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.

Objectives:

• 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:

1. Classic SPS
2. Partial SPS variants
3. 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.

Etiology

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

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]

Evaluation

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: 

1. Stiffness in the limb and axial muscles, prominent in the abdomen and thoracolumbar region
2. Painful spasms precipitated by unexpected tactile and auditory stimuli
3. Evidence of the continuous motor unit activity in agonist and antagonist muscles demonstrated by EMG
4. Absence of other neurological impairments that could support an alternative diagnosis
5. Positive serology for anti-GAD65 or anti-amphiphysin autoantibodies
6. 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
• Tetanus
• Functional neurological disorder

Prognosis

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.