Cureus 0012 00000011995
Cureus 0012 00000011995
Cureus 0012 00000011995
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
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.
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:
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:
- Full-text papers
- The following types of studies were excluded: systematic reviews, literature reviews, and meta-analysis
were not used.
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
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.
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].
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].
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
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].
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.
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
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.
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].
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].
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.
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