal Medicine,
Liaquat University of Medical and Health Sciences, Jamshoro, PAK 5. Medicine, Carlos Andrade Marín Hospital, Quito,
ECU

Corresponding author: Juan Fernando Ortiz, sumjuanfer41@gmail.com

Abstract
Stiff-person syndrome (SPS) is a rare and disabling central nervous system disorder with no satisfactory
treatment. Muscle rigidity, sporadic muscle spasms, and chronic muscle pain characterize SPS. SPS is
strongly correlated with autoimmune diseases, and it is usual to find high titers of antibodies against acid
decarboxylase (GAD65). Due to its highly disabling nature and complicated treatment, we aim to create a
treatment protocol through a narrative review of currently available treatments that show efficacy. We
expect to facilitate management based on treatment responses ranging from first-line medication to
refractory medication. We conducted a medical subject heading (MeSH) strategy. We used the term SPS with
the subheading treatment: "Stiff-Person Syndrome/Therapy" [MeSH]. An initial data gathering of 270 papers
came out with the initial research. After using the inclusion criteria, we had 159 articles. We excluded 31
papers for being either systematic reviews, literature reviews, or meta-analysis. From the 128 remaining
articles, we excluded another 104 papers because the extraction of the data was not possible or the study
outcome did not meet our demands. There are two main treatments for SPS: GABAergic (gamma-
aminobutyric acid) therapy and immunotherapy. For treatment, we suggest starting with benzodiazepines
as first-line treatment. We recommend adding levetiracetam or pregabalin if symptoms persist. As second-
line therapy, we recommend oral baclofen over rituximab and tacrolimus. We also suggest rituximab over
tacrolimus. For patients with refractory treatment, we can use intrathecal baclofen, intravenous
immunoglobulin (IVIG), or plasmapheresis. We conclude that intrathecal baclofen and IVIG are more
effective than plasmapheresis in patients with refractory symptoms. Propofol may be used as a bridge -
temporary therapy before initiating a permanent treatment.

Categories: Anesthesiology, Neurology, Pain Management


Keywords: stiff-person syndrome, stiff-limb syndrome

Introduction And Background


Received 11/09/2020
Review began 11/21/2020 Stiff-person syndrome (SPS) is a progressive central nervous system disorder with a prevalence of one to two
Review ended 11/23/2020 patients per million. The disease affects women two to three times more than men [1]. SMP presents with
Published 12/09/2020 muscle rigidity, which starts in the proximal muscles and progresses distally. Patients have recurrent falls,
© Copyright 2020 muscle spasms, and chronic muscle pain [1]. The stiffness is due to the coactivation of agonist and
Ortiz et al. This is an open access article antagonist muscles. It principally occurs in abdominal and paraspinal muscles producing rigidity, lumbar
distributed under the terms of the hyperlordosis, and postural instability. Postural instability in these patients causes recurrent falls, as
Creative Commons Attribution License
mentioned before. The disease progression can also lead to limb rigidity, which can make walking incredibly
CC-BY 4.0., which permits unrestricted
use, distribution, and reproduction in any
tricky and, in some cases, can hinder walking completely. Psychiatric symptoms such as depression and
medium, provided the original author and anxiety often accompany the disorder and can be misdiagnosed as a psychiatric illness [2]. Other
source are credited. neurological symptoms include horizontal and vertical supranuclear gaze palsy, nystagmus, increased
reflexes, and paroxysmal dysautonomic crisis [1].

We can divide SPS into III categories: type I, associated with other autoimmune conditions and usually GAD-
positive; type 2, paraneoplastic, anti-amphiphysin-positive most of the time; and type 3, seronegative SPS,
which is mainly idiopathic [2]. The etiology of SPS has an apparent autoimmune root, but its pathogenesis is
not completely clear. It is generally associated with antibodies against glutamic acid decarboxylase (GAD)
and antibodies against gephyrin, the glycine-alpha1 receptor, or gamma-aminobutyric acid (GABA)
receptor-associated protein [3]. Lack of signals dependent on GABA causes rigidity and stiffness of the
truncal muscles and increases sensitivity to touch or noise. Other autoimmune disorders can be diagnosed,
such as Type 1 diabetes and Hashimoto’s thyroiditis, due to its autoimmune basis. In contrast,
paraneoplastic SPS is generally linked to anti-amphiphysin antibodies and is associated with malignant
tumors of the lung, thymus, breast, and lymphoma [3].

Diagnosing SPS requires a high index of suspicion. Nevertheless, there are no accepted criteria at the
moment. The significant features that increased the suspicion of fear are the following:

How to cite this article


Ortiz J, Ghani M R, Morillo Cox Á, et al. (December 09, 2020) Stiff-Person Syndrome: A Treatment Update and New Directions. Cureus 12(12):
e11995. DOI 10.7759/cureus.11995
1. Stiffness in the limb and axial muscles, which results in the impairment of ambulation.

2. Presence of spasms that are precipitated by movements, noises, or emotional upset.

3. Positive response to diazepam.

4. Continuous motor unit activity on electromyography (EMG), which is suppressed with diazepam.

5. Lack of other neurological signs that point out another diagnosis [4].

Significant advances have been developed in diagnosing and understanding SPS. Nevertheless, the
treatment of SPS has not been clearly established, and physicians struggle to treat this condition. Because
the prognosis of SPS can be devastating, it is important to establish a correct treatment protocol [4]. We
conduct a narrative review of the treatment of SPS to establish a treatment protocol (first-line medication,
second-line medication, refractory medication, and so on). The effectiveness and the physiological
explanation of each treatment of SPS are discussed in this article.

Review
Methods
For gathering information for this paper, we conducted a medical subject heading (MeSH) strategy. We use
the term SPS with the subheading treatment: "Stiff-Person Syndrome/Therapy" [MeSH]. An initial data
gathering of 270 papers came out with the initial research. For inclusion criteria, we used the following
criteria:

- Papers published in English

- Papers published in the last 20 years

- Full-text papers

- Studies conducted only on humans

For exclusion criteria, we used the following criteria:

- The following types of studies were excluded: systematic reviews, literature reviews, and meta-analysis
were not used.

- Papers in which data extraction was not possible.

- Publications that did not meet our study outcomes.

Results
An overview is given in Table 1 with the number of papers after applying the inclusion and exclusion criteria
in the following order.

Number of Papers

Initial gathering of information 270

Studies published in English 213

Studies conducted on humans 212

Papers published in the last 20 years 170

Use of full-text papers 159

TABLE 1: Data extraction after using the inclusion and exclusion criteria

After using the inclusion criteria, we had 159 papers. We excluded 31 papers for being either systematic
reviews, literature reviews, or meta-analysis. From the 128 remaining papers, we excluded another 104
papers because the extraction of the data was not possible, or the study outcome did not meet our demands.

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 2 of 9


Discussion
We divide the discussion into two sections regarding the treatment of SPS. In the first section, we discussed
GABAergic therapy with the following drugs: benzodiazepines, levetiracetam (LEV), gabapentin, propofol,
and baclofen. In the second section, we discuss immunotherapy with the following drugs: rituximab,
tacrolimus, intravenous immunoglobulin (IVIG), and plasmapheresis.

GABAergic therapy
Benzodiazepines

Antibodies attack GAD enzyme, which is essential in GABA manufacturing, a neurotransmitter for muscle
movement control. The attack on GAD decreases GABA [5]. Benzodiazepine (such as diazepam and
clonazepam) is a psychoactive drug that enhances GABA neurotransmitter's effect at the GABA receptor in
enhancing inhibitory circuits. The drug has been used as sedative, muscle relaxant, and anticonvulsant [6].
Patients with classic or partial SMS and GAD-65-positive antibody have shown improvement in stiffness
and spasm symptoms with long-term benzodiazepine treatment. However, this change cannot solely be
attributed to monotherapy of benzodiazepine as adjunct medications were also commonly administered.
Currently, diazepam is the mainstay of therapy. Most of the patients respond well to diazepam. However, the
doses required for response are usually up to 60 mg daily [7]. A concern of benzodiazepine is the potential
for withdrawal from the long-term and high doses used. This has triggered the use of alternative therapy,
such as N-methyl-D-aspartate receptor (NMDAR) blocker therapy tizanidine. The main concern regarding
the treatment with diazepam is the sedation and somnolence. Tizanidine is an alpha 2 inhibitor that also
causes glutamate release inhibition, preventing glutamatergic hyperactivity, which can lead to convulsions
in SMS patients [5]. Management should also be individualized in practice based on patients’ symptoms [6].

Oral and Intrathecal Baclofen

As mentioned before, benzodiazepines are first-line treatment for a patient with SPS. Oral baclofen is a
second-line therapy in patients with SPS. Patients usually required high doses of both medications. Sedation
and respiratory depression are an important consideration for the treatment of both conditions [8].

We found four studies that evaluated the efficacy and role of intrathecal baclofen in SPS during our search.
We discovered that baclofen effectively treats SPS because being a direct agonist of GABA-B receptors does
not require endogenous GABA to produce presynaptic inhibition [9]. All the studies showed how intrathecal
baclofen (ITB) improved the patients’ clinical picture. In Table 2, the key findings from the included studies
for the treatment of stiff-man syndrome and baclofen are given [10].

Author and year of Study Diagnostic


Methodology Conclusion
publication design criteria

The patient was In this case report, the patient had a


The patient received an intrathecal initial baclofen
Case GAD (-) and had a continued positive therapeutic
Newton et al. (2013) [9] dose of 50 µg/d. Gradual titration to 150 µg/d was
Report history consistent effect with improved motor function
performed.
with SPS. at six months follow-up.

ITB is effective for medically


Nine patients that received ITB infusion at either intractable spasticity due to SPS. It
SPS patients
25 or 50 µgs were included. The outcome helps reducing oral medication
identified from the
Abbatemarco et al. Case measures used were pain numeric rating scale, doses. Patients improve their
IRB-approved
(2017) [8] Series spasm frequency scale, lower extremity modified quality of life and maintain
clinical registry of
Ashworth scale, and timed 25-feet walk. ambulation. Most patients, but not
ITB therapy.
Outcomes were assessed at six and 12 months. all, have a decrease in spasm
frequency.

Nerve conduction The patient was prescribed ITP (50


negative. mg). His symptoms dramatically
The patient was treated initially with oral
Case Electromyography improved. The stiffness was
Maramattom (2010) [10] diazepam, baclofen, and continuous infusion of
Report show sustain reduced. The doses of oral
diazepam. Nevertheless, symptoms persisted.
contraction. GAD medication were reduced. Ashworth
(+). scale change from five to two.

TABLE 2: Intrathecal baclofen


ITB, intrathecal baclofen; IRB, institutional review board; GAD, glutamic acid decarboxylase.

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 3 of 9


Levetiracetam

A clinical trial of LEV of three patients with an anti-GAD65 antibody level of 145 U/mL (normal < 1.0 U/mL)
was conducted. Two of the patients were on IVIG and diazepam 15 mg daily, which led to an improvement in
reducing the axial rigidity. However, the frequency of hypoxemic respiratory arrest attacks remained
unchanged in the first patient. The second patient was on immunotherapy with IVIG, plasmapheresis, and
diazepam (orally) 15 mg daily. The patient had partially eased the stiffness that improved with walking.
However, on admission to the hospital, the patient showed residual motor deficits and found it very difficult
to climb the stairs. The third patient with SPS had no treatment [11].

All the patients were treated with oral LEV of 500 mg twice daily. All patients had an improvement in axial
rigidity and disappearance of the paroxysmal respiratory arrests within three days after starting therapy. A
similar improvement was noted in the other two patients with a marked reduction in legs' stiffness and
difficulty walking. On LEV treatment, all patients improved as assessed by all outcome measures. In
particular, at EMG recordings, patients relaxed their musculature better [11].

In two of the patients being treated for one week with LEV, they were switched to placebo, which led to
rigidity becoming worse, and paroxysms of respiratory arrest reappeared. In the third patient, the placebo
was tried twice daily for 12 hours for one week before treating the patient with LEV, which led to no
significant benefit.

LEV was well-tolerated. Patient with SPS could improve their muscle stiffness and paroxysmal respiratory
spasms with LEV. Nevertheless, long-term therapy has not been documented. The mechanism involves the
effect of LEV on SPS, which is mainly unknown. It is proposed that LEV stabilizes and strengthens GABA-A
action. Also, LEV decreases the hyperexcitability in spinal cord neurons [11].

Pregabalin

In a case report, pregabalin improved the symptoms of a 71-year-old woman with marked stiffness of trunk
and lower limb muscles with sudden, painful spasms for eight months. She was taking diazepam, but it was
withdrawn because of excessive sedation. She had intense back pain. To relieve lumbar pain, she was
prescribed pregabalin (75 mg, twice a day). The day after, rigidity and painful spasms dramatically improved,
and she could walk without assistance. At three months follow-up, she still reported the improvement on
rigidity and spasms; gait and osteotendinous reflexes were normal, and there were bilateral flexor plantar
responses [12].

The clinical benefit was paralleled by a significant decrease in continuous motor unit activity at the EMG.
Transcranial magnetic stimulation (TMS) studies in SPS demonstrated decreased intracortical inhibition
consistent with GABA-A and GABA-B impaired transmission and increased intracortical facilitation,
compatible with an enhancement of glutamatergic transmission [12].

The proposed mechanism of the action of pregabalin is inhibition of calcium influx and subsequent release
of excitatory neurotransmitters, including glutamate and norepinephrine. As a possible mechanism of action
in SPS, pregabalin might have compensated for the imbalance between inhibitory and excitatory
intracortical circuits. The prolongation of the GABA-B supports this hypothesis-mediated cortical silent
period (CSP) after pregabalin introduction. Interestingly, similar to osteotendinous reflexes, plantar
responses were normalized after three months of treatment. One possible explanation of inverted plantar
responses is that pregabalin might have reduced pathological enhancement of exteroceptive reflexes by
supraspinal modulation of GABAergic transmission [12].

Propofol

In a case report, a patient with severe symptoms was taking high-dose benzodiazepines, baclofen,
corticosteroids, LEV, IVIG, and IV ethanol. Nevertheless, the symptoms persist. After that, the patient
received a small dose of propofol, which surprisingly improves the patient's symptoms. We also documented
a patient with stiff-limb syndrome (a variant of SPS) with refractory therapy who responded well to
propofol [13].

The mechanism by which propofol interacts in the nervous system is not entirely understood. Nevertheless,
it is suggested that it might be related to increased GABAergic activity in the brain [13]. As it is unrealistic to
have a patient with a long-term therapy to propofol, the authors suggest that propofol could be used as a
bridge therapy to a more permanent intervention in patients with SPS [14].

Immunotherapy
Rituximab

It is known that more than 80% of SPS patients have elevated titer antibodies against glutamic acid

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 4 of 9


decarboxylase (GAD-65), and up to 15% have antibodies to glycine receptor α-subunit. The causative link
between SPS and these antibodies is uncertain, but they may be involved in the disease's
pathophysiology [15].

As the B cells are the producers of antibodies, it is reasonable to use drugs that affect their function.
Rituximab is a genetically engineered monoclonal antibody directed against CD20, which causes a sustained
depletion of B cells and has demonstrated promising results in several autoimmune neurological
diseases [15]. Accordingly, we found four articles that used rituximab in patients with SPS. Two of them
were case reports: one was a letter to the editors, while the other was a double-blind, placebo-controlled
trial. In Table 3, we summarized the characteristics of the studies mentioned [15-18].

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 5 of 9


Author and
Study
publication Methodology Conclusion
design
year

A total of 24 patients with confirmed SPS fulfilling established diagnostic


criteria were enrolled. They were randomized to receive two bi-weekly This controlled trial, defined as the
Placebo-
Dalakas et infusions of 1 gram of rituximab or placebo (normal saline solution) while largest conducted in SPS patients,
controlled
al. being allowed to continue receiving non-immunosuppressive drugs. The showed no statistically significant
randomized
(2017) [15] primary outcome was a change in stiffness scores at six months, and difference in the efficacy measures
trial
secondary outcomes were changes in heightened sensitivity and quality of between rituximab and placebo.
life scores.

A 56-year-old male with a history of type 1 diabetes, hyperthyroidism, Rituximab improved the clinical
hypertension, SPS, and progressive stiffness and painful spasms on his condition, but anti-GAD was reduced
limbs and axial region. He took levetiracetam 500 mg bd, gabapentin 1,200 considerably after one year of
mg tds, and diazepam 10 mg tds as a symptomatic treatment for SPS. treatment (400 U/ml). Previous reports
Weeks before admission to the hospital, he presented worsening of axial suggested a beneficial response to
Qureshi muscular spasms, anxiety attacks, generalized weakness, anorexia, and immunosuppressive therapy in
and Letter to weight loss. On the day of admission, he had a Glasgow Coma Scale score patients with severe disease
Hennessy the editors of 6/15 and was intubated because of respiratory failure. He also received unresponsive to benzodiazepines
(2012) [16] propofol and lorazepam. CSF demonstrated the presence of oligoclonal and/or baclofen. Lymphocyte B
bands. Anti-GAD antibodies were positive with high titers > 1,000 U/ml. After depletion may be beneficial in
extubation failed several trials, a tracheostomy tube was inserted for long- refractory forms of the disease with
term ventilation. Physicians tried with plasmapheresis and oral steroids intensive antibody production. In this
without improvement. Finally, rituximab was introduced, and his physical case, also, respiratory failure
state improved rapidly with a decrease in stiffness. responded well to rituximab.

Two days after the rituximab’s


infusion, her muscular tonus
A 41-year-old female presented with a history of seven years of progressive decreased, prompting reduced
rigidity to the abdominal wall and paravertebral muscles, with painful intravenous benzodiazepine doses.
spasms in the lower back region, increased tonus on shoulders, and After the second dose, 15 years later,
exaggerated lumbar lordosis. Physicians investigated SPS as a possible she tolerated oral diazepam without
Lobo et al.
Case report diagnosis and tested for anti-GAD, which was positive with high titers. spasms. This patient presented
(2010) [17]
Electromyography also supported the diagnosis. The patient was treated clinical improvement, but unlike other
with intravenous diazepam and botulinum toxin type A. Trials to change her reports, anti-GAD titers continue
IV medication to per os was not well-tolerated. After an extensive discussion, rising despite rituximab. The authors
specialists decided to try rituximab for the treatment of SPS. suggested that the anti-GAD antibody
titer may have no relation to the
disease’s clinical presentation.

Fifteen days after the infusion of


rituximab, stiffness began to resolve,
and the patient was able to shower
A 41-year-old with a diagnosis of SPS admitted to the hospital as an herself for the first time in more than
emergency with prolonged and painful extensor spasms affecting the neck, two years. Anti-GAD titers became
back, arms, and legs. She had been bed-bound for several months. Regular undetectable 17 days after treatment.
medication included baclofen 40 mg tds, dantrolene sodium tds, fentanyl 25 After the sixth week, she was re-
Baker et al.
Case report mg path twice weekly, and up to 80 mg of parenteral diazepam per day, up admitted and treated with another
(2005) [18]
to 25 mg of diamorphine. Anti-GAD antibodies were positive. course of rituximab and
Antispasmolytics and various disease-modifying treatments were tried over mycophenolate mofetil. Her condition
the year without remarkable benefit. During this hospitalization, she received improved and was able to stand and
rituximab. walk with help, sit, and shower. This
report is considered the first of the
successful use of rituximab in the
treatment of SPS.

TABLE 3: Studies describing the use of rituximab in SPS


SPS, Stiff-person syndrome; GAD, glutamic acid decarboxylase; CSF, cerebrospinal fluid; tds: three times daily; bd: twice daily.

There is a lack of evidence to establish if rituximab improves patients' symptoms and outcomes with
SPS. Although the case reports and letters to the editors showed benefit in the patients described, the
placebo-controlled randomized trial, a most complex study, demonstrated no statistically significant

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 6 of 9


difference. It is important to consider that even if the series represents the largest study in SPS in the
clinical trial, the number of patients involved may still be small. More investigation appears to be crucial to
determine whether the anti-B cell agents are useful or not.

Tacrolimus

Two patients with unsuccessful treatment of other modalities were treated with tacrolimus. Tacrolimus
belongs to the same class of medication as cyclosporine (calcineurin inhibitor) but is more potent.
Tacrolimus inhibits the activity of T cells [19]. At the start of the treatment, both patients had muscle
stiffness, spasm, and high GAD antibodies' titters. The first patient was treated with tacrolimus and
intravenous Ig. The second patient was treated with prednisone and tacrolimus. The patients’ symptoms
improved after four weeks, and the antibody titters decreased. The mechanism by which tacrolimus interacts
is very interesting. Tacrolimus decreases the levels of IL-2, which impaired the function of T helper cells. If
the T helper cells can conduct their function, there will be less activation of B cells to produce antibodies.

Interestingly, tacrolimus also seems to have a neuroprotective effect [19]. At the moment, there is more
evidence of efficacy with rituximab over tacrolimus. We can prefer at the moment rituximab over tacrolimus.
However, new studies could change our perspective in the future.

Intravenous Immunoglobulin Therapy

The mainstay treatment of SPS is the control of symptoms. Patients with severe or unsatisfactory symptoms
must initiate immunomodulators like IVIG other than conventional therapies [20]. A double-blind placebo-
controlled study used 2 g/kg of IVIG twice daily for three months vs. half-normal saline as a placebo. Three
months after the end of the course, the study assessed the patients based on the number of stiff areas. Of 16
patients in the study, six received IVIG and demonstrated a significant improvement in the tested clinical
parameter. Patients could walk without assistance, stopped falling, crossed the street, and no spasms during
household chore activities were noted.

Furthermore, those assigned to the placebo group did not show significant changes; however, after receiving
IVIG, these patients improved significantly but worsened after the placebo. In terms of safety, IVIG was safe
and effective, as clinical outcomes showed [20]. Likewise, one cross-over study used IVIG for three months
vs. placebo. The study was followed by a one-month washout period and then three months of therapy with
an alternative regimen. Patients under the IVIG regimen had lower stiffness scores over the placebo group.
IVIG regimen was safe and had more efficacy over the placebo group as well. The improvement duration of
IVIG therapy was six weeks to one year.

Moreover, there was a drop of IgG titers (anti-GAD), as was not the case in the placebo group. The anti-GAD
levels did not correlate with the severity of the disease [7]. Another small clinical trial of six patients found
that IVIG improves the patients' quality of life. This study showed improvement in pain subscores, social
functioning, mental health, and energy level [21].

Plasma Exchange (Plasmapheresis) Therapy

SPS presents with a myriad of outcomes; some patients respond to initial treatment, while others fail to
respond. After the use of several treatments and the patients continue to fail to improve, plasma exchange
therapy could be another option. Nevertheless, conflicting results have emerged from therapy from
plasmapheresis [22]. Plasmapheresis is usually conducted in one cycle with five sessions of plasma
exchange. A study conducted by Casa-Fages et al. found two patients who responded to therapy and had an
insufficient response to other therapies before. Despite improvements in both patients' symptoms, the anti-
GAD levels remain elevated after treatment [22].

It is suggested that plasmapheresis' therapeutic effect is related to the elimination component of the
immune system. Among them are the complements, cytokines, or other modulatory components of the
immune system [22]. Another case series demonstrated the short-term effectiveness of plasmapheresis in
patients with refractory treatment to IVIG [23]. In a clinical trial with 10 patients with SPS, six patients
continue the treatment chronically on an outpatient basis. However, three patients have complete remission
of their symptoms, while seven patients only partially relieve symptoms [24]. Studies suggest that plasma
exchange may be useful as adjuvant therapy, mainly in patients with no IVIG regimen response. In an acute
and long-term setting such as respiratory depression, plasmapheresis could save the patient's life, although
with variable response [24].

Establishing a treatment protocol


We suggest starting with benzodiazepines because part of the SPS criteria is the improvement of symptoms
with benzodiazepine and is also the oldest treatment. So, benzodiazepines are both useful for therapy and
diagnosis [7].

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 7 of 9


We suggest adding or switching LEV and pregabalin as first-line treatment. Both drugs have low toxicity
levels and proven effectiveness in patients with SPS [11,12]. As the second line, we suggest oral baclofen if
the symptoms do not improve. We recommend trying immunotherapy or intrathecal baclofen if refractory
symptoms persist [9,10]. Propofol should be used as a bridging treatment when the patient has refractory
symptoms and anticipates switching to a more permanent therapy, thus using propofol as the short-term
treatment of the symptoms [13]. Regarding immunotherapy, we discussed four available options: rituximab,
tacrolimus, plasma exchange therapy, and IVIG.

Benzodiazepines remain the preferred first-line treatment. However, immunotherapy can be used as a
second-line therapy due to the side effects. We could start with rituximab because there are fewer studies on
tacrolimus [15-19]. Suppose one or both treatments fail; in that case, we suggest to start with IVIG over
plasmapheresis [21]. Plasmapheresis, in our findings, had mixed results compared with IVIG, which had
consistent effects and improved symptoms of SPS [24].

Conclusions
As described, medical treatment for SPS has two main groups: GABAergic therapy and immunotherapy.
GABAergic therapy includes benzodiazepines, pregabalin, levetiracetam, and baclofen. In comparison,
immunotherapy includes rituximab, tacrolimus, plasma exchange, and IVIG. The mechanism of propofol is
not very clear. Benzodiazepines and pregabalin enhance GABA transmission by acting as direct agonists of
GABA-A receptors. In comparison, baclofen plays a role in the GABA-B receptor. Levetiracetam is not only a
calcium channel blocker, it also has GABAergic activity. Rituximab causes a sustained depletion of B cells
and tacrolimus impairment of T helper cell function. Both of these mechanisms are directed to inhibit anti-
GAD antibody production. Intravenous immunoglobulin has an exciting mechanism with
immunomodulatory effects based on antigen-antibody interactions. Finally, plasmapheresis causes
depletion of circulating antibodies or immunocomplexes and pro-inflammatory proteins.

In conclusion, benzodiazepines should be the initial treatment in persons with SPS. We recommend adding
levetiracetam or pregabalin if symptoms persist. As second-line therapy, we recommend oral baclofen over
rituximab and tacrolimus. Baclofen has fewer side effects than rituximab and tacrolimus. Between rituximab
and tacrolimus, we recommend rituximab because it has higher efficacy. For patients with refractory
treatment, we can use intrathecal baclofen, IVIG, or plasmapheresis. Intrathecal baclofen and IVIG are more
effective than plasmapheresis in patients with refractory symptoms. Finally, we found that propofol is
effective in patients with refractory symptoms; nevertheless, it is not practical, and we can only use it for
the short term. Before using another long-term therapy, we suggest using propofol as a bridge before using
more permanent treatment.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.

References
1. Baizabal-Carvallo JF, Jankovic J: Stiff-person syndrome: insights into a complex autoimmune disorder . J
Neurol Neurosurg Psychiatry. 2015, 86:840-8. 10.1136/jnnp-2014-309201
2. Buechner S, Florio I, Capone L: Stiff person syndrome: a rare neurological disorder, heterogeneous in
clinical presentation and not easy to treat. Case Rep Neurol Med. 2015, 2015:278065. 10.1155/2015/278065
3. Bhatti AB, Gazali ZA: Recent advances and review on treatment of stiff person syndrome in adults and
pediatric patients. Cureus. 2015, 7:427. 10.7759/cureus.427
4. Dalakas MC: Stiff person syndrome: advances in pathogenesis and therapeutic interventions . Curr Treat
Options Neurol. 2009, 11:102-10. 10.1007/s11940-009-0013-9
5. Zdziarski P: A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful
rituximab and tizanidine therapy. Medicine (Baltimore). 2015, 94:e954. 10.1097/MD.0000000000000954
6. McKeon A, Robinson MT, McEvoy KM, Matsumoto JY, Lennon VA, Ahlskog JE, Pittock SJ: Stiff-man
syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol. 2012, 69:230-8.
10.1001/archneurol.2011.991
7. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B: High-dose intravenous immune globulin for stiff-
person syndrome. N Engl J Med. 2009, 345:1870-1876.
8. Abbatemarco JR, Willis MA, Wilson RG, Nagel SJ, Machado AG, Bethoux FA: Case series: intrathecal
baclofen therapy in stiff-person syndrome. Neuromodulation. 2018, 21:655-9. 10.1111/ner.12765
9. Newton JC, Harned ME, Sloan PA, Salles SS: Trialing of intrathecal baclofen therapy for refractory stiff-
person syndrome. Reg Anesth Pain Med. 2013, 38:248-50. 10.1097/AAP.0b013e318288b8f9
10. Maramattom BV: Intrathecal baclofen pump implantation in a case of stiff person syndrome . Neurol India.
2010, 58:115-7. 10.4103/0028-3886.60420

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 8 of 9


11. Sechi G, Barrocu M, Piluzza MG, Cocco GA, Deiana GA, Sau GF: Levetiracetam in stiff-person syndrome. J
Neurol. 2008, 255:1721-5. 10.1007/s00415-008-0007-7
12. Squintani G, Bovi T, Ferigo L, et al.: Efficacy of pregabalin in a case of stiff-person syndrome: clinical and
neurophysiological evidence. J Neurol Sci. 2012, 314:166-8. 10.1016/j.jns.2011.10.023
13. Hattan E, Angle MR, Chalk C: Unexpected benefit of propofol in stiff-person syndrome . Neurology. 2008,
70:1641-2. 10.1212/01.wnl.0000284606.00074.f1
14. Vernino S, McEvoy K: Propofol for stiff-person syndrome: learning new tricks from an old dog . Neurology.
2008, 70:1584-5. 10.1212/01.wnl.0000310971.62712.40
15. Dalakas MC, Rakocevic G, Dambrosia JM, Alexopoulos H, McElroy B: A double‐blind, placebo‐controlled
study of rituximab in patients with stiff person syndrome. Ann Neurol. 2017, 82:271-7. 10.1002/ana.25002
16. Qureshi A, Hennessy M: Stiff person syndrome (SPS) complicated by respiratory failure: successful
treatment with rituximab. J Neurol. 2012, 259:180-1. 10.1007/s00415-011-6123-9
17. Lobo ME, Araújo MLB, Tomaz CAB, Allam N: Stiff-person syndrome treated with rituximab. BMJ Case Rep.
2010, 2010:bcr0520103021. 10.1136/bcr.05.2010.3021
18. Baker MR, Das M, Isaacs J, Fawcett PRW, Bates D: Treatment of stiff person syndrome with rituximab . J
Neurol Neurosurg Psychiatry. 2005, 76:999-1001. 10.1136/jnnp.2004.051144
19. Nakane S, Fujita K, Shibuta Y, et al.: Successful treatment of stiff person syndrome with sequential use of
tacrolimus. J Neurol Neurosurg Psychiatry. 2013, 84:1177-80. 10.1136/jnnp-2013-305425
20. Dalakas MC: The role of IVIg in the treatment of patients with stiff person syndrome and other neurological
diseases associated with anti-GAD antibodies. J Neurol. 2005, 252:i19-i25. 10.1007/s00415-005-1105-4
21. Gerschlager W, Brown P: Effect of treatment with intravenous immunoglobulin on quality of life in patients
with stiff-person syndrome. Mov Disord. 2002, 17:590-3.
22. De la Casa‐Fages B, Anaya F, Gabriel‐Ortemberg M, Grandas F: Treatment of stiff-person syndrome with
chronic plasmapheresis. Mov Disord. 2013, 28:396-7.
23. Pham HP, Williams LA 3rd: Therapeutic plasma exchange in two patients with stiff-person syndrome . J Clin
Apher. 2016, 31:493-4.
24. Albahra S, Yates SG, Joseph D, Simone ND, Burner JD, Sarode R: Role of plasma exchange in stiff person
syndrome. Transfus Apher Sci. 2019, 58:310-12. 10.1016/j.transci.2019.03.015

2020 Ortiz et al. Cureus 12(12): e11995. DOI 10.7759/cureus.11995 9 of 9

You might also like