Therapies in Stiff-Person Syndrome

Abstract

Among the glutamic acid decarboxylase (GAD)-antibody–spectrum disorders, the most common phenotypic subset is the stiff-person syndrome (SPS), caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis. If not properly treated or untreated because of delayed diagnosis, SPS progresses leading to disability; it is therefore fundamental to apply the best therapeutic schemes from the outset. This article is focused on the rationale of specific therapeutic strategies based on the SPS pathophysiology targeting both the impaired reciprocal GABAergic inhibition to symptomatically improve the main clinical manifestations of stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression. A practical, step-by-step therapeutic approach is provided, highlighting the importance of combination therapies with the preferred gamma-aminobutyric acid–enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin, that provide the first-line symptomatic therapy, while detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab. The pitfalls and concerns of long-term therapies in different age groups, including children, women planning pregnancy, and especially the elderly considering their comorbidities are emphasized, also highlighting the challenges in distinguishing the conditioning effects or expectations of chronically applied therapies from objective meaningful clinical benefits. Finally, the need for future targeted immunotherapeutic options based on disease immunopathogenesis and the biologic basis of autoimmune hyperexcitability are discussed, pointing out the unique challenges in the design of future controlled clinical trials especially in quantifying the extend and severity of stiffness, episodic or startle-triggered muscle spasms, task-specific phobias, and excitability.

Late-onset stiff-person syndrome: challenges in diagnosis and management

“…12 Rather, the limiting factor in the use of IVIg as continuing therapy in LOSPS is more related to tolerance and the existence of serious comorbidities due to cardiac problems, history of thromboembolic events, or poor venous access that necessitate early discontinuation; further subcutaneous IgG, which is preferable when IVIg is not tolerated or not considered safe, cannot be given to those LOSPS receiving anticoagulant therapies. Accordingly, in certain circumstances, rituximab which is also effective in 40% of SPS patients based on our large controlled study, 14 may be considered earlier in the immunotherapeutic algorithm in LOSPS, compared to their younger counterparts, to prevent disability. Toward this goal, the newly discussed future immunotherapies in SPS, 14 if proven effective, may be also considered earlier in LOSPS when rituximab is not effective.…”

“…The experience from the present series suggests that personalized treatment regimens are required for older patients with SPS because their poor tolerance to antispasmodics and sedating analgesics necessitates the need for earlier initiation of immunotherapy with IVIG, which is considered first-line immunotherapy. 14 Because SPS is a progressive disease, 10 treatment with IVIg should start as soon as antispasmodics are ineffective or poorly tolerated. 14 Despite their rapidly evolving disability however, our data show that LOSPS patients did not seem to have a significantly lower rate of response to IVIg because all nine patients were treated with IVIg and only two were non-responders; this represents a response rate similar to our prior study which identified a 67% responder rate to IVIg, although in LOSPS their response was partial and seemed to decline faster.…”

“…14 Because SPS is a progressive disease, 10 treatment with IVIg should start as soon as antispasmodics are ineffective or poorly tolerated. 14 Despite their rapidly evolving disability however, our data show that LOSPS patients did not seem to have a significantly lower rate of response to IVIg because all nine patients were treated with IVIg and only two were non-responders; this represents a response rate similar to our prior study which identified a 67% responder rate to IVIg, although in LOSPS their response was partial and seemed to decline faster. 12 Rather, the limiting factor in the use of IVIg as continuing therapy in LOSPS is more related to tolerance and the existence of serious comorbidities due to cardiac problems, history of thromboembolic events, or poor venous access that necessitate early discontinuation; further subcutaneous IgG, which is preferable when IVIg is not tolerated or not considered safe, cannot be given to those LOSPS receiving anticoagulant therapies.…”

“…LOSPS with disease onset above the age of 60 is often misdiagnosed for other conditions commonly seen in the elderly populations, especially lumbosacral and cervical radiculopathies, complicated by unnecessary surgeries and other orthopedic therapies, necessitating the need for increased awareness by the practicing neurologists. Patients with LOSPS appear to have clinically more severe disease, not necessarily related to poorer response to immunotherapy, but rather due to a combination of factors, including: (a) faster disease progression related to delayed diagnosis and therapy initiation; (b) poor tolerance to antispasmodics and benzodiazepines which, in contrast to the younger SPS patients, 14 are poorly tolerated in the elderly because of excessive somnolence and falls; (c) degenerative arthritic changes in joints, cervical, and thoracolumbar spine that, even if not causative, contribute to pain and enhance symptom severity; and (d) deconditioning due to poor mobility that occurs faster in older-age patients due to cumulative effect of other comorbidities which, in combination with SPS-related stiffness, muscle spasms, and gait dysfunction, lead to early reliance on assisting devices.…”

“…Among them, two did not respond; two discontinued IVIg early, despite positive response, due to cardiovascular comorbidities and thromboembolic events or receiving anticoagulation; one started to respond but died soon thereafter ; two partially responded or showed diminishig benefit; and one other exhibited a conditioning effect, commonly seen during chronic IVIg maintenance therapy due to fear that discontinuing it will worsen their disease or lead to disease progression. 14 Regarding B-cell therapies, only one (patient #4, Table 1) received rituximab since 2018. Several patients exhibited poor tolerance to high doses of oral antispasmodics including combinations of clonazepam, diazepam, and baclofen (see Table 1), whereas two of them could not tolerate them due to somnolence.…”