Pragmatic Treatment of Stiff Person Spectrum Disorders

Abstract

Background

Stiff person spectrum disorders (SPSD) are a group of rare conditions clinically characterized by stiffness, spasms, and heightened stimulus sensitivity. They also share a spectrum of antibodies.

Methods

We reviewed the literature and our own experience with the aim of providing a practical approach to the treatment of SPSD.

Results

Because of the rarity of SPSD, there is little evidence to guide treatment decisions. The treatment of SPSD is based on the triad of symptomatic treatment, immunotherapy, and tumor treatment where appropriate. Moreover, the management involves continuous and appropriate monitoring of the symptoms of the disease, its autoimmune associations, and potential treatment side effects.

Conclusions

Here we delineated a pragmatic treatment approach to SPSD, based on our experience and existing literature. We also highlighted how our understanding of neuronal antibodies and their implications reflects on management considerations.

Introduction

The rapid developments in neuroimmunology also reflect on the field of movement disorders. Recently, we outlined the broadening spectrum of movement disorders with neuronal antibodies and a syndromic approach to diagnosis.1 However, our increasing recognition of these potentially treatable disorders contrasts with a lack of guidance on therapy and management. Here we will discuss the principles of the management approach of stiff person spectrum disorders.

Diagnostic Work‐up: Clinical Spectrum, Implications of Antibody‐Subtyping, and Other Investigations

In their original description, Moersch and Woltman used the term “syndrome,” and indeed, 60‐years later, it appears that the broad clinical spectrum and the different antibodies would indicate different underlying pathophysiologies, rather than one single disease.2, 3 Clinically, we recognize not only the classic stiff person syndrome (SPS; gradually evolving stiffness of proximal legs and the lumbar paravertebral muscles leading to the typical stiff‐legged gait and hyperlordotic posture), but also focal forms like stiff limb syndrome (SLS), variants with additional neurological features, or even fulminant presentations with widespread neurological involvement such as in progressive encephalomyelitis with rigidity and myoclonus (PERM). Although to varying degrees and distribution, all these entities share the core features of stiffness, spasms, and heightened stimulus sensitivity including hyperekplexia, and are thus termed stiff person spectrum disorders (SPSD). Most frequently, there is an insidious onset with a progression over months and a subsequent stable, chronic disease course, but there may be exacerbations. Subacute presentations, often rapidly progressive, are particularly seen in PERM. Progression from one form to another (e.g., from SLS to PERM) can occur.

The different phenotypes do not necessarily correlate with the antibodies, but there are some associations, which can give a clue. For example, the co‐occurrence of SPSD symptoms with cerebellar ataxia or focal epilepsy, often with concomitant organ‐specific autoimmune disorders such as type 1 diabetes, thyroid disease, vitamin B12 deficiency, or vitiligo is typically seen with GAD‐antibodies. DPPX‐antibodies give rise to an SPSD variant with marked hyperekplexia combined with other neurological signs such as cerebellar ataxia or sensory or memory disturbance. Prolonged diarrhea is the important red flag symptom of DPPX‐antibodies. Features that potentially point to amphiphysin antibodies are the loss of deep tendon reflexes and sensory ataxia due to neuronopathy. Glycine receptor (GlyR) antibodies were firstly described in PERM and indeed tend to associate with prominent brainstem or cranial nerve signs. However, GlyR‐antibodies associate with all disease types, including classic SPS. Given that there is a significant phenotypical overlap, it is often hard to predict the underlying antibody, and therefore, testing for the whole panel is recommended. Parallel testing of serum and CSF has the highest sensitivity and specificity, and is thus considered the gold standard.

The different antibodies have different management implications as they stand for different underlying pathophysiological mechanisms that reflect on links with autoimmune or paraneoplastic disease, and treatment responses (Table 1).3, 4, 5, 6, 7

Table 1.

Stiff person spectrum disorders ‐ antibodies and their implications

	Glutamic acid decarboxylase (GAD) antibodies	Glycine receptor (GlyR) antibodies	Amphiphysin antibodies	Dipeptidylpeptidase‐like protein‐6 (DPPX) antibodies
Frequency in SPSD	Very frequent (∼70‐80%)	Frequent (∼10%)	Rare (∼5%)	Rare (∼3%)
Immunopathophysiology	Role of antibodies controversial, possibly also T cell involvement	Neuronal surface antibodies which are considered to be directly pathogenic	Antibody‐pathogenicity suggested by experimental evidence, but also T cell involvement	Neuronal surface antibodies which are directly pathogenic
Tumor association	Very rare (various tumors reported)	Occasionally (∼9%): thymoma > lung cancer, breast cancer, Hodgkin lymphoma, chronic lymphocytic leukaemia	Strongly associated with breast and lung cancer	Occasionally (∼7%): B cell neoplasms
Concomitant autoimmunity and other red flag features	Frequent (∼80%): diabetes, thyroid disease, vitiligo, pernicious anaemia	Occasionally (∼29%): thyroid disease > other (psoriasis, rheumatoid arthritis, sarcoid…)	‐	Occasionally (∼20%): thyroid disease > SLE, pernicious anaemia
Associated neurological symptoms and red flags	Cerebellar ataxia, focal epilepsy (rarely limbic encephalitis)	Prominent brainstem signs	Sensory neuronopathy, myelopathy	Gastrointestinal hypermobility/diarrhoea, less‐frequently constipation; frequently prominent heightened stimulus sensitivity and other neurological signs, e.g. cerebellar ataxia
Particular management implication	• Screening and monitoring for concomitant autoimmunity and associated neurological symptoms (s.o.), and, if applicable, treatment • Tumors very rare, but keep in mind • Typically chronic disease course • Mixed responses to immunotherapy • Caveat: corticosteroids in diabetic patients	• Typically good response to immunotherapy • Mono‐ and polyphasic courses with (intercalated) complete remission can be seen • In patients with PERM and thymoma dramatic improvement after thymectomy	• Paraneoplastic syndrome which can respond well to tumor treatment and immunotherapy • Monitoring for other paraneoplastic neurological symptoms and, if applicable, early intervention with immunotherapy	• Typically good response to immunotherapy • Usually chronic course, may require long‐term immunosuppressant therapy

The table lists the most common antibodies in SPSD and their relative frequency, immunopathysiological relevance, tumor, and autoimmune associations and how these reflect on management. Rare antibodies or antibodies of unestablished significance like those against gephyrin, GABAAR, GABAAR receptor associated protein and glycine transporter 2 are not listed here, but reviewed elsewhere.3

Of note, there is a subgroup of (so far) seronegative cases. Moreover, antibodies themselves are not disease‐specific per se.8 Thus, the diagnosis of SPSD is based on the synopsis of clinical findings, antibody testing, electrophysiological investigations, and CSF analysis (Table 2). Differential diagnostic considerations are listed in Table 3. The role of imaging in this context is to exclude structural lesions.

Table 2.

Diagnostic workup and monitoring in SPSD

Diagnostic work up
History and examination	• Autoimmune predisposition in patient or family (in particular: diabetes, thyroid disease, vitiligo) • Stiffness (often fluctuating), resulting abnormal postures (e.g., lumbar hyperlordosis, pes equinus) • Spasms, often precipitated by touch, pain, cold, movement, or by negative emotions (e.g., fear) • Characteristic fear of walking unaided, exacerbation of symptoms (e.g., on stairs, crossing roads, open spaces) • Exaggerated startle (hyperekplexia), head retraction reflex • Additional neurological signs
Laboratory	• Antibody testing: GAD, GlyR, amphiphysin, DPPX, Hu, Ri * • Lumbar puncture: basic parameters including assessment of intrathecal IgG synthesis and antibodies, antibody index
Electrophysiology	• Enhanced exteroceptive reflexes with a short latency • Continuous motor unit activity (not specific for SPS) • Increased brainstem excitability with loss of reflex inhibition (e.g. masseter inhibition)
MRI	• To exclude structural lesions / alternative diagnoses
Other	• Tumor screening in patients with onset < 5 yrs
Monitoring on follow up
Eamination	• Distribution and degree of stiffness, spasms, hyperekplexia • Timed activities (see text) • Additional neurological signs
Laboratory	• Screening for autoimmune endocrinopathies (in particular in GAD‐antibody positive patients: thyroid and gastric antibodies, vitamin B12 levels, HbA1c) • Depending on immunotherapy monitoring of blood count, lymphocyte subpopulations, kidney and liver functions
Other	• Tumor screening if original search negative but high index of suspicion (e.g. with paraneoplastic antibodies)

^*Rare antibodies or antibodies of unestablished significance like those against gephyrin, GABA_AR, GABA_AR receptor associated protein, and glycine transporter 2 are not listed here, but reviewed elsewhere.3

Table 3.

Differential diagnoses of SPSD and clinical clues

Differential diagnosis	Clinical clues
Tetanus	(Sub‐) acute presentation; usually begins with lockjaw
Strychnine poisoning	(Sub‐) acute presentation; usually begins with lockjaw
Axial dystonia	Sensory geste, dystonic symptoms affecting other body parts40
Hyperekplexia, hereditary or acquired	Stiffness ceases completely between attacks; Congenital symptoms and family history in hereditary forms
Functional disorder	Variability, distractibility, disproportionate effort (“huffing and puffing sign”),41 delayed startle response
(Neuro‐)muscular diseases, (e.g., Neuromyotonia, Rigid spine syndrome, McArdle disease, Satoyoshi syndrome	Muscle weakness and wasting, muscle relaxation disorder, fasciculations elbow and other contractures, respiratory insufficiency, myalgia, myoglobinuria, diarrhoea, alopecia, amenorrhoea
Skeletal diseases, (e.g., ankylosing spondylitis)	Absence of spasms, improvement with exercise, other rheumatological signs like uveitis
Myositis ossificans	Focal muscular tautness and contracture, no spasms
Structural lesions in brainstem and spinal cord, (e.g., Demyelinating lesions as in Neuromyelitis optica or multiple sclerosis, tumors)	Additional neurological signs: Painful tonic spasms after hyperventilation, tactile stimuli or voluntary movement

Apart from the absence of typical SPSD features (e.g. the characteristic fear of walking unaided, stimulus‐sensitivity of spasms, hyperekplexia, see Table 2), above listed clinical features may point to differential diagnoses of SPSD.

Management: Immunotherapy, Symptomatic Treatment, and Monitoring

The treatment of SPSD centers on the triad of symptomatic treatment, immunotherapy, and tumor treatment where appropriate. The management involves continuous monitoring of symptoms of the disease, its autoimmune associations, and potential treatment side effects (Fig. 1, Table 2).

Figure 1.

The management of SPSD.

Tumor Screening and Treatment

Above we have outlined how the underlying antibody defines subtypes of SPSD and inform prognosis and possible paraneoplastic associations (detailed in Table 1). In the case of an underlying tumor, its identification and removal or treatment is of course of paramount importance. If no tumor is found, active monitoring and repeated tumor searches are recommended up to four years whenever a high index of suspicion is justified (e.g., the existence of amphiphysin or other onconeuronal antibodies).9 Very rarely, however, tumors triggering paraneoplastic autoimmunity are detected a decade later.10 For more detailed recommendations regarding tumor screening in paraneoplastic syndromes, we refer to existing guidelines.11 FDG‐PET/CT allows to precisely localize lesions with avid FDG uptake and has a higher specificity than FDG‐PET alone.11 Of note, consideration of the appropriate investigations is important, as not all neoplasms are detected by FDG‐PET. In up to 20% of cases, it may miss small tumors (< 7 mm) or tumors which are not FDG‐avid.12 Although paraneoplastic syndromes are considered to have a rather poor response to immunotherapy,13 irreversible neuronal damage may be prevented by early treatment and immunosuppression when possible.14, 15, 16 Moreover, patients with GlyR‐antibodies and thymoma showed dramatic improvement (up to complete remission) after thymectomy and immunotherapy.17, 18 Also, patients with amphiphysin‐antibody related SPSD showed an excellent response to tumor excision and immunotherapy.19 Of note, in paraneoplastic cases, complete tumor removal is typically mandatory before initiation of immunosuppression.

Immunotherapy

In general, the armamentarium of immunosuppression is often categorized as “first line” and “second line” immunotherapies. First line immunotherapy (corticosteroids, plasma exchange, intravenous immunoglobulins) can bring about a rapid impact on immune dysregulation and is therefore often used to start treatment, but can also be used as maintenance therapy in chronic cases if proven beneficial. The effects are mainly confined to the time of application. Second line therapeutics (rituximab, cyclophosphamide, mycophenolate) provide more rigorous immunosuppression, but at the price of a higher risk of adverse events like opportunistic infections and neoplasms. Particularly, if long‐term treatment with a second‐line immunotherapy or combination therapies is planned, it is important to check beforehand the immune status, exclude chronic infections (e.g., HIV, HCV, tuberculosis), and safeguard sufficient primary immunization. The most commonly applied immunotherapeutic strategies with their mode of action, typical regimens, and most important side effects are outlined in Table 4.

Table 4.

Overview of the most common immunotherapeutic strategies applied in neuronal autoantibody‐associated disorders

	Mechanism	Dosing	Side effects / caveats
1st line immunotherapy
Corticosteroids	Targets cellular and humoral immune responses	• Pulse therapy with 500‐1000 mg / day I.V. for 3‐5 days (single / repeated) • Maintenance: Prednisone 1 mg/kg or 60‐80 mg P.O. once daily, oral tapering • Co‐medication for thrombosis prophylaxis (in high dose therapy), gastric ulcers (always) and osteoporosis (in chronic use)	Immediate side effects: hyperglycaemia, hypertension, leucocytosis, thrombocytosis, peptic ulceration, insomnia. Side effects in chronic use: diabetes, osteoporosis, skin atrophy, cataracts, glaucoma
Intravenous immunoglobulins (IVIG)	Blockade of cell–cell interactions, neutralisation of cytokines, activated complement proteins and autoantibodies, blockade of immune complex binding, modulation of innate immune effector cells and B cells	• No standard dose; frequently 0.4 g/kg bodyweight per day over 3‐5 days as initial dose, then maintenance with 0.4 g/kg bodyweight monthly; or monthly infusion of 1 g/kg bodyweight per day on 2 consecutive days • Co‐medication for thrombosis prophylaxis	Caveat: patients with IgA deficiency (risk of anaphylactic shock); patients with nephropathy Immediate side effects: headache, flushing, malaise, chest tightness, fever, chills, myalgia, fatigue, dyspnoea, back pain, nausea, vomiting, diarrhoea, blood pressure changes, tachycardia. Late side effects (rare): renal failure, thromboembolic events, aseptic meningitis, neutropenia, autoimmune haemolytic anaemia, skin reactions
Plasma exchange (PLEX)	Reduction of serum levels of antibodies (and other pro‐inflammatory mediators)	• 3‐6 times every other day, depending on severity	Side effects: cardiovascular stress, catheter infection, sepsis; plasma needs to be replaced by human albumin or fresh frozen plasma (risk of infections, allergic reactions).
2nd line immunotherapy
Rituximab	B‐cell depleting monoclonal antibody	• 1000 mg two weeks apart • 375 mg/m2 body surface once per week over four weeks • premedication: intravenous corticosteroids, anti‐histaminics and paracetamol	Risk of severe infusion reactions; higher risk of infections
Cyclophosphamide	Targeting of cellular and humoral immune response	• 750 mg/m2 body surface once every 4 weeks I.V. • 500 mg per day for 2–4 days per month I.V. • monthly dose of 1000 mg I.V. • maximal cumulative lifetime dose 80 g	Increased risk of myelo‐ or lymphoproliferative malignancies; urinary tract and renal toxicity (particularly haemorrhagic cystitis; therefore premedication with mesna if more than 2g I.V. or if urothelial toxicity was noticed on previous administration); cardiotoxicity, pulmonary toxicity
Mycophenolate mofetil	Inhibition of lymphocyte proliferation	• 1000 to 1500 mg/day P.O. twice a day • maximal cumulative lifetime dose 140 mg/m2	Gastrointestinal symptoms; myelosuppression. Patients require periodic monitoring of blood cell count and of liver enzymes and renal function

Other drugs available for immunosuppression are e.g. azathioprine, methotrexate, cyclosporine A, mitoxantrone, and tacrolimus. Immunoadsorption is another procedure to remove antibodies and immuncomplexes from the blood; the main difference to PLEX is that the patient's plasma is reintroduced in the circulation. Important: Please note that this list is not exhaustive and does not represent treatment recommendations. Readers must always check the product information and the latest codes of conduct and safety regulations.

The rarity of SPSD presupposes to a lack of randomized controlled trials, and there is no licensed immunotherapy for SPSD. Hence, any treatment recommendations are mostly based on smaller case series, retrospective studies, and expert opinions. Because of one small, randomized, double‐blind, placebo‐controlled study with crossover design testing IVIG in GAD‐antibody positive SPSD reporting safety and efficacy of treatment, IVIG infusions are often considered the standard immunotherapy in SPSD.20 However, in other, retrospective series, the response to IVIG was ambiguous.7, 21

Steroids (e.g. induced as pulse therapy with oral maintenance dose) can be efficient in SPSD but can be difficult to use in patients with diabetes. In case of long‐term therapy, the use of steroid‐sparing agents like azathioprine, cyclophosphamide or mycophenolate should be considered.

The monoclonal CD20‐antibody rituximab has also been used in SPSD. There has been a negative placebo‐controlled, double‐blind, randomized trial of rituximab in 24 GAD‐antibody positive SPSD patients,22 and a double‐blind, randomized, placebo‐controlled crossover study in monozygotic twins,23 both suggesting that rituximab is not effective in GAD‐antibody positive SPSD. However, noticeable improvement in single cases, even within the trial mentioned above,22 and in some case reports of patients with GAD‐antibodies,24 suggest that rituximab should not be completely discarded as a therapeutic option. The overall impression is that the treatment response to immunotherapies, in general, is highly variable in GAD‐antibody SPSD and that a restitutio ad integrum is rare, particularly in chronic cases, paralleling the experience with GAD‐antibody‐related cerebellar ataxia.25 In contrast, it appears that GlyR‐antibodies seem to predict a better response to immunotherapy in general,6, 26 including rituximab.27 Similarly, a relatively good outcome after immunotherapy was noted in patients with DPPX‐antibodies, although often constant and escalated treatment seems to be required.5, 28 The various immunotherapies have different modes of action, and it is difficult to predict treatment responses. Therefore, it is common practice to try different immunotherapies, sometimes in combination (e.g., rituximab and repeated high‐dose steroid pulses, or a combination of rituximab and cyclophosphamide).

Symptomatic Treatment

While immunotherapy may take some time to show any effect in SPSD, symptomatic treatment provides quick relief. In particular, it expedites mobilization, which may establish the basis for a trustful patient–doctor relationship and also give some leeway when trying to establish the best immunotherapeutic regimen. Symptomatic treatment typically involves benzodiazepines (e.g., clonazepam, 1 to 6 mg/d; or diazepam, 5 to 50 mg/d). Other options are baclofen (50 to 100 mg/d), tizanidine (20 to 40 mg/d), or antiepileptic medication like gabapentin (up to 2400 mg/d), pregabalin (70 to 200 mg/d), or valproic acid (up to 1200 mg/d). The principle here is “start low and go slow” to avoid side effects, and to spread the dose to achieve a good coverage throughout the day. Another key point is to keep the symptomatic therapy stable when starting/changing immunotherapy.

Botulinum toxin injections can alleviate focal stiffness and spams and are used to avoid contractures or subluxations. Of note, the need for symptomatic therapy adjustments should be continually evaluated, as it may be influenced by the response to immunotherapy.

Monitoring

Appropriate monitoring is important, and apart from monitoring potential side effects of immunotherapy (Table 4), this also involves detailed documentation of the treatment response, which will then influence the decision to continue, escalate, or downscale immunotherapy. Such an assessment may, for example, involve the degree and distribution of stiffness, the response to a repeated standard stimulus such as a loud clap or a cold spray to the foot sole, and appropriate timed activities like walking a predefined distance, taking a flight of stairs, or in a patient with a stiff arm, the nine‐hole peg test. In patients with combined syndromes such as SPSD with cerebellar ataxia, additional measures should include, for example, the scale for the assessment and rating of ataxia.29 It is mainly the clinical course that should guide treatment decisions, and Figure 2 provides a suggestion of a treatment algorithm based on the clinical symptoms and course. Neuronal surface antibodies can provide additional, supportive information (e.g., GlyR‐ and DPPX‐antibody titers tend to correlate with disease severity) and their decrease may herald the immunotherapy being effective.5 However, GAD‐antibodies are not useful as a monitoring biomarker because they do not correlate with symptoms.30, 31

Figure 2.

Example of a treatment approach based on the clinical course and antibody‐related subtypes. Abbreviations: IVIG, intravenous immunoglobulins; i.v., intravenous; MP, methylprednisolone; PLEX, plasma exchange; p.o., per os.

Cautions and Caveats in the Management of SPSD

We outlined the basic principles and considerations relevant to manage SPSD. Given that most cases of GAD‐antibody‐related SPSD have a chronic disease and treatment response particularly to immunotherapy is highly variable, it is important to keep in mind a balance between trying immunosuppression and the “nil nocere” (first, do no harm) principle.

One of the main problems in the assessment of the treatment response is the fluctuating nature of symptoms, which may be strongly influenced by stress and anxiety. The latter have been long recognized as inherent non‐motor features of the disease and are commonly related to the fear of falling.32 However, also generalized anxiety disorder and depression can occasionally be seen in SPSD. The caveat here is that pharmacotherapy with antidepressants may have even negative ramifications and aggravate symptoms, as reported for tricyclic antidepressants or serotonin‐norepinephrine reuptake inhibitors.33, 34, 35

Importantly, sometimes accompanying neurological symptoms such as cerebellar ataxia (e.g., in GAD‐antibody positive cases, or sensory ataxia in amphiphysin‐antibody positive cases), and not stiffness and spasms, can be the main contributors to disability. Thus, careful monitoring for early detection of such symptoms and, if applicable, rapid intervention with immunotherapy is important to prevent neurological deficits, which in contrast to SPSD core symptoms are not amenable to symptomatic treatment approaches.

In some cases, continuous long‐lasting or frequent attacks of spasms (spasmodic storm) may compromise respiration and result in myoglobinuria with renal failure.36 It may be accompanied by severe dysautonomia with hypertensive crises and tachycardia. This potentially lethal situation requires a continuous intravenous administration of midazolam or propofol via perfusion pump, beta‐blockade, and monitoring in an intensive care unit. Implantation of an intrathecal baclofen pump has been successfully used in SPSD, but important caveats to its application are improper refilling, catheter leakage and pump failure, which may have immediate and potentially lethal consequences.37

Conclusions and Perspective

Here we delineated a pragmatic treatment approach to SPSD, based on our experience and existing literature. We also highlighted how our understanding of neuronal antibodies and their implications reflect on management considerations. The recent developments in neuroimmunology also include an ever‐expanding armamentarium of immune‐modulating or immune‐suppressing drugs, some of which may be potentially useful in SPSD. Because of the rarity of SPSD, evidence to guide treatment decisions is rather scarce, and the few existing guidelines are mainly based on expert recommendations.38 Further studies with the concerted action of multiple centers would be desirable to help define the best treatment strategies. With a better understanding of the pathophysiology of the different subtypes of SPSD, we will hopefully be able to offer more effective and personalized treatments.

Author Roles

1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

B.B.: 3A

H.M‐M.: 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding sources and conflicts of interest: BB is supported by an EAN research fellowship and by the Robert‐Bosch‐Stiftung.

Financial disclosures for previous 12 months: The authors do not have any disclosures to make and do not have any conflicts of interest.