Stiff Person Syndrome

Disease/Disorder

Definition

Stiff person syndrome (SPS) is a rare autoimmune disorder of the central nervous system consisting of fluctuating, progressive rigidity of truncal and proximal limbs due to continuous co-contracture of agonist and antagonist muscles, with episodic painful muscle spasms.^1,2 It is a clinic diagnosis and can be further delineated into classic SPS or several phenotypic variations, each with unique clinical features.

Etiology

The exact cause of SPS is currently unknown, though evidence supports an autoimmune etiology. An association between SPS and several nonspecific autoantibodies has been demonstrated.¹ Reduced neurotransmission of g-aminobutyric acid (GABA) is thought to play a key role through an immune-mediated process.² SPS is often associated with other autoimmune conditions.² 

Epidemiology including risk factors and primary prevention

Stiff person syndrome is rare, with an estimated prevalence of 1-2 cases per million and an annual incidence of 1 case per million.³ Classic SPS is the predominant phenotype. It accounts for approximately 70% of cases, typically presents between the ages of 20-50, and affects women 2-3 times more frequently than men.^3,4 SPS and its spectrum of disorders are often associated with other autoimmune conditions, most notably insulin-dependent diabetes mellitus. Other associated conditions include pernicious anemia and autoimmune diseases that affect the thyroid and gastrointestinal system.^1,2 Non-neoplastic etiologies encompass about 95% of cases. However, several malignancies have demonstrated an association with SPS, including breast cancer, small cell lung cancer, lymphoma, and thymoma.^3,4 Timely diagnosis of SPS is challenging. In addition to being rare, it is considered a diagnosis of exclusion.² Time to diagnosis can range from 1 to 18 years, taking 6.2 years on average.^2,5

Patho-anatomy/physiology

The pathophysiology of SPS is thought to involve reduced neurotransmission of g-aminobutyric acid (GABA) in the central nervous system through an immune-mediated process.^2,6 Most individuals with SPS have circulating anti-glutamate decarboxylase (GAD) antibodies, which inhibit GABA synthesis in the central nervous system.⁶ This leads to reduced GABA concentration in the brain and subsequent loss of neural inhibition of the muscles, which results in excessive unintentional muscle contractions.^2,6,7 Current research shows 70-85% of patients with SPS demonstrate high-titer serum antibodies against the isoform GAD65.⁴ As such, antibodies against GAD65 can aid in the diagnosis of SPS. Additionally, antibodies against the GABA_A receptor (GABARAP) have been found in 65-70% of patients with SPS.^2,4 Autoantigens postulated to be involved in SPS are listed in Table 1. Additional possible mechanisms of immunopathology include T cell-mediated cytotoxicity, autoantibody-mediated inhibition and/or internalization of neuronal cell receptors (i.e., glycine receptors), autoantibodies to accessory proteins on neuronal membranes, and autoimmune interference of pre-synaptic vesicular recycling and neuronal signaling.⁴

Table 1. Autoantigens associated with stiff person syndrome.^2,4

Autoantigen	Special notes
Glutamic Acid Decarboxylase (GAD65)	Most-common autoantibody in classic SPS
GABAA Receptor-Associated Protein (GABARAP)	Second most-common autoantibody in classic SPS
Glycine-a1 Receptor
Amphiphysin	Paraneoplastic SPS, especially in those with breast cancer
Gephyrin	Paraneoplastic SPS
Neuronal Nuclear Antigen (Ri)	Paraneoplastic SPS

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

• Disease progression occurs insidiously. Rigidity and stiffness of trunk muscles occur due to co-contraction of thoracolumbar and abdominal musculature. These are the earliest symptoms, leading to the classic lumbar spine “hyperlordosis” appearance of SPS.⁵ In the early phase, patients may be misdiagnosed with Parkinson’s disease, primary lateral sclerosis, multiple sclerosis, or a primary psychiatric disorder.² Rigidity progresses from the trunk outward to involve proximal lower limb muscles, leading to development of a slow, wide gait. Eventually, total body stiffness develops.²
• Muscle spasms, superimposed on muscle rigidity, are initially intermittent. They are commonly caused by startle, psychological factors, and passive or active range of motion of either affected or unaffected muscles.⁵ Spasms are painful and disabling, can occur in bouts, and tend to last several minutes or until removal of the precipitating stimulus.⁵ Phobias and anxieties associated with spasm triggers may also become severe, and falls become a frequent concern. Patients may present to emergency departments with severe spasms which, when affecting respiratory and thoracic paraspinal muscles, lead to severe breathing difficulty in a phenomenon coined “status spasticus.”^1,2
• Due to development of total body stiffness and increased frequency and intensity of muscle spasms, patients are often bedridden in later stages of the disease. Individuals may become entirely dependent on others for mobility and completion of activities of daily living.²

Table 2. Diagnostic criteria for stiff person syndrome.^1,3

Major criteria

Stiffness of axial and limb muscles with co-contracture of abdominal and thoracolumbar paraspinals leading to “hyperlordosis” of the lumbar spine

Superimposed painful spasms precipitated by tactile stimuli, emotional stressors, or unexpected noises

EMG evidence of continuous motor unit activity in agonist and antagonist muscles simultaneously

Absence of other neurologic disease to explain stiffness and rigidity

Minor criteria

Positive anti-GAD65 (or anti-amphiphysin) serum antibodies

Clinical response to benzodiazepines

Specific secondary or associated conditions and complications

Progressive muscle rigidity and painful muscle spasms lead to gait difficulties and frequent falls. Falls from severe spasms may appear ‘statue-like’ missing the typical reflexic response to soften the impact and prevent injury.^2,3 This may result in long-bone fractures or joint dislocations.⁵ More severe complications may include dysautonomic crises, esophageal obstruction due to cricopharyngeal muscle spasm, and hypoxemic respiratory failure. Some of the more common SPS clinical phenotypes and their hallmark symptoms are outlined in table 3.

In addition to the classic neurological features, patients with SPS often present with anxiety and task-specific phobias. This can sometimes lead to misdiagnosis of a primary psychogenic disorder. These phobias generally stem from genuine concerns over falls, spasm episodes, and known symptom triggers, distinguishing them from a psychiatric disorder.^2,3

Table 3. Clinical phenotypes of stiff person syndrome spectrum disorders.⁴

Phenotype	Common characteristics
Classic	Torso and lower extremity > upper extremity involvement
	Hallmark muscle rigidity and spasms
	Robust response to GABAergic agonists early in course
Partial	Isolated to one extremity or torso
	Hallmark muscle rigidity and spasms
	Robust response to GABAergic agonists early in course
SPS-plus	Classic phenotype plus brainstem and/or cerebellar symptoms
		• Brainstem findings: oculomotor dysfunction, dysarthria, dysphagia
		• Cerebellar findings: central nystagmus, appendicular or gait ataxia
	Robust response to GABAergic agonists early in course
Pure cerebellar ataxia	Central vertigo, scanning speech, oculomotor dysfunction, appendicular dysmetria, gait ataxia, incoordination, poor manual dexterity
	Cerebellar volume loss/atrophy on MRI
Progressive encephalomyelitis with rigidity and myoclonus (PERM)	Neck, torso, extremity, brainstem, and/or cerebellar symptoms
	Mixture of other phenotype findings plus encephalopathy and severe torso rigidity and/or myoclonus (multifactorial or generalized)
	Generalized slowing and/or epileptic discharges on EEG
	Autonomic dysfunction
	CSF pleocytosis
	T2 contrast-enhancing lesion(s) in brainstem on MRI

Essentials of Assessment

History

A detailed history should assess time course, including onset of symptoms and nature of symptom progression. Providers should ask about location, quality, and frequency of muscle rigidity and spasms and any associated triggers. It is important to inquire about prior workup, history of falls, and psychological symptoms.^1,5 Pain is common and should always be assessed. While spasms can be painful, pain can also be a trigger for spasms.⁷ Prior medical history and family history including cancer, autoimmune conditions, and muscle or nerve disorders is paramount. Social history should be discussed as well, with focus on level of independence and performance of self-care tasks.

Physical examination

Classic physical exam findings include hyperlordosis of the lumbar spine and increased tone in truncal muscle groups, resulting in a characteristic “woody” feel on palpation. Increased tone in the legs more than the arms is often present as the disease progresses and is greatest in proximal muscle groups.^4,5 Muscle rigidity results in reduced active and passive range of motion, postural instability, and a slow, wide, cautious gait.^2,5 Reflexes can also be hyperactive. The head retraction reflex, a nonspecific abnormal cutaneo-muscular brainstem reflex elicited by tapping the nasal ridge, upper lip, glabella, or chin, provoking backward jerk of the head or truncal retropulsion, may be present.^3,5 Visual function disturbances, such as gaze palsies or nystagmus, are often present if the cerebellum and/or brainstem are involved. Coordination impairment is additionally noted with cerebellar involvement.^4,5

Full muscle strength is maintained until late disease stages. Sensation, cognition, and sphincter function are expected to be normal if assessed on physical exam.⁵

Functional assessment

Functional assessment should be comprehensive and multifaceted with a focus on determining an individual’s ability to perform activities of daily living and assess their ability to participate meaningfully in their community. It will vary significantly depending on disease burden and time course. Some widely used tools such as the Modified Rankin Scale (mRS) for neurologic disability, the Functional Independence Measure (FIM), and the 36-Item Short Form Survey (SF-36) for quality of life could aid in functional assessment of individuals with SPS.^4,8

Laboratory studies

Consider the following studies⁵

• Basic serology such as complete blood count, comprehensive metabolic panel, fasting glucose, hemoglobin A1C, liver function tests, thyroid function tests, creatine kinase
• Inflammatory markers (erythrocyte sedimentation rate and C-reactive protein)
• Autoantibody panels
  • Anti-GAD65
  • Anti-gephyrin and anti-amphiphysin in patients who test negative for anti-GAD65 antibodies
  • Anti-GABA_A receptor-associated protein (anti-GABARAP) and anti-Ri in atypical presentations
  • Anti-parietal cell, anti-tissue transglutaminase, anti-intrinsic factor, anti-thyroid microsomal autoantibodies, antinuclear antibodies, and extractable nucleic antigen panel to identify co-existing autoimmune diseases (if clinically relevant)

Imaging

Imaging is mainly useful to rule out other central nervous system pathologies and for detection of malignancy. MRI of the brain and spinal cord may be obtained for visualization of the central nervous system. Neoplastic workup may include any of the following when clinically indicated to identify a potential primary tumor⁵

• Chest x-ray
• Spinal x-ray
• CT scan of the chest, abdomen, pelvis
• Colonoscopy
• Mammography
• Breast ultrasound
• Thyroid ultrasound and/or nuclear imaging
• Whole body FDG-PET scan

Supplemental assessment tools

Diagnosis of SPS is established by clinical characteristics and confirmed by antibody testing and/or electromyography (EMG). EMG demonstrates involuntary continuous motor unit activity in agonist and antagonist muscle groups occurring simultaneously at rest. The motor unit action potentials have normal morphology and firing rates, and there are no findings to suggest denervation.⁹

Early predictions of outcomes

SPS follows a variable course that can be difficult to predict. Phenotypic variations of stiff person syndrome may present and progress differently from one another, and cases secondary to malignancy often depend on prognosis and management of the underlying condition. Those with classic SPS tend to respond well to treatment, with their condition gradually stabilizing over time. That said, paroxysmal autonomic dysfunction or sudden death occurs in about 10% of cases.⁵ Delay to diagnosis and treatment is significantly related to long-term progression and increased disease severity.³ The presence of cerebellar- or brainstem-related symptoms and an increased level of disability at time of diagnosis are associated with poorer outcomes compared to those with classic or partial SPS phenotypes.⁴

Recent data suggests some association exists between elevated anti-GAD65 serum titers beyond a certain threshold and increased disease burden.^4,10 However, prior studies demonstrated no correlation between serum or cerebrospinal fluid anti-GAD65 titers and disease severity or duration.^2,11 This limits the potential usefulness of antibody titer monitoring throughout the disease course and underlies the need for biomarkers that aid in predicting future disability and monitoring treatment response.^2,4

Environmental

As the disease progresses, it is important to maintain a safe home environment and reduce fall risk. Many patients will require assistive devices and/or assistance from another individual for safe functional mobility and completion of activities of daily living. Some individuals may use mobility aids due to fear of falling, even when the degree of muscle rigidity is not severe.⁵ Avoidance of stressful environments is essential to prevent triggering episodes of dysautonomia or muscle spasm.

Social role and social support system

Up to 65% of individuals with SPS require physical assistance to perform activities of daily living.² A strong support system is extremely important, particularly as the disease progresses to its later stages.

Professional issues

Stiff person syndrome is particularly challenging to diagnose and treat due to its rarity, the lack of known biomarkers to aid in diagnosis, and limited treatment modalities. Delays in diagnosis and treatment have significant negative implications on disease progression. In addition to a strong support system and suitable home environment, a comprehensive medical and rehabilitation team is vital to maintain safety and maximize quality of life.

Rehabilitation Management and Treatments

Available or current treatment guidelines

The low prevalence of SPS cases limits the ability to design and carry out high quality clinical trials. As such, there are no expert consensus guidelines for pharmacotherapy or rehabilitation. In clinical practice, the mainstay of SPS treatment involves a combination of disease modifying immunotherapy and symptom management with GABA-enhancers, muscle relaxants, anti-epileptics, and nonpharmacologic therapies.^2,3,5

Rehabilitation interventions should focus on improving passive range of motion, balance, coordination, postural control, gait training, and relaxation techniques.^8,12 Additional modalities include massage, electrotherapy, hydrotherapy, heat therapy, myofascial techniques, and osteopathic manipulation.⁴

At different disease stages

• Symptom management
  • Benzodiazepines, which are GABA_A enhancers, are the mainstay of treatment. Diazepam is the first line option for SPS. Total daily doses can range from 5mg to 100mg, with an average of about 20-60mg.² High doses are frequently required as the disease progresses. Patient tolerance may be limited by excessive sedation.²
  • Baclofen, a GABA_B agonist, is a useful adjunct to treatment with benzodiazepines to reduce rigidity and muscle spasms. One potential side effect is cognitive slowing.^2,3
  • Antiepileptics such as gabapentin, vigabatrin, valproic acid, and carbamazepine can be considered. Vigabatrin, though effective, is often avoided due to its potential to cause visual field constriction.^2,5
  • Muscle relaxants such as dantrolene and tizanidine can also assist with management of spasms and tone^2,5
• Disease modifying immunotherapy
  • Intravenous immunoglobulin (IVIg) is the best second-line treatment behind benzodiazepines. It is especially useful as maintenance therapy in those with severe or refractory SPS. It has been studied at 2g/kg divided into two daily doses, and has been shown to improve stiffness, startle response, and ambulation, reduce falls and phobias, and improve functionality and community participation.^2,5,13
  • Additional pharmacotherapies have demonstrated benefit in case reports, case series, and small clinical trials:
    • Levetiracetam improved muscle rigidity and paroxysmal symptoms in three women with SPS.¹⁴
    • Plasmapheresis demonstrated a potential benefit for both acute exacerbations and long-term maintenance therapy when used as an adjunct or as monotherapy.^4,15
    • Propofol, rituximab, and botulinum toxin injections demonstrated possible benefit, whereas corticosteroids have demonstrated surprisingly little utility thus far.^2,5,16,17
    • Intrathecal baclofen reduced spasticity and pain; however, it is often considered a last-resort treatment due to the possibility of acute withdrawal and catastrophic spasms that could result from pump malfunction.^2,18,19

Coordination of care

Management of stiff person syndrome is complex and requires multidisciplinary care between numerous specialties. The treatment team typically includes primary care, neurology, physical medicine and rehabilitation, physical therapy, occupational therapy, speech language pathology, neuropsychology, and psychiatry.^5,8,12 Neurosurgery may be engaged when intrathecal baclofen pump implantation is being considered as part of the treatment plan.^18,19

Patient & family education

Patients and their families should receive continuous education on the anticipated clinical course and potential disease-related complications. Long-term outcomes and expectations for increasing levels of assistance with self-care should also be discussed. Various treatment options should be proposed, while being forthcoming about the lack of robust clinical research. Establishing patient and family goals early after diagnosis and reassessing throughout the disease process is paramount.

Measurement of treatment outcomes

While there are currently no rating scales specific to SPS that are routinely used in clinical practice, there are several assessment tools that can be useful for tracking treatment outcomes. Disease severity and response to treatment may be monitored through changes in functional outcomes based on the Center for Medicare and Medicaid Services Inpatient Rehabilitation Facility–Patient Assessment Instrument (previously Functional Independence Measure), spasticity via the Modified Ashworth Scale or Tardieu Scale, gait speeds, balance scores, and other general clinical examination findings. Symptom burden, quality of life, and psychological factors can be monitored through subjective reporting or questionnaires.^5,8,19

Two main scales have been developed to monitor response to treatment with immunotherapies in clinical trials.^2,11 Each item is rated as present or absent. The presence of each item adds 1 point.

1. Distribution of stiffness and cramps (maximum score 6)
   • Stiffness in the face
   • Stiffness in the arms
   • Stiffness in the upper trunk
   • Stiffness in the abdomen
   • Stiffness in the lower trunk
   • Stiffness in the legs
2. Heightened sensitivity to external stimuli (maximum score 7)
   • Noise-induced stiffness and cramps
   • Visual stimuli–induced stiffness and cramps
   • Somatosensory-induced stiffness and cramps
   • Voluntary activity–induced spasms
   • Emotional upset and “stress”-induced spasms
   • Awakenings due to nocturnal spasms
   • Untriggered cramps and spasms

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

When a diagnosis of SPS is being considered, clinicians should be careful to rule out other central nervous system disorders and underlying malignancies. Once other diagnoses have been ruled out, SPS workup with electromyography and autoantibody panels should occur quickly, as the delay in stiff person syndrome diagnosis has huge implications on its overall progression. In paraneoplastic stiff person syndrome, the primary management is treatment of the underlying malignancy.⁸

Cutting Edge/Emerging and Unique Concepts and Practice

Emerging treatments include subcutaneous immunoglobulin (SCIG) and autologous hematopoietic stem cell transplantation (auto-HSCT). Individual case reports and case series have described auto-HSCT as well-tolerated and potentially beneficial for a subgroup of patients with refractory SPS presenting with intermittent symptoms, absence of limb rigidity, lack of hyperreflexia, presence of anti-GAD65 in the CSF, and unremarkable EMG findings.⁴

Gaps in the Evidence-Based Knowledge

The low prevalence of stiff person syndrome and its various phenotypes limits the ability to conduct large-scale clinical trials. Improved understanding of the pathophysiology and identification of useful clinical biomarkers would enable the development of more refined diagnostic criteria and facilitate earlier diagnosis and treatment. This is essential to slowing disease progression and limiting future disability.⁴ Identifying biomarkers that correlate with disease severity would also support prognostication and guide treatment.

References

1. Dalakas MC, Fujii M, Mian Li, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000;55(10):1531-1535. doi:10.1212/WNL.55.10.1531.
2. Dalakas MC. Stiff person syndrome: Advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-110. doi:10.1007/s11940-009-0013-9.
3. Baizabal-Carvallo JF, Jankovic J. Stiff-person syndrome: insights into a complex autoimmune disorder. Journal of Neurology, Neurosurgery and Psychiatry. 2015;86(8):840-848. doi:10.1136/jnnp-2014-309201.
4. Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than meets the eye. Journal of neuroimmunology. 2022;369:577915. doi:10.1016/j.jneuroim.2022.577915.
5. Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. Stiff person syndrome. Practical Neurology. 2011;11(5):272-282. doi:10.1136/practneurol-2011-000071.
6. Levy LM, Levy-Reis I, Fujii M, Dalakas MC. Brain γ-Aminobutyric Acid Changes in Stiff-Person Syndrome. Archives of neurology (Chicago). 2005;62(6):970-974. doi:10.1001/archneur.62.6.970.
7. Cirnigliaro FA, Gauthier N, Rush M. Management of refractory pain in Stiff-Person syndrome. BMJ case reports. 2021;14(1):e237814. doi:10.1136/bcr-2020-237814.
8. Dogruoz Karatekin B, Sahin SN, İcagasioglu A. Rehabilitation in paraneoplastic stiff-person syndrome – Case Report. Journal of musculoskeletal & neuronal interactions. 2021;21(2):322-325. https://www.ncbi.nlm.nih.gov/pubmed/34059578.
9. Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: Understanding of electrophysiological and immunological processes. Muscle & nerve. 2012;45(5):623-634. doi:10.1002/mus.23234.
10. Budhram A, Sechi E, Flanagan EP, et al. Clinical spectrum of high-titre GAD65 antibodies. Journal of neurology, neurosurgery and psychiatry. 2021;92(6):645-654. doi:10.1136/jnnp-2020-325275.
11. Rakocevic G, Raju R, Dalakas MC. Anti–Glutamic Acid Decarboxylase Antibodies in the Serum and Cerebrospinal Fluid of Patients With Stiff-Person Syndrome: Correlation With Clinical Severity. Archives of neurology (Chicago). 2004;61(6):902-904. doi:10.1001/archneur.61.6.902.
12. Potter K. Physical Therapy During In-Patient Rehabilitation for a Patient with Stiff-Person Syndrome. Journal of neurologic physical therapy. 2006;30(1):28-38. doi:10.1097/01.NPT.0000282147.18446.b8.
13. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-Dose Intravenous Immune Globulin for Stiff-Person Syndrome. The New England Journal of Medicine. 2001;345(26):1870-1876. doi:10.1056/NEJMoa01167.
14. Sechi G, Barrocu M, Piluzza MG, Cocco GA, Deiana GA, Sau GF. Levetiracetam in stiff-person syndrome. J Neurol. 2008;255(11):1721-1725. doi:10.1007/s00415-008-0007-7.
15. Albahra S, Yates SG, Joseph D, De Simone N, Burner JD, Sarode R. Role of plasma exchange in stiff person syndrome. Transfusion and apheresis science. 2019;58(3):310-312. doi:10.1016/j.transci.2019.03.015.
16. Hattan E, Angle MR, Chalk C. Unexpected benefit of propofol in stiff-person syndrome. Neurology. 2008;70(18):1641-1642. doi:10.1212/01.wnl.0000284606.00074.f1.
17. Dalakas MC, Rakocevic G, Dambrosia JM, Alexopoulos H, McElroy B. A double‐blind, placebo‐controlled study of rituximab in patients with stiff person syndrome. Annals of neurology. 2017;82(2):271-277. doi:10.1002/ana.25002.
18. Geffen S, Chiang N. Successful Treatment of Stiff Person Syndrome with Intrathecal Baclofen. Journal of rehabilitation medicine. Clinical communications. 2019;2(1):1000016. doi:10.2340/20030711-1000016.
19. Abbatemarco JR, Willis MA, Wilson RG, Nagel SJ, Machado AG, Bethoux FA. Case Series: Intrathecal Baclofen Therapy in Stiff‐Person Syndrome. Neuromodulation (Malden, Mass.). 2018;21(7):655-659.

Author Disclosure

Zachary Satin, MD
Nothing to Disclose

Laura Malmut, MD
Nothing to Disclose