Muranova A, Shanina E. Stiff Person Syndrome. 2022 Jul 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 34424651.
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:
Partial SPS variants
Progressive encephalomyelitis with rigidity and myoclonus (PERM).
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. 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.
Several clinical variants of SPS have been described and include stiff limb syndrome, jerky SPS, cerebellar variant, SPS with epilepsy, and dystonia. The paraneoplastic variant is associated with breast, colon, thyroid, lung malignancies, Hodgkin and non-Hodgkin lymphomas and tends to clinically manifest before cancer itself.
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.
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.
Yi J, Dalakas MC. Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody-Positive Stiff-Person Syndrome. Neurol Neuroimmunol Neuroinflamm. 2022 Jul 7;9(5):e200011. doi: 10.1212/NXI.0000000000200011. PMID: 35798561; PMCID: PMC9262284.
Background and objectives: IVIg has been the preferred immunotherapy in stiff-person syndrome (SPS) based on a 3-month controlled trial, but whether it is also effective in inducing long-term benefits or arresting disease progression is unknown. The information is needed because SPS is a progressively disabling disease and IVIg is liberally used as chronic therapy without efficacy data. The present study explores the long-term effects of IVIg in the largest cohort of well-characterized patients with SPS followed by the same clinicians over 10 years.
Methods: Data of 36 patients (32 glutamic acid decarboxylase [GAD] positive), diagnosed and treated with monthly maintenance IVIg by the same neurologists, were analyzed. Response was assessed by physician-observed changes, patients' reports of symptom improvement, modified Rankin Scale (mRS) scores, and dependency trials evaluating symptom recurrence after stopping IVIg, prolonging infusion frequency, decreasing monthly dose, or wearing-off effects in between doses. Clinically meaningful long-term response was defined by improved mRS scores, improvement in physician-assessed stiffness, balance and gait, and functional decline with dependency trials.
Results: Twenty-four of 36 (67%) patients had clinically meaningful response over a median 40-month period. Patients with improved mRS scores by 1-2 points manifested improved gait, posture, balance and decreased stiffness, spasms, and startle response; some patients using a wheelchair and those ambulating with devices walked unassisted. In 25% of responders, treatment benefit was sustained for a 40-month median period, but in 29.1%, it declined over a 39-month period; 12.5% exhibited a conditioning effect. Three of 5 patients with cerebellar GAD-SPS variant also improved over time. The 12 patients who did not respond the first 3 months remained unresponsive even if IVIg continued for several months.
Discussion: This is a large study in 36 patients with SPS demonstrating that monthly maintenance IVIg therapy offers long-term benefits in 67% of patients for a median 3.3-year period. Because 29.1% experienced diminishing benefit over time due to disease progression, the study highlights the need for more effective therapies.
Yeshokumar AK, Sun LR, Newsome SD. Defining the Expanding Clinical Spectrum of Pediatric-Onset Stiff Person Syndrome. Pediatr Neurol. 2021 Jan;114:11-15. doi: 10.1016/j.pediatrneurol.2020.09.007. Epub 2020 Sep 23. PMID: 33189024.
Background: We aimed to characterize the spectrum of clinical features and examination findings in pediatric-onset stiff person syndrome.
Methods: Medical records were reviewed for all patients treated for stiff person syndrome with symptom onset in childhood at a tertiary medical center between March 2001 and February 2019.
Results: Of the 15 individuals who met inclusion criteria, 11 (73%) were female and 13 (87%) were Caucasian. Median age at symptom onset was 14.8 years (range 8.4 to 16.9), and median latency from symptom onset to diagnosis was 6.2 years (range 0.4 to 15.0). Nine individuals (60%) were not diagnosed until adulthood. The most common presenting features were painful spasms (n = 12, 80%), hyper-reflexia (n = 11, 73%), axial rigidity (n = =9, 60%), lower extremity rigidity or spasticity (n = 8, 53%), gait abnormalities (n = 6, 40%), and hyperlordosis (n = 6, 40%). Other noted features included anxiety (n = 5, 33%), dysautonomia (n = 3, 20%), and cranial neuropathies (n = 3, 20%). Personal (n = 9, 60%) and family history (n = 9, 60%) of autoimmune conditions was common. Serum antiglutamate decarboxylase 65 antibodies were found in 13 individuals (87%). Nearly all individuals received immunotherapy (n = 14, 93%), symptomatic medications (n = 15, 100%), and nonpharmacologic therapies (n = 14, 93%). However, most had persistent physical limitations, particularly impaired walking (n = 7, 47%) and inability to carry out previous activities (n = 14, 93%).
Conclusions: There is a wide spectrum of typical and less common features seen in individuals with pediatric-onset stiff person syndrome. Despite symptom onset in childhood, diagnosis is often delayed until adulthood, at which point disability accrual is frequently seen. Early recognition is vital to address symptoms and may potentially limit future disability.
Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than meets the eye. J Neuroimmunol. 2022 Aug 15;369:577915. doi: 10.1016/j.jneuroim.2022.577915. Epub 2022 Jun 12. PMID: 35717735; PMCID: PMC9274902.
Stiff person syndrome spectrum disorders (SPSD) are a group of rare neuroimmunological disorders that often include painful spasms and rigidity. However, patients have highly heterogeneous signs and symptoms which may reflect different mechanistic disease processes. Understanding subsets of patients based on clinical phenotype may be important for prognosis and guiding treatment. The goal of this review is to provide updates on SPSD and its expanding clinical spectrum, prognostic markers, and treatment considerations. Further, we describe the current understanding in immunopathogenesis and highlight gaps in our knowledge appropriate for future research directions. Examples of revised diagnostic criteria for SPSD based on phenotype are also presented.