stiff person syndrome presentation

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Stiff person syndrome.

Alexandra Muranova ; Elena Shanina .

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Last Update: July 10, 2023 .

• Continuing Education Activity

Stiff person syndrome (SPS) is a rare progressive and often underdiagnosed immune-mediated disorder of the central nervous system characterized by progressive rigidity and triggered painful spasms of predominantly axial and proximal limb muscles. The condition has an insidious onset with gradual worsening over time and, if left untreated, can lead to permanent disability and mortality. This activity reviews the evaluation and treatment of patients with SPS and emphasizes the importance of the interprofessional approach to managing this condition.

• Review the etiology of stiff person syndrome (SPS).
• Describe the clinical presentation and diagnostic criteria of stiff person syndrome (SPS).
• Summarize the management options for stiff person syndrome (SPS).
• Outline the importance of early recognition of patients with stiff person syndrome (SPS) and an interprofessional approach to improve outcomes.
• Introduction

Stiff person syndrome (SPS) is a rare disorder of the central nervous system characterized by rigidity and stimulus triggered painful muscle spasms of predominantly axial and proximal limb muscles. It was first described in 1956 by Frederick Moersch and Henry Woltman based on a case series of 14 patients with progressive fluctuating tightness of the spinal, abdominal, and thigh muscles. This condition was formerly named stiff-man syndrome and is also known as Moersch-Woltman Syndrome.  

The current clinical classification of SPS includes:

Classic SPS

• Partial SPS variants
• Progressive encephalomyelitis with rigidity and myoclonus (PERM). [1]

Classic SPS is the most common clinical form, present in 70 to 80% of SPS patients. It is associated with anti-glutamic acid decarboxylase (anti-GAD) antibodies.  [2]  The condition has an insidious onset with gradual worsening over time and often leads to permanent disability and, in some cases, mortality. SPS may coexist with other autoimmune disorders, including  Diabetes Mellitus Type 1 (DM-1), autoimmune thyroid disease, pernicious anemia, celiac disease, vitiligo. [3]  

Several clinical variants of SPS have been described and include stiff limb syndrome, jerky SPS, cerebellar variant, SPS with epilepsy, and dystonia. [1] [3]  The paraneoplastic variant is associated with breast, colon, thyroid, lung malignancies, Hodgkin and non-Hodgkin lymphomas and tends to clinically manifest before cancer itself.  [2]  

PERM, first described in 1956, is known as SPS-plus syndrome. Patients have the rigidity of axial and limb muscles, diffuse myoclonus in addition to prominent autonomic instability. [3]

There is increasing evidence for immune-mediated etiology of this disorder. Identification of associated antibodies and common comorbidities with other autoimmune diseases and malignancies has been important for a better understanding of disease mechanisms and approaches to treatment.

SPS is an autoimmune condition associated with high titers of autoantibodies to various components of inhibitory synapses, which leads to their impaired functioning through a low level of gamma-aminobutyric acid (GABA) on pre-synaptic or post-synaptic neuronal junctions. 

The paraneoplastic form accounts for 5% to 10% of all cases and is characterized by the presence of antibodies to amphiphysin and less frequently to gephyrin. The most common malignancy associated with paraneoplastic variant includes breast adenocarcinoma followed by adenocarcinoma of the colon, small-cell lung carcinoma, malignancies of thymus and thyroid gland, and Hodgkin’s lymphoma. [3]

Genetic predisposition has been determined by the presence of DQB1 and DRB1 MHC-II alleles which increase the risk of idiopathic and paraneoplastic variants of SPS. [4]

• Epidemiology

The estimated prevalence of classic SPS in the general population is 1 to 2 cases per million, with females being affected twice as often as males, regardless of race. [5]  Most patients develop symptoms between the ages of 20 and 60, most commonly in their thirties and forties. PERM usually occurs in older adults between their fifties and sixties. Only 5% of cases of SPS have been reported in children. [6]

• Pathophysiology

The pathogenesis of SPS has been explained by B-cell-mediated autoimmune inflammation that affects different components of inhibitory GABAergic neurons and their synapses. Production of autoantibodies against antigens involved in GABA synthesis and release within the central nervous system results in a dysfunction of major inhibitory pathways leading to impaired truncal and axial muscles' impaired relaxation due to hyperexcitability the motor cortex. Glutamic acid decarboxylase (GAD) is an intracellular enzyme that transforms glutamate into GABA and is a primary target and the most common antigen identified in classic SPS. [7]  GAD exists in 2 isoforms: GAD67 and GAD65. The baseline production of GABA is regulated by GAD67, while the second isoform provides additional GABA when there is an increased demand. [4] [8]

Primarily, the production of anti-GAD65 antibodies is a hallmark of a pathological process in classic SPS and is found in 70-80% of cases. In addition to classic SPS, anti-GAD antibodies have been associated with other autoimmune neurological disorders, including limbic encephalitis, autoimmune epilepsy, cerebellar ataxia, myoclonus, and nystagmus. They now comprise GAD antibody-spectrum disorders (GAD-SD). [9]  It is currently unclear if different epitope binding patterns can cause diverse clinical presentations of GAD-SD. Low titers of anti-GAD antibodies also are seen in patients with DM-1, and up to 30% of patients with GAD-SD, including SPS, have DM-1. However, high titers of anti-GAD antibodies are seen only in GAD-SD. [10]  

Additional antigens described with SPS include GABA(A) receptor-associated protein (GABARAP), dipeptidyl-peptidase-like protein-6 (DPPX) as well as glycine receptor (GlyR), which is associated with PERM. [11]

A paraneoplastic variant of SPS is associated with antibodies against amphiphysin or gephyrin. Amphiphysin is an intracellular presynaptic protein involved in the endocytosis of the vesicle membrane and regulates the expression of GABA receptors at the axon membrane. It is demonstrated that antibodies against amphiphysin can decrease the amount of GABA receptors by reducing the endocytosis of the GABA-containing vesicles. Therefore, this diminishes the presynaptic vesicle pool and leads to impaired GABA transmission. [2] [12]

• Histopathology

Some of the characteristic histopathologic features of SPS include loss of GABAergic neurons in the spinal cord and cerebellum with scattered areas of inflammatory changes. Additionally, chromatolysis and vacuolization of anterior horn cells of the lower spinal cord segments were also described. [13] [14]   Paraneoplastic SPS is associated with more pronounced inflammatory changes in the temporal lobes, brainstem, and spinal cord. [15]

• History and Physical

Classic SPS is a condition with an insidious onset and gradual progression over few months. It usually starts with rigidity and stiffness of the trunk muscles, specifically in the thoracolumbar region, due to continuous contraction of both abdominal and paraspinal muscles. Patients describe difficulties bending and turning, feeling that they walk like a “tin-man.” Later, the rigidity spreads to proximal upper and lower extremities. [10]  Eventually, it leads to multiple chronic orthopedic abnormalities such as increased lumbar lordosis, joint deformities, and abnormal posturing, which results in a “statue-like” appearance and is accompanied by gait disturbances and multiple falls. In addition, patients develop painful generalized muscle spasms and exaggerated startle responses precipitated by unexpected tactile, visual, or acoustic stimuli and strong emotions. Patients often develop depression, task-specific phobias, fear of open spaces, anticipatory anxiety due to triggered spasms, and pathological startling. [5]  

Due to common psychiatric comorbidities, SPS is being misdiagnosed for a functional neurological disorder or a primary psychiatric condition. Patients usually have diurnal fluctuations of symptoms, worse with physical and emotional stress, cold weather, and infection. Distal and facial muscles are spared until later in the disease course. The frequency and duration of painful spasms vary. In some cases, severe spasms can last for hours ("status spasticus"), often requiring an emergency room visit for treatment intravenous muscle relaxants. In rare cases, respiratory muscles can be involved. [16]

Partial SPS Variants

Stiff limb syndrome presents with isolated limb spasms and mostly spared trunk muscles. Abnormal posturing of the distal limb can resemble dystonia. Stiffness can eventually involve other muscles, but it remains most severe in one limb. In stiff trunk syndrome, spasms involve only axial musculature, sparing extremities. Rarely extraocular abnormalities with oscillopsia, opsoclonus, and nystagmus were reported. [16]  Patients with cerebellar variant (SPS-Cer) present with dysmetria, gait ataxia, and nystagmus superimposed on stiffness. [17]

Paraneoplastic SPS

It was described by some authors that paraneoplastic SPS demonstrates more significant stiffness in the neck and upper extremities. These patients usually show a faster response to therapy and significant clinical improvement once their malignancy is removed. [8]  

Progressive Encephalomyelitis with Rigidity and Myoclonus

PERM is a more severe variant of SPS, and it is characterized by relapsing-remitting course and more extensive involvement of different parts of the CNS, including the brainstem. This results in decreased consciousness or altered mentation, extraocular muscle dysfunction, ataxia, and autonomic failure. [8] [5]

A diagnosis of SPS is usually made clinically by thorough neurological examination with the support of electrodiagnostic and laboratory findings. [8]  Diagnostic criteria for SPS evolved over the years, and most accepted are criteria revised by Dalakas in 2009. [18]

The current diagnostic criteria for classic SPS  include: 

• Stiffness in the limb and axial muscles, prominent in the abdomen and thoracolumbar region
• Painful spasms precipitated by unexpected tactile and auditory stimuli
• Evidence of the continuous motor unit activity in agonist and antagonist muscles demonstrated by EMG
• Absence of other neurological impairments that could support an alternative diagnosis
• Positive serology for anti-GAD65 or anti-amphiphysin autoantibodies
• Clinical response to therapy with benzodiazepines

The level of anti-GAD antibodies in serum higher than 10,000IU/mL supports a clinical impression of SPS. [10]   CSF analysis is usually unremarkable. In patients with PERM, a mild increase in CSF cell count with elevated protein and positive oligoclonal bands has been demonstrated as well as positive autoantibodies against glycine receptors. [5]  

Electrodiagnostic testing is useful to rule out other nerve and muscle pathologies and to confirm the clinical diagnosis. Routine nerve conduction studies in SPS are usually normal. Needle electromyography (EMG) in SPS shows continuous involuntary motor unit activity even at rest, despite volitional effort to relax. Continuous motor unit activity and co-activation of agonists-antagonists muscles are key diagnostic features and are mostly detected in trunk muscles, especially paraspinal and abdominal muscles and proximal limb muscles. [2]

MRI brain and spinal cord are usually non-diagnostic in classic SPS, but they are often performed to rule out other causes of rigidity and stiffness.

Magnetic resonance spectroscopy can show a focal change in GABA levels in the motor area of the brain in SPS. [19]   In patients with PERM, MRI might show hyperintense signals in the spinal cord and the brainstem. [8]  

To diagnose a paraneoplastic variant, it is important to check for antibodies against amphiphysin and gephyrin and initiate a prompt neoplastic workup.

Since around 35 % of patients diagnosed with SPS have DM-1 and about 5 % have associated autoimmune thyroid disease, a search for coexisting autoimmune conditions is commonly performed.

• Treatment / Management

Treatment options for SPS can be divided into two main categories: symptomatic and disease-modifying or immunotherapy. [3]   These lines of therapy are commonly used in combinations, depending on the severity of the disease.

Symptomatic management is a standard of initial therapy and focuses on decreasing stiffness, rigidity, and painful muscle spasms. It is achieved using medications that promote GABA effects, such as benzodiazepines, baclofen, gabapentin, and vigabatrin. Diazepam is known to be a first-line symptomatic agent for patients with SPS. Still, it is not uncommon to develop a tolerance and addiction to benzodiazepines over time, resulting in a loss of its beneficial effects. Intrathecal baclofen is also effectively used in some patients. Other commonly used muscle relaxants include dantrolene and tizanidine. [2]  Symptom management also includes treatment of co-existing seizures and psychiatric comorbidities with anti-epileptic and antidepressant medications, respectively.

Disease-modifying therapy is a specific immune-modulating treatment that aims at reducing or removing autoantibodies. Intravenous immunoglobulin (IVIG) is proven to be the most effective immunotherapy in SPS, promoting a clinical improvement for up to 1 year after a standard course of five sessions. Unlike IVIG, the benefit of plasma exchange is not yet fully established, and most patients only demonstrate temporary or no improvement in symptoms. [5] [20]  

Corticosteroid effectiveness is controversial in SPS. Rituximab, a monoclonal antibody against CD20 antigen on B-cells, has provided a long-lasting benefit in non-randomized trials. [21]  Use of other immunomodulating agents including mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, tacrolimus, and sirolimus is reported with variable effects. [5]

• Differential Diagnosis

The differential diagnosis for SPS is broad, and it includes disorders of the brain, spinal cord, and muscles:

• Myelopathy: compressive, inflammatory, infectious, ischemic
• Myopathies and muscular dystrophies
• Idiopathic Parkinson disease and Parkinson-plus syndromes
• Autoimmune encephalitis
• Primary lateral sclerosis
• Progressive multiple sclerosis
• Generalized or focal dystonia
• Neuromyotonia
• Isaac syndrome
• Ankylosing spondylitis
• Hereditary spastic paraplegia
• Hereditary hyperekplexia
• Leukodystrophies
• Neuroleptic malignant syndrome, serotonin syndrome, or malignant hypothermia
• Functional neurological disorder

The prognosis for patients with SPS depends on multiple factors, including clinical presentation, the longitude of symptoms, co-existing neoplastic process, and a response to therapy. It is crucial to timely initiate therapy to prevent or lessen progression and avoid long-term complications. Most of the patients improve with medications, however fluctuations precipitated by physical and emotional stressors still occur. Despite the availability of multiple treatment options, some patients with SPS show disease progression over time, leading to permanent orthopedic abnormalities, inability to walk, and disability. [8] [5]  In one longitudinal study, only 19% of patients could work after 4 years of follow-up. [16]  Patients report markedly reduced quality of life due to physical and social limitations.

• Complications

Patients with SPS are at higher risk of developing orthopedic problems such as lumbar hyperlordosis, joint deformities, and muscle atrophies, leading to abnormal posturing and gait abnormalities with increased fall risk. As the disease progresses, unexpected tactile and auditory stimuli could trigger the occurrence of autonomic failure with tachycardia,  hypertension, and hyperthermia. [5] [8]

• Enhancing Healthcare Team Outcomes

SPS is often an underdiagnosed or misdiagnosed condition that can lead to permanently impaired physical and mental health if not treated timely. Therefore, health care providers should aim at recognizing and managing the disease as early as possible and under the care of a neurology specialist. Patients with SPS would be best managed by an interprofessional team, including a physical therapist, psychiatrist, and orthopedic surgeon to increase their chance for recovery and preserve their quality of life. In addition, it is crucial to monitor patients who receive immunotherapy for possible side effects. For patients with a paraneoplastic variant, a thorough search for underlying malignancy should be promptly initiated. 

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Disclosure: Alexandra Muranova declares no relevant financial relationships with ineligible companies.

Disclosure: Elena Shanina declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Muranova A, Shanina E. Stiff Person Syndrome. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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INTRODUCTION

Classic SPS and its major variants, partial SPS and paraneoplastic SPS, are reviewed here. Progressive encephalomyelitis with rigidity and myoclonus (PERM) and other paraneoplastic disorders of the nervous system are discussed in detail separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" .)

PATHOGENESIS

An autoimmune process was originally postulated to underlie SPS, as the disorder often occurs in conjunction with any one of a variety of autoimmune diseases, particularly T1DM; other associated conditions include thyroiditis, vitiligo, and pernicious anemia [ 1,5-8 ]. An association between anti-glutamic acid decarboxylase (GAD) antibodies and SPS has also been noted [ 8,9 ]. These antibodies were found to target GABAergic neurons and their nerve terminals. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme GAD [ 10 ].

Autoimmunity  —  The pathogenic role of the anti-GAD antibodies in SPS remains to be defined. GAD is an intracellular enzyme and is not readily accessible to binding by antibodies, although transfer experiments in mice, using serum obtained from affected patients, resulted in recipients becoming stiff. However, in SPS the titer of anti-GAD antibodies does not always correlate with disease activity, and about 30 percent of patients are antibody-negative.

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At the time the article was created Frank Gaillard had no recorded disclosures.

At the time the article was last revised Daniel J Bell had no recorded disclosures.

• Stiff man syndrome

Stiff person syndrome , previously known as stiff man syndrome , is a very rare neuromuscular disease .

On this page:

Epidemiology, clinical presentation, radiographic features, treatment and prognosis, history and etymology.

Onset is usually between 30 and 50 years of age. An association with autoimmune disease and various malignancies is described and these are thought to play a role in the pathophysiology.

Clinical presentation is characterized by:

• progressive muscle stiffness predominantly affecting the axial muscles (especially the abdominal and thoracolumbar paraspinal musculature) and lower limbs
• muscle spasms triggered by external stimuli or emotional stress
• symptoms typically relieved by benzodiazepines

The diagnosis is usually confirmed with EMG and serology (anti-GAD and anti-amphiphysin antibodies). These are specific, however they are only present in 60% of cases.

Stiff person syndrome is part of the spectrum of autoimmune encephalitides  4 . Anti-GAD antibodies may bind to and lead to the progressive destruction of GABAergic neurons involved in motor pathways 2-4 .

Additionally, a paraneoplastic syndrome causing anti-amphiphysin antibodies is described (the most common malignancies being of the breast followed by thymic , colorectal and lung ) 4 .

Imaging is usually unremarkable 4 . T2 hyperintensities of the brain and spinal cord on MRI have been described in a minority of case reports 4,5 .

In addition to benzodiazepines, baclofen has been used for treatment. More recently, intravenous immunoglobulins (IVIG) have been used in combination with other drugs 3,4 .

Stiff person syndrome was first described in 1956 by Moersch and Woltman of the Mayo Clinic 1 .

• 1. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 2003;31 (15): 421-7. Pubmed citation
• 2. Solimena M, Folli F, Denis-Donini S et-al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N. Engl. J. Med. 1988;318 (16): 1012-20. doi:10.1056/NEJM198804213181602 - Pubmed citation
• 3. Karlson EW, Sudarsky L, Ruderman E et-al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum. 1994;37 (6): 915-8. Pubmed citation
• 4. Sarva H, Deik A, Ullah A, Severt WL. Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports. (2016) Tremor and other hyperkinetic movements (New York, N.Y.). 6: 340. doi:10.7916/D85M65GD - Pubmed
• 5. Byrne, Thomas N., Isakoff, Steven Jay, Rincon, Sandra P., Gudewicz, Thomas M.. Case 27-2012. (2012) The New England journal of medicine. 367 (9): 851-61. doi:10.1056/NEJMcpc1114036 - Pubmed

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• Volume 11, Issue 5
• Stiff person syndrome
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• Shahrzad Hadavi 1 ,
• Alastair J Noyce 1 ,
• R David Leslie 2 ,
• Gavin Giovannoni 1
• 1 Department of Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
• 2 Centre for Diabetes, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
• Correspondence to Dr Shahrzad Hadavi, Department of Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK; shahrzadhadavi{at}doctors.org.uk

Stiff person syndrome (SPS) is a rare disorder, characterised by fluctuating rigidity and stiffness of the axial and proximal lower limb muscles, with superimposed painful spasms and continuous motor unit activity on electromyography. Although rare in general neurology practice, once observed it is unforgettable. The general neurologist may see only one or two cases during his or her career and as such it remains underdiagnosed. Left untreated, SPS symptoms can progress to cause significant disability. Patients have a poor quality of life and an excess rate of comorbidity and mortality. The severity of symptoms and lack of public awareness of the condition create anxiety and uncertainty for people with the disease. This review aims to raise awareness of SPS and to improve the likelihood of its earlier diagnosis and treatment.

https://doi.org/10.1136/practneurol-2011-000071

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Introduction

Stiff person syndrome (SPS) is rare, although its true frequency has not been fully ascertained. The British Neurological Surveillance Unit identified 119 cases among the UK population over 5 years (2000–2005), implying a prevalence of 1–2 cases per million.

The natural history of SPS has yet to be completely described. The symptoms range from mild to severe and can progress, resulting in significant disability. Perhaps 65% of patients cannot independently perform normal activities of daily living due to rigidity and stiffness, phobias, unpredictable spasms and frequent falls. 1

Almost all SPS has an autoimmune basis; most have the glutamic acid decarboxylase (GAD) autoantibody but there are also paraneoplastic varieties. Main line therapies include γ-aminobutyric acid (GABA)-ergic and other antispasmodic agents to alleviate symptoms, but immunomodulatory agents can also attenuate the aberrant immune process.

Moersch and Woltman described ‘stiff man syndrome’ in 1956 in 14 patients with tightness of the back, abdominal and thigh muscles. 2 Their observations spanned a 32-year period and they detailed progressive fluctuating rigidity and painful spasms, leading to a characteristic ‘wooden man’ appearance, with postural instability and falls. Diabetes mellitus (DM) accompanied a handful of cases.

Eleven years later, Gordon et al set out clinical criteria to address the need for improved diagnostic certainty. 3 These were modified by Lorish et al in 1989 4 and by Dalakas in 2009. 1 These latest criteria are currently in use. Moersch and Woltman described the electromyographic findings of motor unit activity resembling ‘that which accompanies contraction of voluntary muscle’. 2 Gordon and colleagues (1967) used electromyography and muscle relaxants, describing ‘persistent tonic contraction reflected in constant firing, even at rest’. 3

In 1988, Solimena et al described the major breakthrough in the pathogenesis of SPS in a patient presenting with diabetic ketoacidosis. Through elegant experiments, they identified an autoimmune link between SPS and DM. They proposed that autoantibodies against GAD, an enzyme found in both the central nervous system and in pancreatic islets of Langerhans, were important to both diseases. 5 The GAD enzyme was already known to synthesise the inhibitory neurotransmitter, GABA; their findings provided a plausible disease mechanism. Of interest, Howard had reported previously that diazepam significantly reduced muscle stiffness and rigidity in SPS, suggesting involvement of GABA-related inhibitory pathways ( figure 1 ). 6

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The timeline of significant dates in the history of SPS. 2 5 , – , 12 GABARAP, γ-aminobutyric acid (A) receptor-associated protein; GAD, glutamic acid decarboxylase; SPS, stiff person syndrome

Pathophysiology

The exact pathogenic role of autoantibodies in SPS remains unclear. All SPS autoantigens identified to date are synaptic proteins involved in inhibitory synaptic transmission. The presynaptic autoantigens are GAD and amphiphysin, and the postsynaptic autoantigens are GABA (A) receptor-associated protein and gephyrin ( figure 2 ). 5 10 , – , 12

A summary diagram of the γ-aminobutyric acid (GABA) metabolic pathway and the molecular biology of GABA neurotransmission. 5 10 , – , 12 19 (A) GABA biochemistry: glutamate is converted to GABA via two isoforms of glutamic acid decarboxylase (GAD65 and GAD67). GABA is then packaged into presynaptic vesicles to allow exocytosis into the GABA synapse. Excess GABA is metabolised to succinate, which then enters the tricarboxylic acid cycle. (B) The GABA synapse: GABA accumulates in the presynaptic vesicle. Fusion of vesicles with the presynaptic membrane enables exocytosis of GABA into the synapse. A protein complex is formed to allow fusion and is composed of synaptosomal-associated protein 25 (SNAP-25), synaptobrevin and syntaxin. The component proteins in this complex are anchored by SNAP receptor (SNARE) proteins; v-SNARE is vesicle-associated and t-SNARE is ‘target’ or presynaptic membrane-associated. Synaptotagmin is involved in docking of the vesicle with the presynaptic membrane and calcium-mediated fusion. Synaptophysin is a ubiquitous synaptic vesicle glycoprotein. Amphiphysin is involved in endocytosis and cycling of synaptic vesicle membrane, following GABA exocytosis. Once GABA has entered the synapse, it binds to GABA receptors. Gephyrin is thought to be involved with clustering of GABA receptors at the postsynaptic membrane, as is the GABA (A) receptor-associated protein (GABARAP). Autoantibodies against GAD, amphiphysin, gephyrin and GABARAP have all been identified in patients diagnosed with stiff person syndrome.

The SPS autoantibodies probably mediate their effect through pharmacological blockade of their target autoantigens rather than by causing structural changes in GABA-ergic neurons. This is supported by the lack of abnormal neurological signs other than increased muscle tone, and the improvement of symptoms with immunotherapy. 13 The fact that most cases have normal postmortem findings supports this theory. Some cases show non-specific neuronal and interneuronal loss in the spinal cord. 14

Interestingly, a report of stiff horse syndrome described a stiff gait and painful muscles to palpation. The clinical examination, electromyographic and serological investigations were strikingly similar to SPS. 15

GAD autoantibodies

About 60–80% of SPS cases have autoantibodies against GAD, a rate-limiting cytoplasmic enzyme responsible for synthesising the inhibitory neurotransmitter GABA in the brain and spinal cord. 1 16 GAD is synthesised mainly in presynaptic GABA-ergic neurons in both the central nervous system and in the islet of Langerhans β-cells of the pancreas ( figure 2 ). 16 The mechanism by which autoantibodies recognise intracellular GAD is unclear.

There are two GAD isoforms—GAD65 and GAD67—but it is GAD65 that is the main target for GAD autoantibodies in both SPS and DM. 17 In SPS, GAD autoantibodies recognise both linear and conformational epitopes, whereas in type 1 DM they recognise only conformational epitopes. 18 An epitope is the specific region of an antigen recognised by the immune system. A linear epitope has a continuous sequence of amino acids and it is this primary structure that the autoantibody recognises. In contrast, a conformational epitope has a three-dimensional shape with discontinuous sequence of amino acids and interacts with autoantibodies based on this tertiary structure.

The GAD autoantibodies in type 1 DM recognise the carboxy-terminal end or the centre of the GAD molecule, while in SPS, the GAD autoantibodies mostly recognise the amino-terminal fragment of GAD. 17 The differential recognition of the GAD molecule is reflected in T cell immunoreactivity to it: T cells from type 1 DM patients recognise epitopes of GAD at the carboxy-terminal while those from SPS recognise epitopes of GAD at the amino-terminal. 17 GAD autoantibodies in type 1 DM tend to be restricted to the immunoglobulin G1 (IgG1) isotype, but in SPS the isotype profile is much broader, including IgG4 and IgM; these differences may either be disease-related or may reflect the much higher GAD titre in SPS. 17 GAD autoantibody titres in SPS are up to 50 times elevated but only 10 times in DM, 1 although not all SPS patients have high GAD autoantibody titres. 17 Of note, the GAD autoantibody titre in serum or cerebrospinal fluid (CSF) does not correlate with symptom severity, 1 and so titre monitoring is unnecessary.

GAD autoantibodies are not specific to SPS and DM, and occur also in cerebellar ataxia, myoclonus, epilepsy and several other neurological disorders (see Differential Diagnosis section). This spectrum of clinical entities results from differences in epitope recognition. 1

Other associated autoantibodies

See table 1 and figure 2 .

• View inline

Other autoantibodies associated with stiff person syndrome (SPS) 10 , – , 12

Clinical features

The symptom onset is typically insidious. Patients may report intermittent aching and tightness in the neck, paraspinal and abdominal muscles. The rigidity spreads slowly through the proximal muscles and is often asymmetrical. 1 Over time, activities of daily living become severely impaired and patients report difficulty dressing, walking and bending forward, for example, when putting on shoes.

The age of onset varies considerably but is usually in adulthood, at an average age of 41.2 years (range 29–59 years). 20 SPS affects twice as many women as it does men, 20 in line with other adult-onset autoimmune diseases: this observation led to a nomenclature change from stiff man syndrome to SPS. Several clinical features given below are consistent mainly with GAD autoantibody positive cases.

Rigidity and stiffness

Rigidity and stiffness of the trunk muscles are the earliest symptoms and result from constant contraction of both lumbar and abdominal muscles ( figure 3 ). The abdominal and lumbar paraspinal rigidity begins insidiously and fluctuates at first. As it progresses, patients develop a fixed posture, giving the characteristic lumbar spine ‘hyperlordosis’, a diagnostic hallmark ( figure 3 ). Importantly, lumbar hyperlordosis persists even when the patient lies flat on their back, but usually alleviates in sleep. 21

Postural abnormalities and examination findings in stiff person syndrome. (A) and (B) Hyperlordosis. (C) Coexistent contraction of abdominal muscles. (D) Note the skin creases in the lumber region of the back, hinting at exaggerated lordosis.

The rigidity progresses slowly from the trunk to the proximal lower limb muscles and can cause walking difficulty. The gait may be bizarre, but typically is slow and wide, in an effort to improve balance. 1 Patients with severe and untreated SPS ultimately become bedridden through progression of the stiffness.

Facial muscle involvement is rare, but can give an ‘emotionless mask’ appearance. 13 If the stiffness affects the thoracic muscles, there may be restriction of chest expansion and breathing difficulty 13 ; this can be catastrophic if treatment is withdrawn abruptly. The hands or feet may be involved in up to 25% of cases 22 ; typically, these cases are GAD autoantibody-negative. The arms, if involved, may have a flexed posture. 3

Superimposed spasms

Muscle spasms, superimposed on muscle rigidity, are initially intermittent and precipitated by startle (particularly sudden auditory or tactile stimulation), by psychological factors and by passive or active movement of the affected or unaffected muscles. Spasms can be extremely painful and disabling. They are usually short lasting (minutes) and disappear gradually on removal of the triggering stimulus. Spasms may also occur in bouts, resembling tetanus, 21 or may lead to a ‘shock-like’ clinical presentation, with sweating, tachycardia and restlessness. 3 Falls from severe spasms are very common, sometimes even with long bone fractures and joint dislocations. 3 The fear of falling may prompt patients to use mobility aids (canes or wheelchairs), even when the severity of rigidity does not make this necessary.

Psychological features

Clinicians treating patients with SPS must be aware of frequent coexisting psychiatric symptoms such as task-specific phobias, depression and generalised anxiety disorders. Major psychological features can dominate the clinical picture and lead to the misdiagnosis of a psychogenic movement disorder. 13 However, SPS patients do not typically have premorbid phobias or anxiety and often have realistic and appropriate fears of certain situations because of their stiffness, spasms and falls. 23 Anxiety-provoking examples include crossing roads, initiating walking without support or descending stairs without a banister. 20 The anxiety encountered in SPS therefore results more from the primary neurological disorder than from a primary phobic disorder, although the reduction in GABA levels may predispose then to an exaggerated anxiety response. 23 These associated features can complicate the diagnosis and lead to suspicions of malingering in undiagnosed cases, often reinforced by the response to diazepam and the pain relief with morphine. As with other chronic disorders, depression commonly coexists in SPS patients and should be sought and treated. 24 The psychological/psychiatric symptoms may be managed in partnership with a psychiatrist once the SPS diagnosis is secure.

Pain is common in SPS. The first symptom may be a persistent, progressively worsening ache, localised to the area of rigidity. The pain is typically chronic but worsens acutely with muscle spasms. The clinician must therefore specifically ask about pain since it significantly impacts on quality of life.

Examination findings

The head retraction reflex occurs in many SPS patients (see box 1 ). 25 This is a non-specific abnormal cutaneo-muscular brainstem reflex, elicited by tapping the nasal ridge, upper lip, glabella or chin, provoking a backward jerk of the head or truncal retropulsion.

Box 1 What to look for during examination

■ Increased tone in the axial/truncal muscle groups

■ Increased tone in the legs (symmetric or asymmetric)

■ Normal power in the upper and lower limbs, unless at an advanced stage of the disease

■ Possible hyper-reflexia, without plantar extension

■ Normal sensory function and coordination

■ Hyperlordosis of the lumbar spine (resulting from cocontraction of abdominal and paraspinal muscles)

■ ‘Woody’ feel on palpation of the muscles, due to spasms

■ Slow, wide and cautious gait

■ Intact cognitive function

■ Normal sphincter function

Eye movement disturbances may occur in SPS but are not sufficiently frequent to be a diagnostic guide. These present as gaze palsies suggestive of third, fourth or sixth nerve palsies, supranuclear gaze palsies or nystagmus. 26 An eye movement abnormality should prompt consideration of one of the ‘SPS plus’ variants or additional pathology ( figure 4 ).

Possible additional ophthalmic signs. (A) Primary position: left eye deviated down and out. (B) and (C) Rightward and leftward gaze: left eye cannot fully adduct. (D) Upward gaze: left eye fails to fully elevate. Cranial nerve palsies can be observed very occasionally in stiff person syndrome (SPS) and are more common in the SPS plus variant, progressive encephalitis with rigidity (see Differential Diagnosis section). However, this patient has Graves' ophthalmopathy with coexistent autoimmune thyroid disease.

Social implications

Up to 65% of SPS patients cannot independently undertake normal activities of daily living, 1 due to disabling rigidity and stiffness, task-specific or non-specific phobias, the unpredictability of dangerous muscle spasms, or frequent falls. 1 Even SPS patients receiving treatment can have markedly reduced quality of life, owing to their problems in social and physical functioning. 24 Stiffness severity can have a major effect on quality of life: for example, severe cervical rigidity may limit head rotation, and cause problems when driving. 4 Coexisting depression can further diminish quality of life.

Diagnosis and diagnostic criteria

SPS is largely a clinical diagnosis, facilitated by a high degree of suspicion; there are no specific neurological signs or laboratory tests. 20 The variability in clinical presentation and recognition of SPS variants further increase the diagnostic uncertainty. 27 The delay in diagnosis ranges from 1 to 18 years, with a mean of 6.2 years. 20

The Dalakas criteria 1 20 (see box 2 ) are used worldwide to diagnose SPS. Patients not meeting these criteria (eg, without the classical axial distribution of stiffness and rigidity) are described as atypical.

Box 2 The Dalakas criteria for the diagnosis of typical stiff person syndrome 1

■ Stiffness in the axial muscles, prominently in the abdominal and thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis)

■ Superimposed painful spasms precipitated by unexpected noises, emotional stress, tactile stimuli

■ Confirmation of the continuous motor unit activity in agonist and antagonist muscles by electromyography

■ Absence of neurological or cognitive impairments that could explain the stiffness

■ Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay

■ Response to diazepam *

Not part of Dalakas' criteria, but commonly included in the diagnostic criteria.

↵ * GAD, glutamic acid decarboxylase.

Autoimmune and other associations

SPS is strongly associated with other autoimmune diseases: about 35% of SPS patients also have type 1 DM. 1 Importantly, most patients with adult-onset type 1 DM do not require treatment with insulin, whether they have SPS or not. 28

About 5–10% of patients also have autoimmune thyroid disease, Graves' disease, pernicious anaemia or vitiligo. 16 Ten per cent of GAD autoantibody-positive SPS patient have epilepsy, possibly from functional impairment of GABA-ergic neurons, 16 and a further 10% have ataxia. 1

Investigations

Details of routine and additional investigations are listed in table 2 .

Differential diagnosis

The differential diagnosis of SPS is summarised in box 3 .

Box 3 Differential diagnosis

■ Clinical differential

■ Myelopathy: compressive, ischaemic, haemorrhagic and inflammatory (including multiple sclerosis and infectious causes)

■ Myopathy: channelopathies, inflammatory, myotonic dystrophy, paramyotonia

■ Neuropathic: neuromyotonia, Isaac's syndrome

■ Parkinson's disease or Parkinson-plus syndromes (eg, progressive supranuclear palsy, multiple system atrophy)

■ Primary lateral sclerosis

■ Dystonia (generalised and focal)

■ Ankylosing spondylitis

■ Neuroleptic malignant syndrome, malignant hyperthermia and serotonin syndrome

■ Psychogenic

■ Hereditary spastic paraparesis

■ Leukodystrophies

■ Drug-induced and toxicity: monoamine oxidase inhibitors, phenothiazines, amphetamines, 5,6-methylenedioxy-N-methyl-2-aminoindane, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, carbon monoxide

■ Spinal interneuronitis with rigidity

■ Diseases associated with positive GAD autoantibodies

■ Cerebellar ataxia

■ Limbic encephalitis

■ Myasthenia gravis

■ Myoclonus

■ Neuromyotonia

■ Batten's disease

GAD, glutamic acid decarboxylase.

Patients are often initially suspected of having a more common neurological, medical or psychiatric disorder. They may be referred to numerous specialists before SPS is diagnosed, for example to orthopaedic surgeons or rheumatologists for back pain and spinal stiffness, or psychiatrists for phobias and anxiety.

SPS variants

Barker et al divided SPS into three subcategories: the SPS, the stiff limb syndrome and progressive encephalomyelitis with rigidity. 27

Stiff limb syndrome

There is a focal onset, usually in one lower limb, with subsequently more widespread symptoms. The stiffness usually remains most prominent in the limb where symptoms began. 1 27 Up to half of these patients have sphincter disturbance and about a third develop brainstem involvement. 27 Electrophysiological findings are similar to those in classical SPS. Most patients are GAD autoantibody-negative and only partially respond to GABA-ergic treatment. 27

Progressive encephalitis with rigidity

Progressive encephalomyelitis with rigidity can present in patients already suspected of having SPS. It presents as a complex progressive illness dominated by an acute onset of painful rigidity and muscle spasms in the limbs and trunk. It has a rapid course, 29 with brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, dysphagia) and profound autonomic disturbance. 30

The CSF shows a mild lymphocytic pleocytosis with elevated protein and oligoclonal IgG bands. MRI may show increased signal intensity throughout the spinal cord and the brainstem. 31 The response to diazepam is mild compared with that in classical SPS. However, the symptoms improve dramatically with methylprednisolone, suggesting that the underlying mechanism is autoimmune mediated inflammation. 30 31

Paraneoplastic variants

Paraneoplastic SPS, comprising 5% of patients, manifests as stiffness mostly in the neck and arms, in contrast to the distribution of typical SPS. 1 Paraneoplastic SPS is associated with malignancies of the breast, colon, lung, thymus and in Hodgkin's lymphoma, occasionally manifesting before the cancer does. Autoantibodies against amphiphysin and gephyrin may occur: this situation should prompt thorough investigation (see table 2 ) and ongoing vigilance.

Less common SPS variants include: persistent focal stiff man or stiff leg syndrome, a cerebellar subtype with truncal ataxia, gait ataxia, dysarthria and abnormal eye movements, and the ‘jerking stiff man syndrome’.

Treatment of SPS

SPS treatments are aimed at symptom relief and/or modulation of the underlying aberrant immune process. The rarity of SPS makes it difficult to recruit sufficient patient numbers for good quality clinical drug trials, hence limiting the quality of treatment guidance. The last 30 years have provided some insight into the various options available and are the foundation upon which current practice is based (see table 3 ). There remains an important role for a multidisciplinary approach to management, including physiotherapy and occupational therapy input.

Main treatment options in stiff person syndrome

Improving symptoms: muscle relaxants and other agents

Benzodiazepines.

Benzodiazepines augment GABA-dependent pathways and are both anticonvulsant and anxiolytic. They are also profound muscle relaxants and have long been a mainstay treatment of SPS. Drugs such as diazepam remain preferred agents for symptom management in SPS. Over time, patients often need increasing doses for symptom relief, sometimes with troublesome side effects. Some patients require and can tolerate very large doses, but uptitration must be undertaken gradually. In general, the trend is for addition or substitution with other therapeutic agents to avoid unwanted effects.

Baclofen is a GABA-B agonist, frequently used to treat spasticity, along with benzodiazepines. Twenty years ago, it was proposed as a treatment for SPS. Most patients are maintained on oral baclofen. Sometimes high doses are needed, which may cause disabling cognitive side effects. Due to poor CSF bioavailability, intrathecal baclofen is used for severe spasticity and can significantly improve the features of both classical SPS and its variant, progressive encephalitis with rigidity and myoclonus. 32

Silbert et al undertook a double-blind placebo-controlled trial of intrathecal baclofen in three patients with SPS. While only one patient reported subjective improvement, all three patients showed significant electrophysiological evidence of improvement and a trend towards improved muscle stiffness on objective scales. 33

Intrathecal baclofen is typically prescribed to patients requiring high-dose benzodiazepines but experiencing intolerable side effects. Clinicians must be cautious when using intrathecal baclofen since interruption in drug delivery can lead to severe symptomatic withdrawal state and even death from autonomic failure. 34 Catheter malfunctions occurs in up to 40% of patients requiring intrathecal infusion devices for spasticity; there is a useful protocol for systematic checks if this is suspected. 35

Other options

Dantrolene and tizanidine have been traditionally used to manage conditions with spasticity, including SPS. These are commonly combined with other muscle relaxants. Tiagabine, gabapentin, valproate and carbamazepine may all help SPS symptoms; vigabatrin is rarely used because of its potential for visual field constriction. Levetiracetam has been the subject of a single-blind placebo-controlled trial in three patients and benefited both symptoms and electrophysiological findings. 36 Propofol helped the stiff limb variant of SPS in a single case refractory to other therapeutic strategies. Intramuscular botulinum toxin A can significantly improve muscle tone and spasms, ambulation and pain in SPS. Analgesics remain an important part of SPS treatment. However, clinicians should be aware that opiate analgesics, while reducing the pain of rigidity and spasms may, on rare occasions, worsen these symptoms; follow-up monitoring is advisable when commencing or uptitrating these drugs.

Disease modifying immunomodulation/immunosuppression

Intravenous immunoglobulin.

Intravenous immunoglobulin (IVIG) is the best second-line treatment for patients with severe or refractory SPS. The evidence for this came originally from several case reports where there were significant improvements in stiffness, startle, functional status and clinical examination findings, as well as most showing radiographic and serological improvements. IVIG has subsequently been shown to improve quality of life in SPS and also to improve symptoms in the GAD-positive stiff limb variant.

A randomised, double-blinded, placebo-controlled, crossover trial of monthly IVIG demonstrated a significant decrease in stiffness, which stabilised during washout and increased again on switching to placebo. IVIG-treated patients reported improvement of symptoms and ability to undertake activities of daily living, lasting between 6 weeks and 1 year. The GAD autoantibody titre also fell after IVIG. 37

While IVIG is generally considered safe, neurologists should be aware of its common and important adverse effects. These include immediate infusion reactions (mild to severe) with a small but potentially risk of fatal anaphylaxis. This occurs typically in IgA-deficient patients, which is therefore a relative contraindication for IVIG. There may also be skin reactions, headaches, aseptic meningitis and renal tubular acidosis. Venous thromboembolic disease is a significant risk, particularly in those with limited mobility. Arterial thrombus formation may lead to stroke, myocardial infarction, pulmonary embolism or ischaemia affecting other tissue beds.

Cost remains a major factor: treatment decisions in the UK are made on a case-by-case basis. However, the rarity of SPS means that the overall cost of treating this patient group is much less than for a more common disease such as chronic inflammatory demyelinating polyradiculoneuropathy. There have been regular updates in the published guidance on the use of IVIG in immune-mediated neuromuscular diseases in recent years. The European Federation of Neurological Sciences recommends IVIG for patients with SPS who respond incompletely to diazepam and/or baclofen and who have a significant disability requiring a cane or walker due to truncal stiffness and frequent falls. 38 The recommended dose is 2 g per kg over 2–5 days.

Plasma exchange

The evidence supporting plasma exchange for SPS is less well established than for IVIG and there have been several conflicting results. Plasma exchange was first used successfully over 20 years ago. In anecdotal reports, some patients enjoyed improvements in symptoms and serological and electrophysiological markers; however, equal numbers had no benefit. Patients showing improvement tended to be on beneficial concomitant medications. To date, there has been no reported randomised placebo-controlled study of plasma exchange in SPS.

As with many autoimmune disorders, the disease course should, in theory, be altered by depletion of mature B cells using rituximab, the chimeric anti-CD20 monoclonal autoantibody. Rituximab was recently shown to give symptomatic and serological remission in patients with otherwise refractory SPS. 39

Other immunomodulatory agents

Corticosteroids have often been used in patients with SPS either as monotherapy or combined with other therapeutic agents with improvement of spasms and autoantibody titre. However, there has never been a good quality clinical trial to determine their overall role in SPS. Other immune system modulating agents give variable benefit, including mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, tacrolimus and sirolimus.

Prognosis and future prospects

SPS follows a variable course over 6–28 years, measured from symptom onset to either the last follow-up visit or death. Its rate of progression depends on several factors, including: (1) whether the initial presentation and symptoms are of classical SPS, (2) belong to the ‘stiff man plus’ category or (3) whether it is associated with disorders such as DM or malignancy. 21 Patients with classic SPS usually respond well to treatment and their condition stabilises over time, although paroxysmal autonomic dysfunction or sudden death occurs in 10% of SPS patients. 21 Autonomic dysfunction results from a succession of spasms or sudden withdrawal of medication. 40

Although SPS is rare, it can cause significant morbidity and mortality; its pathogenesis relates to diseases with major public health impact, including DM and cancer. Further exploration of the link between SPS and DM could help to predict and classify DM, to alter the implications of its therapy and to prevent its associated morbidities. 29

Practice points

■ Stiff person syndrome (SPS) is underdiagnosed and often misdiagnosed.

■ The most prominent clinical finding is hyperlordosis due to lumbar paraspinal and abdominal muscle cocontraction with superimposed spasms.

■ Most cases have a clear autoimmune basis, characterised by autoantibodies against glutamic acid decarboxylase and γ-aminobutyric acid (A) receptor-associated protein. Rarer paraneoplastic variants occur, with antibodies against gephyrin and amphiphysin.

■ In all, 30–40% of SPS patients have, or develop, diabetes mellitus.

■ The diagnosis of SPS should be based on established clinical, laboratory and electromyography criteria. Cases that do not fit within these criteria should be labelled atypical or an alternative diagnosis sought.

■ Psychiatric disorders are common in SPS; referral to a psychiatrist may be necessary as part of the long-term management strategy.

■ Therapeutic approaches include symptomatic therapy and immunomodulatory therapy. Some patients require (and can tolerate) very large doses of diazepam; combination symptomatic treatments are often necessary. Intravenous immunoglobulin is a mainstay treatment for those refractory to symptomatic treatment and is used increasingly early in the disease.

For SPS, the aim should be earlier recognition and treatment under the care of a neurologist. SPS is severely disabling, can substantially affect life expectancy and impair physical and mental capabilities. Disability results in a reduced quality of life and affects an individual's potential for education and earning. Therefore, a better understanding of the natural history, mechanisms of disease and the impact of disease progression over time, along with the long-term effects of treatment, are needed to make further progress.

Acknowledgments

The authors thank Dr Jeremy Rees for permission to reproduce figure 3 . This paper was reviewed by Jeremy Brown, London, UK.

• Moersch FP ,
• Gordon EE ,
• Januszko DM ,
• Lorish TR ,
• Thorsteinsson G ,
• Howard FM Jr .
• Solimena M ,
• Denis-Donini S ,
• Piccolo G ,
• Zandrini C ,
• Vicari AM ,
• Cornman EW ,
• Rakocevic G ,
• Cofiell R ,
• Butler MH ,
• Hayashi A ,
• Ohkoshi N ,
• Dalakas MC ,
• Thompson PD
• Vanderstraeten G ,
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• Aparisi R ,
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• Leslie RD ,
• Atkinson MA
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• Johnson A ,
• Gershanik OS
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• Ruivard M ,
• Achaibi A ,
• Economides JR ,
• Barker RA ,
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• McCombe PA ,
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• Dressnandt J ,
• Silbert PL ,
• Matsumoto JY ,
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• Bardutzky J ,
• Barrocu M ,
• Piluzza MG ,
• Elovaara I ,
• Apostolski S ,
• van Doorn P ,
• Mitsumoto H ,
• Schwartzman MJ ,

Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

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• Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia H Takenoshita et al., Journal of Neurology, Neurosurgery & Psychiatry, 2001
• Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity R A Barker et al., Journal of Neurology, Neurosurgery & Psychiatry, 1998
• Glutamic acid decarboxylase (GAD) antibody-positive paraneoplastic stiff person syndrome associated with mediastinal liposarcoma Binoy Yohannan et al., BMJ Case Reports, 2022
• Asymmetric slowness and dystonic posturing Emily Casaletto et al., Practical Neurology, 2022
• Autoantibodies to glutamic acid decarboxylase in downbeat nystagmus G Antonini et al., Journal of Neurology, Neurosurgery & Psychiatry, 2003
• Specific phobia is a frequent non-motor feature in stiff man syndrome P Henningsen et al., Journal of Neurology, Neurosurgery & Psychiatry, 2003
• Humoral and cellular immune parameters before and during immunosuppressive therapy of a patient with stiff-man syndrome and insulin dependent diabetes mellitus M Hummel et al., Journal of Neurology, Neurosurgery & Psychiatry, 1998
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• Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases H-M Meinck et al., Journal of Neurology, Neurosurgery & Psychiatry, 2001

Stiff Person Syndrome: Explained Stiff Person Syndrome Explained

Stiff Person Syndrome (SPS) is a rare and often misunderstood neurological disorder that can have a profound impact on the lives of those affected. This condition, characterized by progressive muscle stiffness and painful spasms, primarily affects the spine and lower extremities, making even simple movements and daily activities a challenge. SPS is a complex and often debilitating disorder that can leave patients feeling isolated, frustrated, and desperate for answers. For those living with SPS, the journey to diagnosis and treatment can be a long and arduous one. The rarity of the condition, combined with symptoms that can mimic other neurological disorders, means that many patients face a lengthy and frustrating process of medical evaluation before receiving a definitive diagnosis. This diagnostic odyssey can take years, with patients often seeing multiple specialists and undergoing numerous tests before finally receiving a conclusive diagnosis of SPS. At its core, SPS is believed to be an autoimmune disorder that targets the central nervous system, particularly the brain and spinal cord. In most cases, the body produces antibodies that mistakenly attack a protein called glutamic acid decarboxylase (GAD), which plays a crucial role in the synthesis of a neurotransmitter that regulates muscle movement. This attack on the nervous system leads to the hallmark symptoms of muscle stiffness and painful spasms. The exact cause of SPS remains unknown, but researchers believe that a combination of genetic and environmental factors may play a role in the development of the condition. Studies have shown that SPS is more common in individuals with a personal or family history of autoimmune disorders, suggesting that there may be a genetic component to the condition. However, the specific genes involved and the mechanisms by which they contribute to the development of SPS have yet to be fully elucidated. The impact of SPS on a person's life can be significant. Patients often experience a gradual onset of muscle stiffness, beginning in the trunk and progressing to the limbs. This stiffness can be accompanied by painful muscle spasms, which can be triggered by sudden movements, emotional stress, or even unexpected tactile stimuli. As the condition progresses, individuals may find it increasingly difficult to perform everyday tasks, such as walking, sitting, or even breathing, leading to a decreased quality of life and a heightened risk of depression and anxiety. The physical toll of SPS can be immense, with patients often experiencing chronic pain, fatigue, and difficulty with mobility. Many individuals with SPS require the use of assistive devices, such as walkers or wheelchairs, to maintain their independence and engage in daily activities. The constant muscle stiffness and spasms can also lead to secondary complications, such as joint deformities, contractures, and pressure sores, further compounding the challenges faced by patients. In addition to the physical impact, SPS can also take a significant emotional and psychological toll on patients and their families. The chronic nature of the condition, combined with the lack of a cure and the often-unpredictable course of the disease, can lead to feelings of frustration, helplessness, and despair. Patients may struggle with the loss of their independence, the strain on their relationships, and the financial burden of managing a chronic illness. Despite the challenges posed by SPS, there is hope for those living with the condition. While there is currently no cure, treatments are available to help manage symptoms and improve quality of life. Medications such as benzodiazepines, baclofen, and intravenous immunoglobulin (IVIg) have been shown to be effective in reducing muscle stiffness and spasms. These medications work by targeting the underlying autoimmune process, reducing inflammation, and promoting muscle relaxation. Physical therapy...

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Case report, statement of ethics, conflict of interest statement, funding sources, author contributions, data availability statement, recurrent acute on chronic respiratory failure in stiff person syndrome.

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Bhumika Bheemavarapu , Arkaja Singh , Nived Jayaraj Ranjini , Venkata Sai Abhilash Meda , Dhrumil Patil; Recurrent Acute on Chronic Respiratory Failure in Stiff Person Syndrome. Case Rep Neurol 22 December 2023; 15 (1): 187–191. https://doi.org/10.1159/000532093

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Stiff person syndrome (SPS) is an extremely rare disease that presents with episodic painful muscle spasms and progressive muscle rigidity. Recent evidence suggests that SPS can rarely manifest with life-threatening respiratory complications. However, the pathophysiology behind respiratory failure in SPS is still not clearly understood. Here, we explored an extremely rare case of a 36-year-old African-American female with SPS presenting with multiple episodes of respiratory failure events for the past 9 years. She had an in-situ tracheostomy and was admitted to the hospital for tracheostomy evaluation and decannulation. 11 years ago she initially presented with gait abnormalities, stiffness, and spastic episodes. She was diagnosed 1 year later with SPS after detecting elevated anti-glutamic acid decarboxylase antibody levels in her blood. Through this report, we were able to follow a very rare case of SPS that presented with multiple episodes of respiratory failure. We pointed out the importance of early start and regular administration of diazepam, baclofen, and IVIg in not only controlling the symptoms and progression of the disease but also in preventing further respiratory failure and possible sudden death.

Stiff person syndrome (SPS) is a rare disorder of the central nervous system characterized by rigidity and stimulus triggered painful muscle spasms of predominantly axial and proximal limb muscles. It was first described in 1956 by Frederick Moersch and Henry Woltman based on a case series of 14 patients with progressive fluctuating tightness of the spinal, abdominal, and thigh muscles. This condition was formerly named stiff-man syndrome and is also known as Moersch-Woltman syndrome [ 1 ].

The disease affects women two to three times more than men with a prevalence of one to 2 patients per million. SPS presents with muscle rigidity, which starts in the proximal muscles and progresses distally. Patients have recurrent falls, muscle spasms, and chronic muscle pain [ 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 ]. The diagnosis is often delayed due to the rarity of the disease and the lack of knowledge of this condition by clinicians [ 2 ].

Acute respiratory failure manifesting with apneic episodes is an extremely rare life-threatening and unpredictable complication of SPS, let alone multiple episodes occurring in a patient over time. Its pathophysiology is not well known. The two suggested mechanisms are as follows: (1) apnea due to muscle rigidity and paroxysmal muscle spasms and (2) paroxysmal autonomic hyperactivity [ 2 ]. In severe cases of SPS, apnea, and sudden death have been described [ 3‒5 ]. In this paper, we present a patient diagnosed with SPS who developed recurrent acute on chronic respiratory failure episodes, currently on ventilator support with intravenous immunoglobulin (IVIG) therapy and GABA-ergic drugs. The report also highlights that physicians should be extremely vigilant in the treatment of SPS patients with a history of respiratory distress.

A 36-year-old African-American female with previously diagnosed stiff person syndrome, with an in-situ tracheostomy was admitted to the hospital for tracheostomy evaluation and decannulation. She was unable to tolerate Passy-Muir valve trials and was temporarily placed under observation on oxygen via nasal cannula and capping of the tracheostomy cannula. But during this period, she developed rapid changes in her mental status. She became unresponsive and developed tachycardia and hypotension. She was transferred to ICU on assist control mode ventilator support. Her blood cultures showed methicillin-sensitive Staph aureus (MSSA) bacteremia and chest X-ray suggestive of right lobar pneumonia. Her first presentation of SPS was in 2010 when she presented with complaints of multiple fall episodes. During the episodes of muscle spasm, she was not able to move her body voluntarily. She had no issues with breathing, swallowing, voiding, or defecation. She initially presumed her fatigue, cramps, and stiffness to be related to her work but presented to the hospital when it started affecting her daily routine. The patient had no history of other autoimmune diseases like type 1 diabetes, pernicious anemia, vitiligo, or carcinoma. Her symptoms continued to worsen over the next year. Psychological and physical stress were the triggering factors for the spastic episodes. Clinical examination during these episodes showed arterial hypertension, profuse sweating, agitation, and increased tone of affected limbs. Mental status was normal between hypertonic crises and there was no neck stiffness, myoclonus, or ataxia. Cardiovascular and respiratory examinations were unremarkable. She underwent various investigations including blood tests, cerebrospinal fluid studies, imaging studies of the brain and spinal cord, and an electroencephalogram. They all were unremarkable, suggesting the need for an alternate diagnosis. She was eventually diagnosed with stiff person syndrome in 2013, after an electromyographic study revealed continuous motor-unit activity and a high titer of circulating anti-GAD antibodies (>1200 U/mL, N <1 U/mL).

Following the diagnosis, symptomatic treatment was initiated with diazepam 10 mg q8h and baclofen 10 mg q8h with IVIg therapy every 6 weeks. Whenever she missed a few doses of IVIg, she started having repeated episodes of stiffness and rigidity with gradual progressive breathing difficulty. In late 2013, she was admitted in the ICU for respiratory failure and was on mechanical ventilation via tracheostomy and feeding tube for nutrition. She was sent for respiratory rehabilitation after decannulation and sent home with her maintenance medications. For the next 3 years, she was able to perform all the activities of daily life independently and her symptoms were well maintained on pharmacological therapy. In 2016, she again developed shortness of breath and was admitted to the hospital for a month with respiratory failure after missing her medications. She was transferred to various hospitals with respiratory failure with minimal improvement and was discharged on diazepam 10 mg q8h and baclofen 10 mg q8h. In 2020, the treating physician at a hospital felt the need to adjust her diazepam dose (10 mg Q8H) as it was not alleviating her respiratory problems and changed it to a dose of 30 mg once daily, but it caused worsening of the respiratory symptoms forcing the doctor to go back to her regular dose of 10 mg Q8H. She had multiple relapses of respiratory failure warranting short hospital admissions over the past few years. With baclofen, diazepam, and IVIG, she reported improvement in her motor symptoms. She could walk on her own with support. Currently, she is responding well with antibiotics for her bacteremia and pneumonia. She is still on ventilatory support via tracheostomy and continues to have spasms on prompt stimulus.

Acute respiratory failure manifesting with apneic episodes is a life-threatening and unpredictable complication of SPS. It is thought that impairment of GABAergic pathways by autoantibodies and a reduction of brain GABA result in clinical manifestations of stiffness, spasms, and phobias. Thus, respiratory difficulties may be caused by spasms of the diaphragm, impaired respiratory function, and sudden tonic rigidity involving the respiratory muscles [ 4 ]. The lack of GABA-ergic inhibition in the intermediolateral cell column, however, may lead to sympathetic overactivity. This autonomic hyperactivity can lead to paroxysmal attacks of transient arterial hypertension, hyperpyrexia, tachycardia, pupillary dilatation, agitation, and diaphoresis during painful muscle spasms. In our case, mechanical ventilation by itself did not alleviate respiratory symptoms; and only neuromuscular-blocking agents allowed correct ventilation parameters. Sudden and unexpected deaths have been reported in SPS, and all described cases have been associated with apnea [ 3‒5 ]. Thus, we believe that the onset of apnea during SPS, regardless of the underlying mechanism, should be considered as a criterion of high severity and should lead to ICU admission for continuous monitoring until the effect of immunotherapy. In patients with life-threatening complications, early immunotherapy by IVIG should be considered [ 6 ]. Multiple discrete episodes of respiratory failures in this patient may have been triggered due to interruptions in the treatment. History elicited from this patient suggests that some episodes were triggered by missing medications. In the most recent episode of respiratory failure needing ventilator support, the patient also had pneumonia with MSSA sepsis which exacerbated the episode or possibly triggered it. So, adherence to regular medications should be a priority while treating a person with SPS. We should anticipate respiratory distress in patients with SPS and should monitor and tailor-make appropriate therapy including early immunotherapy, especially in patients with a previous history of respiratory distress. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material1 (for all online suppl. material, see https://doi.org/10.1159/000532093 ).

Progression to respiratory failure in stiff person syndrome is a fatal deteriorating complication leading to prolonged ICU stay for continuous monitoring. Many described cases of sudden and unexpected deaths being reported in SPS have been strongly associated with apnea and respiratory failure. We strongly believe in the need to know more about the pathophysiology behind the respiratory failure events in this patient as it has a pernicious effect on her mental and physical health. We also were able to point out the efficacy of early start and regular administration of diazepam, baclofen, and IVIg in controlling symptoms and progression of the disease to an extent. Physicians should anticipate respiratory distress in SPS, especially in patients with a prior history of respiratory distress. Clinicians should be vigilant of further episodes and must ensure adherence to medical therapy at all possible situations to prevent respiratory failure events and possible sudden death.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

No funding sources were used for this report.

Bhumika Bheemavarapu: gathering data, drafting, and reviewing. Arkaja Singh: gathering data, drafting, and reviewing. Nived Jayaraj Ranjini: gathering data, drafting, and reviewing. Venkata Sai Abhilash Meda: drafting and reviewing. Dhrumil Patil: drafting and reviewing.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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Céline Dion Shares Stiff Person Syndrome Health Update: “I Hope That We’ll Find a Miracle”

By Kase Wickman

Céline Dion knows that Stiff Person Syndrome, the rare condition that causes uncontrollable and often violent muscle spasms, will always be a part of her life in some way. In a new interview with Vogue France , published Monday, Dion shared health updates and said she’s “well, but it’s a lot of work. I’m taking it one day at a time.”

“I haven’t beat the disease, as it's still within me and always will be,” she said. “I hope that we’ll find a miracle, a way to cure it with scientific research, but for now I have to learn to live with it. So that’s me, now with Stiff Person Syndrome.”

The 56-year-old singer shared her diagnosis in early 2022 after a series of postponements for her tour. She largely disappeared from public outings , but she has recently been making notable appearances, including presenting Taylor Swift with her record-breaking fourth Album of the Year award at the 2024 Grammys and hugging it out with the singer backstage . Dion told Vogue that “five days a week I undergo athletic, physical and vocal therapy. I work on my toes, my knees, my calves, my fingers, my singing, my voice... I have to learn to live with it now and stop questioning myself.”

Dion is focused on moving forward, done lingering on the existential woe.

“Life doesn’t give you any answers. You just have to live it!” she said. “I have this illness for some unknown reason. The way I see it, I have two choices. Either I train like an athlete and work super hard, or I switch off and it’s over, I stay at home, listen to my songs, stand in front of my mirror and sing to myself. I’ve chosen to work with all my body and soul, from head to toe, with a medical team. I want to be the best I can be. My goal is to see the Eiffel Tower again!”

The interview turned philosophical as she looked forward: “People question life all the time,” she said. “Stop questioning life, we should be living it. It’s not always beautiful, but it’s here.”

That seeming acceptance, however, doesn’t come easily. “It’s hard, I’m working very hard and tomorrow will be even harder. Tomorrow is another day,” she said. “But there's one thing that will never stop, and that’s the will. It’s the passion. It's the dream. It’s the determination.”

Though she couldn’t say when or even whether she’ll be ready to perform again publicly, she emphasized the “gift” of support from her loved ones and “the means to have good doctors and good treatments.”

“What’s more, I have this strength within me,” she said. “I know that nothing is going to stop me.”

Her dream, she said, is to “live in the present.”

“I am truly very lucky,” Dion said. “And I am honored to be doing a photo shoot for Vogue France because although I had better health and beauty at 30, I didn’t get asked to do one then. I am very proud that at 55, I am being asked to reveal my beauty. But what is beauty? Beauty is you, it’s me, it’s what’s on the inside, it’s our dreams, it’s today. Beauty is what surrounds us, it is there. There are people that see it, and there are people that observe it. Today, I am a woman who feels strong and positive about the future. One day at a time.”

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What you need to know about Stiff Person Syndrome (SPS)

Chronic condition that causes muscle stiffness and painful muscle spasms.

Stiff Person Syndrome (SPS) ...

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Céline Dion Details Stiff Person Syndrome Diagnosis: ‘I Hope That We’ll Find a Miracle … but for Now I Have to Learn to Live With It’

By Ellise Shafer

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Pop legend Céline Dion is opening up about her life with Stiff Person Syndrome, saying that she still hopes “we’ll find a miracle,” but is learning “to live with it.”

In a new interview with Vogue France, the Canadian singer discussed the neurological disorder, which causes progressive muscular stiffness. Following her diagnosis in December 2022, Dion has halted her touring schedule and stayed largely out of the spotlight, though she made a surprise appearance at the Grammys in February and earned a huge standing ovation.

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Dion said that she felt she had two choices: “Either I train like an athlete and work super hard, or I switch off and it’s over, I stay at home, listen to my songs, stand in front of my mirror and sing to myself.”

She continued, “I’ve chosen to work with all my body and soul, from head to toe, with a medical team. I want to be the best I can be. My goal is to see the Eiffel Tower again!”

However, Dion confirmed that any plans to perform are still undetermined as she works to get stronger.

‘For four years I’ve been saying to myself that I’m not going back, that I’m ready, that I’m not ready… As things stand, I can’t stand here and say to you: ‘Yes, in four months,'” she said. “I don’t know… My body will tell me. On the other hand, I don’t just want to wait. It’s morally hard to live from day to day. It’s hard, I’m working very hard and tomorrow will be even harder. Tomorrow is another day. But there’s one thing that will never stop, and that’s the will. It’s the passion. It’s the dream. It’s the determination.”

Read Dion’s full interview on Vogue France’s website .

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Celine Dion goes into detail about stiff person syndrome in heartbreaking revelation

The singer's health struggles have been public since her diagnosis was announced in late 2022.

In an intimate and revealing new interview, the legendary Celine Dion shared her ongoing battle with stiff-person syndrome and her unwavering determination to one day return to the stage. 

The iconic singer, at 56, discusses the challenges and the inner strength she draws from to face each day with hope and resilience.

Celine's health struggles have been public since her diagnosis was announced in late 2022, but it is her enduring spirit that truly captivates. 

"I can't answer that… Because for four years I've been saying to myself that I'm not going back, that I'm ready, that I'm not ready," she confessed to Vogue France, reflecting the profound uncertainty that stiff-person syndrome has cast over her storied career. 

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This rare neurological disease causes severe muscle spasms and impacts motor functions, making public performances a monumental challenge.

Despite the hurdles, Celine's resolve remains unbroken. "It's morally hard to live from day to day. It's hard, I'm working very hard and tomorrow will be even harder," she admits. 

Yet, it is her will that sustains her: "But there's one thing that will never stop, and that's the will. It's the passion. It's the dream. It's the determination."

Her routine is grueling, involving five days of rigorous physical, vocal, and athletic therapy each week. 

"I work on my toes, my knees, my calves, my fingers, my singing, my voice," she details, giving insight into the comprehensive efforts to manage her condition.

The Canadian superstar also opens up about the emotional toll of her illness: "At the beginning I would ask myself: why me? How did this happen? What have I done? Is this my fault?" These reflections reveal her vulnerability and the human side of dealing with a life-altering condition.

The "I'm Alive" singer's optimism shines through her pragmatic outlook. "Life doesn't give you any answers. You just have to live it! I have this illness for some unknown reason," she states, accepting the randomness of her situation but refusing to be defined by it.

Celine envisions her future with two options: to retreat or to fight. Her choice is clear as she plans to "train like an athlete" with a dedicated medical team, aiming to regain enough strength to live her dreams once again. 

"My goal is to see the Eiffel Tower again!" she shares, symbolizing her hope to return to normalcy and perhaps, the stage.

Fans of Celine will get a closer look at her journey in the upcoming Prime Video documentary I Am: Celine Dion , which promises to chronicle her life and current health struggles.

 Get the lowdown on the biggest, hottest celebrity news, features and profiles coming out of the U.S.  Sign up to our HELLO! Hollywood newsletter and get them delivered straight to your inbox. 

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