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Review
Stiff-person syndrome
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  1. Smriti Bose1,
  2. Saiju Jacob1,2
  1. 1 Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  2. 2 University of Birmingham Institute of Immunology and Immunotherapy, Birmingham, UK
  1. Correspondence to Professor Saiju Jacob; saiju.jacob{at}uhb.nhs.uk

Abstract

Stiff-person syndrome (SPS) is an autoimmune disease associated mainly with antibodies to glutamic acid decarboxylase (GAD) or to glycine, characterised by intermittent painful spasms, stiffness and rigidity of the proximal and truncal muscles. Neuro-ophthalmological and gastrointestinal symptoms also occur. The symptoms are caused by neuronal excitability due to impaired inhibitory (gamma amino butyric acid [GABA] and glycine) neurotransmission. SPS is part of a larger spectrum of GAD antibody-spectrum disorders, which overlaps with autoimmune epilepsy, cerebellar ataxia, myoclonus, progressive encephalomyelitis, rigidity and myoclonus (PERM) and limbic encephalitis. PERM is often caused by antibodies against the glycine receptor. Some SPS cases are paraneoplastic. Diagnostic delay is often associated with irreversible disability, and therefore, clinicians need a high degree of clinical suspicion to make an earlier diagnosis. This review updates the various clinical presentations that should raise suspicion of SPS and its related conditions and includes a diagnostic algorithm and various treatment strategies including immunotherapy and GABA-ergic drugs.

  • STIFF MAN SYNDROME
  • NEUROIMMUNOLOGY

Data availability statement

No data are available.

https://doi.org/10.1136/pn-2023-003974

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    Introduction

    Stiff-person syndrome (SPS) is a heterogeneous condition with multiple phenotypes and an autoimmune basis. It is rare and often misdiagnosed early in the course of the illness; delayed diagnosis can cause irreversible disability.1 Understanding the pathophysiology is crucial for the development of future treatments.

    In 1956, Moersch and Woltman identified 14 patients over 30 years in the Mayo Clinic2 with features typical of classic SPS, namely muscle stiffness, rigidity, hyper-reflexia, truncal and proximal muscle spasms. Howard et al first described diazepam as a well-established treatment.3 The initial description of stiff-man syndrome was adapted to SPS in 1999 with the recognition of its female predominance.4 Since then, there have been reports of partial SPS and SPS spectrum disorders, which include classical SPS combined with cognitive impairment, brainstem signs, cerebellar ataxia, seizures or myoclonus. The SPS diagnostic criteria first given by Gordon et al 5 have been periodically updated. An autoimmune basis for the disease was established after Solimena et al recognised its association with anti-glutamic acid decarboxylase (GAD) antibodies in 1988.6 Piccolo et al reported the possible benefit of corticosteroids.7 The first study showing the efficacy of intravenous immunoglobulin (IVIG) was in 19948; high-dose IVIG was shown to be beneficial in 20019 but the efficacy of long-term IVIG maintenance therapy was established only recently.10 11 Figure 1 depicts the evolution of the knowledge of SPS spectrum disorders.

    Figure 1
    Figure 1

    History of key milestones in the diagnosis and treatment of stiff person syndrome. SPS, stiff-person syndrome.

    Aetiopathogenesis

    Typical autoimmune SPS patients have positive anti-GAD antibodies, with or without other comorbid autoimmune conditions. Nearly one-third of people with SPS have type 1 diabetes mellitus12 and 5%–10% of patients have vitiligo, pernicious anaemia or thyroid-related disorders.13 Five per cent of SPS patients may have a paraneoplastic cause, often associated with antibodies to amphiphysin and gephyrin.1 Some have other paraneoplastic antibodies, such as anti-Ri antibodies.14 Commonly reported malignancies are breast, thymus, colon and lung; less common are mesothelioma, haematological malignancies (lymphoma and leukaemia) and melanoma.15 Up to 19% of patients have no evidence of cancer or autoimmunity (serum and CSF negative) and are diagnosed as cryptogenic SPS.15 There have been two recent reports of SPS exacerbation following viral infection: one each following COVID and West Nile virus infections. Type 1 diabetes may worsen or be triggered by enterovirus or COVID-19 infection. There are reports of progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with Epstein-Barr virus, COVID-19, hepatitis C and brucellosis. The evidence is conjectural.16

    Passive transfer of anti-GAD antibodies in animal models has given mixed and non-reproducible results. Active immunisation has provoked antibody production but without disease symptoms.17 Antibodies to amphiphysin may cause SPS-like symptoms in rats receiving encephalitogenic T-helper cells for induction of a leaky blood–brain barrier.18

    Both cytotoxic and helper T cells have a role in the pathogenesis.1 Anti-GAD antibodies are probably a marker of T-cell autoimmunity rather than being directly involved in the pathogenesis. The recognition of linear epitopes by GAD 65 also favours the role of memory T cells.19

    GAD antibodies

    Gamma amino butyric acid (GABA) and glycine are inhibitory neurotransmitters that cause hyperpolarisation of the postsynaptic membrane potential and thus increase the action potential threshold.20 GAD is a rate-limiting enzyme in the conversion of glutamate to GABA and is found in synaptic vesicles of pancreatic beta cells, brain, ovaries, testes, liver and adrenals.15

    GAD exists in two isoforms: GAD65 (occurring in nerve terminals and activity-dependent) and GAD67 (cytoplasmic and providing a steady production). Anti-GAD antibodies in high titres (>20 nmol/L by radioimmunoassay or >10 000 IU/mL by ELISA) are highly specific for SPS. Lower titres may occur in non-specific neurological disease whereas concentrations above 2000 IU/mL may occur in type 1 diabetes mellitus.1 High GAD65 antibody titres support the diagnosis, as opposed to low titre antibodies, which occur in nearly 80% of patients with type 1 diabetes mellitus and 8% of healthy people.17 The lack of correlation between antibody concentrations, disease severity and response to treatment, and limited access of the antibodies to GAD, which are in the vesicles, raise doubts about whether GAD is directly pathogenic or just a marker of immune response.15 Various studies have shown GAD-positive autoimmune conditions may be associated with the human leucocyte class II antigen, and there are also sporadic reports of an association with SPS. We need more reliable reports to support a genetic vulnerability. There is growing evidence to support B cell-mediated autoimmunity in SPS.19 Spinal interneuronitis may be a cause of more focal presentations, such as stiff-limb syndrome.15

    Figure 2 illustrates the GABA pathway and other antibody targets. These antibodies limit the production of GABA or its interaction in the postsynaptic terminals, and thus allow uninhibited action of the lower motor neurones, leading to excess response to descending reticulospinal tract activity.14 The altered GABA pathway also affects autonomic responses, arousal and behaviour (table 1). Non-organ-specific antibodies may also occur, including antibodies to nuclear, thyrogastric antibodies, smooth muscle, islet-cell and mitochondrial antigens,21 but their role in the pathogenesis is unclear.

    Figure 2
    Figure 2

    GABA pathway and antibody targets in SPS. Glutamic acid decarboxylase (GAD) (1) is responsible for converting glutamate to GABA. Amphiphysin (2) recycles GABA vesicle membranes. The GABAA receptor (3) controls inhibitory signalling and GABAA receptor associated protein (GABARAP) (4) provides structural support to the GABAA receptor. Gephyrin (5) is a scaffolding protein that binds to both the GABAA receptor and the glycine receptor (6) with help of microtubules (9). Glycine transporter 2 (GLY T2) (7) recycles glycine from the synapse. Dipeptidyl-peptidase-like protein-6 (DDPX) (8) regulates Kv4.2 potassium channels. Currently, only anti-GAD and anti-glycine antibodies are practically useful for clinical management. Anti-amphiphysin antibodies occur predominantly in the paraneoplastic variants. SPS, stiff-person syndrome.

    View this table:
    Table 1

    Antibody targets in SPS

    Demographics

    SPS affects around one in a million people22 but is probably greatly underdiagnosed and so its exact prevalence is unknown. The male-to-female ratio in adults is around 1:2.23

    Clinical features

    Classical SPS

    This is the most common type with around 70% of patients presenting in this way (figure 3). Symptoms typically start with insidious onset of stiffness in the proximal lower limbs, followed by spasms and rigidity of the thoracolumbar, paraspinal and abdominal muscles and proximal upper limbs, with a duration spanning months to years. This may lead to painful lordosis, increased startle response and dystonic posturing of the limbs. Patients often walk with a hyperlordotic posture, described as walking ‘like a statue’ or ‘as if frozen’.23 The hyperlordosis of SPS is more flexible (may straighten out when lying down) than the axial dystonia of movement disorders, where the lordosis is more fixed.24

    Figure 3
    Figure 3

    The phenotypic variations in GAD antibody positive syndromes. GAD, glutamic acid decarboxylase; SPS, stiff-person syndrome.

    Symptoms are episodic and stimulus-sensitive, typically triggered by loud sounds, touch and emotional upset (‘exaggerated startle response’). Spasms of axial dystonia are usually exaggerated spontaneously or on walking24 and may improve with sensory tricks. Patients often fear falling, which makes some tasks, such as crossing the road and walking in open spaces, physically challenging (task-specific phobias).25 On examination, some patients have pes equinus and hyperlordosis26 with hung-up27 or exaggerated deep tendon and diminished superficial reflexes, flexor plantar responses with or without clonus. Hung-up reflexes may be misdiagnosed as a functional movement disorder, hypothyroidism or Huntington’s disease.27 Patients often have enhanced exteroceptive (reflexes in response to tactile, auditory or other sensory stimuli) and brainstem reflexes.14 Another useful sign to differentiate SPS from axial dystonias is the head retraction reflex, defined as an abnormal brainstem reflex where truncal or head retropulsion occurs on tapping the nasal bridge, lips, chin or glabella.28

    Paraneoplastic SPS may present slightly differently from classical SPS, with more prominent upper limb and neck stiffness and can involve the other parts of the neuroaxis, with neuronopathy, encephalopathy or myelopathy.15 The cryptogenic group has the best prognosis, as these patients often respond to diazepam; however, clinicians must be extra vigilant before diagnosing seronegative SPS. Clinical features must meet the diagnostic criteria and electromyography should give supportive evidence, in order to rule out functional neurological disorders.15

    Neuro-ophthalmological features

    Vestibular and ocular dysfunction such as diplopia and dizziness may be a presenting symptom and can be misleading, causing a delay in diagnosis of up to 6 years.25 Examination may identify saccadic pursuits, downbeat nystagmus,29 dysconjugate gaze and horizontal or vertical gaze palsies.14 Other atypical clinical features include severe photosensitivity (possibly due to GABA-ergic neurones in retina), impaired visual acuity and thinning of the retinal layer. Each region of the body affected may be associated with a proportionate decrease in the ganglion cell-inner plexiform layer,30 suggesting that optical coherence tomography may be a useful biomarker for SPS disease burden.

    Gastrointestinal symptoms

    About a quarter of patients present with dysphagia, nausea, vomiting, constipation or weight loss, possibly from gastrointestinal dysmotility31 of uncertain cause. Medication and associated comorbidities such as diabetes may contribute. Some patients with early SPS develop anorectal spasms with incomplete relaxation on manometry.32 Dipeptidyl-peptidase-like protein-6 (DPPX) antibody-related SPS may also develop gut-related problems since DPPX is widely expressed in the gut neurones.33

    Cognitive impairment and mental health problems

    Some patients develop reduced attention, processing speed, verbal fluency, learning and recall.34 Clinicians’ use of regular cognitive screening tools may clarify whether these symptoms are progressive, or whether they are fluctuating due to comorbid conditions and treatments. Anxiety and depression are common presentations associated with SPS and their treatment can be difficult because of suspected worsening of SPS symptoms with serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants.25 Other psychiatric comorbidities can include eating disorders, alcohol abuse and depression.14 Many psychiatric symptoms like anxiety and task-specific phobias occur much more commonly in SPS than in other conditions causing stiffness (eg, multiple sclerosis, spinal cord injury) and suggests that neuronal hyperexcitability might play a pathophysiological role.

    Misdiagnosis of SPS-spectrum disorders happens three times more often than its initial correct diagnosis. Patients with generalised anxiety disorder may describe similar symptoms. Also because anxiety itself may trigger spasms, these patients are easily misdiagnosed as having functional neurological disorders or mood-related disorders.35 Patients with SPS have a higher risk than the general population of developing psychiatric disorders (which may be secondary to altered GABA concentrations).36

    Autonomic features

    Patients can have an increase in respiratory and heart rate, blood pressure, body temperature and autonomic crisis.14

    Respiratory symptoms

    Spirometry can be useful to measure in those with respiratory symptoms.37 Several affected body regions (legs, arms, face, lower and upper trunk, brain stem and cerebellum) may predict the presence of respiratory symptoms. There have been occasional deaths in PERM patients due to the secondary respiratory complications.38 Respiratory crises may need treatment with intravenous diazepam or, as in one case report with recurrent respiratory crises, intranasal midazolam.39

    Status spasticus

    Continuous spasms in the background of muscle rigidity causing tachycardia, breathing difficulty and muscle injury (rhabdomyolysis) can be life-threatening. This is treated with intravenous diazepam, muscle relaxants, invasive ventilation and IVIG. This acute presentation has a wide differential diagnosis, including neuroleptic malignant syndrome, strychnine poisoning, serotonin syndrome, encephalitis and malignant catatonia.40

    Incomplete SPS variants

    Many patients have symptoms limited to the facial muscles (stiff face syndrome)23 or the trunk (stiff trunk syndrome).41 Facial involvement may be associated with hypomimia, which can be mistaken for a parkinsonian feature.42 Associated lock jaw, dysphagia and dysarthria may be mistaken for tetanus.43 Patients with isolated limb involvement (usually the leg—stiff limb syndrome but can progress to the trunk) may have limited seropositivity and response to GABAergic treatments. They may become wheelchair users after a median period of 3.5 years.44 In particular, paraneoplastic and amphiphysin antibody variants often manifest as stiff limb syndrome.

    SPS plus or SPS spectrum disorders or overlap syndromes

    There have been reports of various combinations of epilepsy, cognitive impairment, cerebellar ataxia, neuro-ophthalmic features, dystonia and jerking stiff-man syndrome (associated with myoclonus).45 These comprise 12%–30% of SPS patients.25 Rarely GAD-positive cerebellar ataxia may transition to SPS-plus in 5–10 years.46

    Progressive encephalomyelitis with rigidity and myoclonus

    The best description of PERM is of remitting–relapsing symptoms of SPS with brainstem signs (extraocular or bulbar weakness) with or without dysautonomia, encephalopathy and prominent myoclonus presenting insidiously in the fifth or sixth decade. It is more common in men than women (unlike classical SPS).43 Although commonly associated with glycine receptor antibody positivity, some cases are associated with anti-GAD, anti-DPPX, anti-amphiphysin and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies.34 43

    PERM can present as an acute, subacute or exacerbation of the chronic course. Untreated patients may die within 2 or 3 years. Around 20% have a paraneoplastic cause.43 47

    MRI can rarely show hyperintensities in the spinal cord and brainstem.15 Treatment with a combination of corticosteroids, IVIG, plasma exchange or rituximab is beneficial.48 Although PERM has a severe presentation with a mortality as high as 40%,49 it often shows a robust response to treatment.15 The prognosis is variable, ranging between a stable non-progressive course to recurrent relapses and death.48

    The differential diagnoses for the often-seen chronic presentations include peripheral nerve hyperexcitability syndromes, movement disorders, tetanus, hereditary spastic paraparesis, myelopathies and frontal lobe rigidity.14 Figure 4 shows a proposed diagnostic algorithm.

    Figure 4
    Figure 4

    Diagnostic algorithm in SPS. The first-line investigation for patients with classical SPS symptoms or signs should be serum anti-GAD antibodies. If serum antibodies are not high (ie, not above 10 000 IU/mL using ELISA), CSF GAD antibodies or antibodies to other targets need to be checked. A positive neurophysiology can help further in confirming the diagnosis. CSF, cerebrospinal fluid; SPS, stiff-person syndrome.

    SPS in pregnancy

    Two patients experienced improvement after the first trimester in three pregnancies. Fetal distress during labour may be an indication for caesarean section. A transient increase in spasms during labour and the immediate postpartum period can be expected. There may be passive transfer of GAD antibody titres, but without causing symptoms in the infant. Children born are at risk of dependence on benzodiazepines and GABA enhancers, and so (after advice from a fetal medicine expert) IVIG and plasma exchange may be the preferred treatment.19 We need larger studies to understand the role of hormones in immunity and fluctuations in pregnancy.50

    Paediatric SPS

    Around two-thirds of paediatric SPS patients are not diagnosed until adulthood. The clinical symptoms are similar to those in adults.51 GABA-ergic agent use may be limited by adverse effects and therefore early IVIG is advised along with psychotherapy1

    Diagnostic markers

    Blood tests

    In doubtful cases or in those presenting within 5 years, the recommended blood tests include full blood count, liver and kidney function, creatine kinase, autoimmune workup (antinuclear antibody, erythrocyte sedimentation rate [ESR], C-reactive protein, rheumatoid factor) and vitamin D . This may assist in supporting or excluding alternative causes for spasms, related conditions and paraneoplastic causes. In patients with a low titre or negative anti-GAD antibodies, CSF examination (see below) or checking for other rarer antibodies (eg, anti-glycine, anti-amphiphysin) is recommended.

    Neurophysiology

    Nerve conduction studies are normal, but the electromyography hallmark of SPS is continuous firing the of the motor units in agonist and antagonist muscles, even at rest. This may worsen with sensory stimuli such as loud noises or may improve with diazepam. These findings support the diagnosis, especially in cryptogenic cases.52 Brainstem excitability on blink reflex studies (enhanced recovery of the R2 component) may help but needs evaluation.23

    Lumbar puncture

    Cerebrospinal fluid (CSF) analysis, with oligoclonal bands and antibody titres, is advisable in suspected cases that have low or absent serum antibodies (ie, <10 000 IU/mL using ELISA). Nearly two-thirds of SPS patients have positive CSF oligoclonal bands and 85% have CSF GAD-specific IgG.53 Patients with negative antibodies and normal EMG findings require the exclusion of other causes for increased muscle tone. Low CSF GABA concentrations and a high GAD65-specific IgG index may occur.23 High GAD65-specific IgG index (calculated using the formula (CSF GAD65–specific IgG)×(serum total IgG)/([CSF total IgG]×[serum GAD65–specific IgG]) indicates intrathecal synthesis of immunoglobulin rather than transudation due to blood–brain barrier breakdown. This makes it a reliable marker of neuroinflammation.54

    CSF antibody titres are useful when there is a diagnostic dilemma, but the results vary with the type of antibody. Anti-GAD antibody SPS patients often have isolated oligoclonal bands in CSF.55 Anti-DPPX-associated SPS patients may have an inflammatory CSF picture while those subtypes with anti-glycine and anti-GABARAP antibody may have normal CSF.56

    Imaging

    Patients presenting within 5 years with SPS spectrum disorders and pyramidal/extrapyramidal signs, encephalopathy or anti-amphiphysin antibody should have MR scans of brain and spine and serum paraneoplastic antibodies. Patients may need a CT scan of thorax, abdomen and pelvis (and possibly a whole-body fluorodeoxyglucose positron emission tomography [FDG-PET] scan in those with systemic symptoms) if they have other symptoms and investigations to support a possible paraneoplastic cause, such as significant weight loss, lymphadenopathy or multiorgan involvement on blood tests and imaging. MR scans are normal in most cases, except in PERM where there may be T2 hyperintensities in the brainstem and spinal cord. MR scanning may be difficult in patients who cannot lie still in the machine54; they may need cautious use of muscle relaxants or sedatives.

    There have been reports of MR spectroscopy showing low GABA in the sensorimotor and occipital areas and of transcranial magnetic stimulation showing cortical hyperexcitability but the relevance of these to diagnosis remains unclear, especially in cryptogenic cases.23

    The diagnostic criteria have recently been modified.35 Based on this, figure 4 shows a proposed diagnostic algorithm.

    View this table:
    View this table:

    Prognostic markers

    High titres of anti-GAD antibody, cerebellar ataxia and an initial modified Rankin scale score of 2 or more appear to be independent predictors of poor outcomes.57Patients with SPS-spectrum disorders may need immunotherapy earlier due to their greater disease burden at onset and hence their higher risk of a poor long-term outcome.58 SPS spectrum disorder patients with glycine receptor antibodies may do better with immunotherapy than those with anti-GAD65 antibodies.59

    Natural history

    The time between symptom onset and presentation of autoimmune SPS exceeds 5 years, compared with the earlier presentations of paraneoplastic SPS (weeks to 13 years) and cryptogenic SPS (median of 9 months).25 Most patients improve although a third may later relapse.15 Neurological improvement can be expected with proper treatment of the cancer and SPS. Cryptogenic SPS often responds to treatment; benzodiazepines are the most commonly used treatment.15

    Despite adequate treatment, over two-thirds of patients eventually are unable to function completely independently, due to unpredictable spasms, stiffness, frequent falls and phobias.12 Some patients may develop status spasticus despite treatment.21

    Treatment

    The treatment options are based mainly on experience and previous reviews,1 figure 5 gives an approach to management.

    Figure 5
    Figure 5

    Therapeutic algorithm in managing patients with SPS. BRIT, Birmingham Response to Immunomodulatory Treatment; CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin; SPS, stiff-person syndrome.

    Pharmacological

    GABA-ergic treatments

    Table 2 shows the drugs used in order of preference and their usual doses. The cornerstone of pharmacological treatments are centrally acting antispasmodic agents and benzodiazepines. Patients given a combination of opioids and other medications for pain require monitoring for respiratory depression. Patients receiving tricyclic antidepressants and duloxetine for anxiety can experience worsening.25 The treatment response to diazepam has historically been used as a marker for SPS, but patients need monitoring carefully for adverse effects and dependence potential.

    View this table:
    Table 2

    Drugs commonly used in the symptomatic management of stiff-person syndrome (SPS), their mechanism of action and doses

    Oral baclofen is probably the first-line treatment in most patients to minimise dependence on benzodiazepines. Even though baclofen pumps help reduce the medication dose to 1/500th of the oral dose, and therefore, reduce the sedative side effects of the medication,60 the risks of severe withdrawal and death from pump failure limit its use.

    Adverse effects of benzodiazepines include tolerance, dependence, somnolence, tiredness and mood changes. Adverse effects of baclofen include drowsiness and confusion.

    Immunotherapy

    Immune modulation remains the mainstay of treatment (table 3) with IVIG being the most effective long-term treatment. Patients who do not respond to the above treatments are candidates for immunotherapy. Patients who do not tolerate IVIG (those at risk of thrombosis, renal failure, aseptic meningitis or infusion reaction) may benefit from subcutaneous immunoglobulin, which provides steady levels of immunoglobulins.25 This also allows many patients to minimise the time taken off work for regular IVIG infusions.

    View this table:
    Table 3

    Immunomodulatory therapies currently used in SPS

    The recommended dose of IVIG is 2 g/kg over 2–5 days, monthly for 3 months.1 The duration of response can be monitored by regular preinfusion and postinfusion quantitative assessments using tools like the Birmingham Response to Immunomodulatory Treatment (BRIT) questionnaire (online supplemental file 1).10 This questionnaire quantifies the functional ability using the modified Rankin score and quality of life, as reported by the patient, adapted from the Flanagan’s quality of life questionnaire. It is advisable to do an assessment before starting and 3–6 weeks after each IVIG course. Figure 6 shows the BRIT questionnaire and scoring criteria. Chronic cases often need regular IVIG to sustain the improvements from the initial treatments.10 The interval can be prolonged to 6–12 weeks, or the dose reduced to 1 g/kg. IVIG can be stopped for a few months if the disease remains stable (to reassess for worsening after stopping treatment) or if there is continued progression even after treatment.1 This will help prevent conditioning and overuse. It is important to counsel and consent patients at the outset for periodic assessments and adjustment of doses or drug withdrawal, if ineffective.

    Supplemental material

    Figure 6
    Figure 6

    Birmingham Response to Immunomodulatory Treatment (BRIT) is used to assess efficacy of intravenous immunoglobulin (IVIG). The BRIT questionnaire uses a combination of functional ability (modified Rankin scale) and quality of life (QoL) questionnaires. Both sections need to be completed before IVIG and ideally 3–4 weeks after the infusion. These need to be repeated for three cycles, unless there are side effects or a clear substantial benefit after the first infusion. Functional ability is scored from 0 to 5, with higher score showing worsening disability. For the QOL section, each response to a question scores between 1 and 7. Maximum score—112 (higher score showing better QoL). Interpretation—functional ability—improvement of 1 point is considered significant. For QoL—an absolute improvement of 10 points or more is considered significant, especially if this is sustained after three infusions. (A relative improvement of 10% or more is considered significant if the baseline scores are very low; however, there should be at least a 10-point improvement from baseline after the initial trial of three infusions). Once there is substantial improvement, the aim is to maintain the scores around that level or better since there is likely to be a ceiling effect.

    Plasma exchange is reserved for patients with subtherapeutic response to first-line therapies or in acute crises. Plasma exchange as maintenance therapy is limited by adverse effects (haemodynamic and catheter-associated problems) and the need for specialist in-patient units to administer.1

    The role of rituximab and autologous stem cell transplantation has been investigated but as yet there are no definite results available. Rituximab may be an option for those not responding after 3 months to the above IVIG regimen. There are no studies showing statistically significant results, but some patients with severe disease have shown dramatic responses. The response may take up to 6 months; patients can receive a repeat infusion only if there is worsening. For patients with earlier worsening, the suggested dose is 1 g every 3 months. Serum immunoglobulin concentrations should be measured every 3–6 months; if low, they should not receive rituximab infusion owing to the risk of infections.1

    Other immunotherapies

    Corticosteroids, methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide give only very limited benefit. Corticosteroids, in particular, must be used with caution due to the association with type 1 diabetes mellitus. Some have suggested benefit from using autologous haemopoietic stem cell transplantation as a last resort in refractory patients with severe symptoms.1

    Non-pharmacological

    A summary of case reports has identified the symptomatic benefit of early physiotherapy. Physiotherapy interventions included relaxation, range of motion exercises, massage, ultrasound, heat therapy, hydrotherapy and stretching.61 Psychotherapy may help those with established mental health problems and children.1

    Conclusion

    Neurologists’ greater awareness of SPS and its related conditions will help to prevent its underreporting. When considering treatment options, clinicians must recognise its coexistence of other autoimmune and psychiatric conditions. Antibody positivity can help to classify SPS into its aetiological types. For example, glycine antibody positivity points to an autoimmune cause whereas amphiphysin suggests a paraneoplastic cause. The recommended management of SPS and comorbidities requires a multidisciplinary team approach that includes neurologists, physiotherapists, occupational therapists, pain team and psychiatrists.

    Potential future treatments for SPS include various treatments directed against the B cell (CD19, CD20), tyrosine kinase inhibitors, FcRn inhibitors and antagonists to interleukin 6, which have been trialled in other autoimmune diseases.1

    The understanding of SPS is evolving. A good clinical understanding is necessary to differentiate it from common causes of muscle cramps and functional neurological disorders. Common antibodies found are anti-GAD, anti-glycine and anti-amphiphysin. Regular IVIG remains the mainstay of treatment while GABA-ergic agents provide symptomatic relief. A maintenance IVIG regimen can be tailored by using quantitative assessment techniques to monitor improvement.

    Key points

    • Stiff-person syndrome is an autoimmune disease often associated with high-titre glutamic acid decarboxylase (GAD) antibodies (also present in the cerebrospinal fluid).

    • Patients present with exaggerated stimulus-sensitive spasms, axial muscle stiffness, hyperlordotic posture, increased muscle tone and hyper-reflexia.

    • Paraneoplastic variants can be associated with stiff-limb syndrome (associated with amphiphysin antibodies); brainstem signs may occur in progressive encephalomyelitis with rigidity and myoclonus, caused by anti-glycine receptor antibodies.

    • Other anti-GAD-spectrum disorders can overlap, including cerebellar ataxia, autoimmune epilepsy, limbic encephalitis and myoclonus.

    • Drugs that augment the GABA-ergic pathway (eg, diazepam and baclofen) are the usual initial medications, but patients often need immunomodulatory therapy in the form of intravenous immunoglobulin (IVIG) and rarely rituximab.

    • The Birmingham Response to Immunomodulatory Treatment scale can help to monitor IVIG response.

    Further reading (key references)

    • Dalakas MC1 Therapies in Stiff-Person Syndrome: Advances and Future Prospects Based on Disease Pathophysiology. Neurol Neuroimmunol Neuroinflammation 10:e200109. https://doi.org/10.1212/NXI.0000000000200109

    • Graus F, Saiz A, Dalmau J (2020) GAD antibodies in neurological disorders - insights and challenges. Nat Rev Neurol 16:353–365. https://doi.org/10.1038/s41582-020-0359-x

    • Bose S, Thompson JP, Sadalage G, et al (2021) Quantitative Assessment of Response to Long‐Term Treatment with Intravenous Immunoglobulin in Patients with Stiff Person Syndrome. Mov Disord Clin Pract 8:868–874. https://doi.org/10.1002/mdc3.13261

    Data availability statement

    No data are available.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    No external support was obtained to write this article. Some of the figures were drawn using www.biorender.com.

    References

    1. ↵
      2. Dalakas MC
      . Therapies in Stiff-Person Syndrome: advances and Future Prospects Based on Disease Pathophysiology. Neurol Neuroimmunol Neuroinflamm 2023;10:e200109. doi:10.1212/NXI.0000000000200109
    2. ↵
      2. MOERSCH FP ,
      3. WOLTMAN HW
      . Progressive fluctuating muscular rigidity and spasm ('stiff-man' syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956;31:421–7.
      OpenUrlPubMed
    3. ↵
      2. HOWARD FM
      . A new and effective drug in the treatment of the stiff-man syndrome: preliminary report. Proc Staff Meet Mayo Clin 1963;38:203–12.
      OpenUrlPubMedWeb of Science
    4. ↵
      2. Levy LM ,
      3. Dalakas MC ,
      4. Floeter MK
      . The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med 1999;131:522–30. doi:10.7326/0003-4819-131-7-199910050-00008
      OpenUrlCrossRefPubMed
    5. ↵
      2. Gordon EE ,
      3. Januszko DM ,
      4. Kaufman L
      . A critical survey of stiff-man syndrome. Am J Med 1967;42:582–99. doi:10.1016/0002-9343(67)90057-5
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      2. Solimena M ,
      3. Folli F ,
      4. Denis-Donini S , et al
      . Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988;318:1012–20. doi:10.1056/NEJM198804213181602
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      2. Piccolo G ,
      3. Cosi V ,
      4. Zandrini C , et al
      . Steroid-responsive and dependent stiff-man syndrome: a clinical and electrophysiological study of two cases. Ital J Neurol Sci 1988;9:559–66. doi:10.1007/BF02337009
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Amato AA ,
      3. Cornman EW ,
      4. Kissel JT
      . Treatment of stiff‐man syndrome with intravenous immunoglobulin. Neurol (ECronicon) 1994;44:1652. doi:10.1212/WNL.44.9.1652
      OpenUrl
    9. ↵
      2. Dalakas MC ,
      3. Fujii M ,
      4. Li M , et al
      . High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;345:1870–6. doi:10.1056/NEJMoa01167
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Bose S ,
      3. Thompson JP ,
      4. Sadalage G , et al
      . Quantitative Assessment of Response to Long-Term Treatment with Intravenous Immunoglobulin in Patients with Stiff Person Syndrome. Mov Disord Clin Pract 2021;8:868–74. doi:10.1002/mdc3.13261
      OpenUrlPubMed
    11. ↵
      2. Yi J ,
      3. Dalakas MC
      . Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody-Positive Stiff-Person Syndrome. Neurol Neuroimmunol Neuroinflamm 2022;9:e200011. doi:10.1212/NXI.0000000000200011
    12. ↵
      2. Dalakas MC
      . Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol 2009;11:102–10. doi:10.1007/s11940-009-0013-9
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      2. Solimena M ,
      3. Folli F ,
      4. Aparisi R , et al
      . Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555–60. doi:10.1056/NEJM199005313222202
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      2. El-Abassi R ,
      3. Soliman MY ,
      4. Villemarette-Pittman N , et al
      . SPS: understanding the complexity. J Neurol Sci 2019;404:137–49. doi:10.1016/j.jns.2019.06.021
      OpenUrlPubMed
    15. ↵
      2. Sarva H ,
      3. Deik A ,
      4. Ullah A , et al
      . Clinical Spectrum of Stiff Person Syndrome: a Review of RecentReports. Tremor Other Hyperkinet Mov 2016;6:340. doi:10.5334/tohm.316
      OpenUrl
    16. ↵
      2. Dalakas MC
      . Severe Stiff-Person Syndrome After COVID: the First Video-Documented COVID Exacerbation and Viral Implications. Neurol Neuroimmunol Neuroinflamm 2024;11:e200192. doi:10.1212/NXI.0000000000200192
    17. ↵
      2. Graus F ,
      3. Saiz A ,
      4. Dalmau J
      . GAD antibodies in neurological disorders - insights and challenges. Nat Rev Neurol 2020;16:353–65. doi:10.1038/s41582-020-0359-x
      OpenUrlCrossRefPubMed
    18. ↵
      Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin - PubMed, Available: https://pubmed.ncbi.nlm.nih.gov/15836889/
    19. ↵
      2. Vlad B ,
      3. Wang Y ,
      4. Newsome SD , et al
      . Stiff Person Spectrum Disorders—An Update and Outlook on Clinical, Pathophysiological and Treatment Perspectives. Biomedicines 2023;11:2500. doi:10.3390/biomedicines11092500
      OpenUrlPubMed
    20. ↵
      2. Kasaragod VB ,
      3. Schindelin H
      . Structure-Function Relationships of Glycine and GABAA Receptors and Their Interplay With the Scaffolding Protein Gephyrin. Front Mol Neurosci 2018;11:317. doi:10.3389/fnmol.2018.00317
      OpenUrlCrossRefPubMed
    21. ↵
      2. Rakocevic G ,
      3. Alexopoulos H ,
      4. Dalakas MC
      . Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder. BMC Neurol 2019;19:1. doi:10.1186/s12883-018-1232-z
      OpenUrlCrossRefPubMed
    22. ↵
      2. Meinck H-M ,
      3. Thompson PD
      . Stiff man syndrome and related conditions. Mov Disord 2002;17:853–66. doi:10.1002/mds.10279
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      2. Dalakas MC
      . Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies. Neurotherapeutics 2022;19:832–47. doi:10.1007/s13311-022-01188-w
      OpenUrlPubMed
    24. ↵
      2. Balint B ,
      3. Meinck H-M ,
      4. Bhatia KP
      . Axial Dystonia Mimicking Stiff Person Syndrome. Mov Disord Clin Pract 2016;3:176–9. doi:10.1002/mdc3.12249
      OpenUrlPubMed
    25. ↵
      2. Newsome SD ,
      3. Johnson T
      . Stiff person syndrome spectrum disorders; more than meets the eye. J Neuroimmunol 2022;369:577915. doi:10.1016/j.jneuroim.2022.577915
      OpenUrlCrossRefPubMed
    26. ↵
      2. Balint B ,
      3. Meinck H-M
      . Pragmatic Treatment of Stiff Person Spectrum Disorders. Mov Disord Clin Pract 2018;5:394–401. doi:10.1002/mdc3.12629
      OpenUrlPubMed
    27. ↵
      2. López-Jiménez A ,
      3. Gutiérrez-Gutiérrez G ,
      4. Guerra-Hiraldo JD , et al
      . Teaching Video NeuroImage: hung-Up Reflex in Stiff Limb Syndrome. Neurol (ECronicon) 2022;99:356. doi:10.1212/WNL.0000000000200938
      OpenUrl
    28. ↵
      2. Hadavi S ,
      3. Noyce AJ ,
      4. Leslie RD , et al
      . Stiff person syndrome. Pract Neurol 2011;11:272–82. doi:10.1136/practneurol-2011-000071
      OpenUrlAbstract/FREE Full Text
    29. ↵
      2. Wang Y ,
      3. Tourkevich R ,
      4. Bosley J , et al
      . Ocular Motor and Vestibular Characteristics of Antiglutamic Acid Decarboxylase-Associated Neurologic Disorders. J Neuroophthalmol 2021;41:e665–71. doi:10.1097/WNO.0000000000001084
      OpenUrlPubMed
    30. ↵
      2. Lambe J ,
      3. Rothman A ,
      4. Prince J , et al
      . Retinal pathology occurs in stiff-person syndrome. Neurol (ECronicon) 2020;94:e2126–31. doi:10.1212/WNL.0000000000008943
      OpenUrl
    31. ↵
      2. Koshorek J ,
      3. Wang Y ,
      4. Maldonado DP , et al
      . The many faces of gastrointestinal dysfunction in stiff person syndrome spectrum disorders. Front Neurol 2023;14:1273256. doi:10.3389/fneur.2023.1273256
      OpenUrlPubMed
    32. ↵
      2. Dumitrascu OM ,
      3. Tsimerinov EI ,
      4. Lewis RA
      . Gastrointestinal and Urologic Sphincter Dysfunction in Stiff Person Syndrome. J Clin Neuromuscul Dis 2016;18:92–5. doi:10.1097/CND.0000000000000143
      OpenUrlPubMed
    33. ↵
      2. Piepgras J ,
      3. Höltje M ,
      4. Michel K , et al
      . Anti-DPPX encephalitis. Neurol (ECronicon) 2015;85:890–7. doi:10.1212/WNL.0000000000001907
      OpenUrl
    34. ↵
      2. Chan CK ,
      3. Pimentel Maldonado DA ,
      4. Wang Y , et al
      . Cognitive and Mood Profiles Among Patients With Stiff Person Syndrome Spectrum Disorders. Front Neurol 2022;13:865462. doi:10.3389/fneur.2022.865462
      OpenUrlCrossRefPubMed
    35. ↵
      2. Chia NH ,
      3. McKeon A ,
      4. Dalakas MC , et al
      . Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria. Ann Clin Transl Neurol 2023;10:1083–94. doi:10.1002/acn3.51791
      OpenUrlPubMed
    36. ↵
      2. Nasri A ,
      3. Gharbi A ,
      4. Ouali U , et al
      . Psychiatric Symptoms in Stiff-Person Syndrome: a Systematic Review and a Report of Two Cases. J Acad Consult Liaison Psychiatry 2023;64:183–91. doi:10.1016/j.jaclp.2022.07.005
      OpenUrlPubMed
    37. ↵
      2. Sexauer W ,
      3. Woodford M ,
      4. Pack K , et al
      . Dyspnea in Patients with Stiff-Person Syndrome. Am J Med Sci 2019;358:268–72. doi:10.1016/j.amjms.2019.07.007
      OpenUrlPubMed
    38. ↵
      2. Pimentel Maldonado DA ,
      3. Balshi A ,
      4. Hu C , et al
      . Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved. Eur J Neurol 2023;30:2498–505. doi:10.1111/ene.15825
      OpenUrlPubMed
    39. ↵
      2. Cosentino G ,
      3. Romano M ,
      4. Algeri M , et al
      . Intranasal midazolam for treating acute respiratory crises in a woman with stiff person syndrome. Neurol Neuroimmunol Neuroinflamm 2020;7:e715. doi:10.1212/NXI.0000000000000715
    40. ↵
      2. Maramattom BV
      . Status spasticus and psoas muscle edema due to anti-GAD antibody associated stiff-man syndrome. Indian J Crit Care Med 2015;19:493–5. doi:10.4103/0972-5229.162474
      OpenUrlPubMed
    41. ↵
      2. Shaw PJ
      . Stiff-man syndrome and its variants. The Lancet 1999;353:86–7. doi:10.1016/S0140-6736(05)76151-1
      OpenUrl
    42. ↵
      2. Balint B ,
      3. Mahant N ,
      4. Meinck H-M , et al
      . Stiff Limb Syndrome Mimicking Corticobasal Syndrome. Mov Disord Clin Pract 2014;1:354–6. doi:10.1002/mdc3.12059
      OpenUrlPubMed
    43. ↵
      2. Ali AH ,
      3. Benterud A ,
      4. Holmøy T , et al
      . Progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with anti-glycine receptor antibodies and urothelial carcinoma: a case report. J Med Case Rep 2023;17:330. doi:10.1186/s13256-023-04059-w
      OpenUrlPubMed
    44. ↵
      2. Barker RA ,
      3. Revesz T ,
      4. Thom M , et al
      . Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–40. doi:10.1136/jnnp.65.5.633
      OpenUrlAbstract/FREE Full Text
    45. ↵
      2. Leigh PN ,
      3. Rothwell JC ,
      4. Traub M , et al
      . A patient with reflex myoclonus and muscle rigidity: 'jerking stiff-man syndrome' J Neurol Neurosurg Psychiatry 1980;43:1125–31. doi:10.1136/jnnp.43.12.1125
      OpenUrlAbstract/FREE Full Text
    46. ↵
      2. Seneviratne SO ,
      3. Buzzard KA ,
      4. Cruse B , et al
      . Cerebellar Ataxia Followed by Stiff Person Syndrome in a Patient with Anti-GAD Antibodies. Case Rep Immunol 2020;2020:8454532. doi:10.1155/2020/8454532
      OpenUrl
    47. ↵
      2. Borellini L ,
      3. Lanfranconi S ,
      4. Bonato S , et al
      . Progressive Encephalomyelitis with Rigidity and Myoclonus Associated With Anti-GlyR Antibodies and Hodgkin’s Lymphoma: a Case Report. Front Neurol 2017;8:401. doi:10.3389/fneur.2017.00401
      OpenUrlPubMed
    48. ↵
      2. Su Y ,
      3. Cui L ,
      4. Zhu M , et al
      . Progressive Encephalomyelitis With Rigidity and Myoclonus With Thymoma: a Case Report and Literature Review. Front Neurol 2020;11:1017. doi:10.3389/fneur.2020.01017
      OpenUrlPubMed
    49. ↵
      2. Duddy ME ,
      3. Baker MR
      . Stiff person syndrome. Front Neurol Neurosci 2009;26:147–65. doi:10.1159/000212375
      OpenUrlPubMed
    50. ↵
      2. Esch ME ,
      3. Newsome SD
      . Improvement of stiff-person syndrome symptoms in pregnancy. Neurol Neuroimmunol Neuroinflamm 2020;7:e684. doi:10.1212/NXI.0000000000000684
    51. ↵
      2. Yeshokumar AK ,
      3. Sun LR ,
      4. Newsome SD
      . Defining the Expanding Clinical Spectrum of Pediatric-Onset Stiff Person Syndrome. Pediatr Neurol 2021;114:11–5. doi:10.1016/j.pediatrneurol.2020.09.007
      OpenUrlPubMed
    52. ↵
      2. Shivaram S ,
      3. Nagappa M ,
      4. Seshagiri DV , et al
      . P-NE014. Electromyography in the diagnosis of stiff-person syndrome. Clin Neurophysiol 2021;132:e92. doi:10.1016/j.clinph.2021.02.207
    53. ↵
      2. Dalakas MC ,
      3. Li M ,
      4. Fujii M
      . Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurol (ECronicon) 2001;57:780–4. doi:10.1212/WNL.57.5.780
      OpenUrl
    54. ↵
      2. Reiber H ,
      3. Peter JB
      . Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 2001;184:101–22. doi:10.1016/s0022-510x(00)00501-3
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      2. Blinder T ,
      3. Lewerenz J
      . Cerebrospinal Fluid Findings in Patients With Autoimmune Encephalitis-A Systematic Analysis. Front Neurol 2019;10:804. doi:10.3389/fneur.2019.00804
      OpenUrlCrossRefPubMed
    56. ↵
      2. Petit-Pedrol M ,
      3. Armangue T ,
      4. Peng X , et al
      . Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276–86. doi:10.1016/S1474-4422(13)70299-0
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      2. Budhram A ,
      3. Sechi E ,
      4. Flanagan EP , et al
      . Clinical spectrum of high-titre GAD65 antibodies. J Neurol Neurosurg Psychiatry 2021;92:645–54. doi:10.1136/jnnp-2020-325275
      OpenUrlAbstract/FREE Full Text
    58. ↵
      2. Mukharesh L ,
      3. Fitzgerald K ,
      4. Wang Y , et al
      . Can Certain Baseline Characteristics in Patients with Stiff Person Syndrome (SPS) Predict Disease Burden and Functional Outcomes? (5277). Neurol (ECronicon) 2020;94:5277. doi:10.1212/WNL.94.15_supplement.5277
      OpenUrl
    59. ↵
      2. Martinez-Hernandez E ,
      3. Ariño H ,
      4. McKeon A , et al
      . Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder. JAMA Neurol 2016;73:714–20. doi:10.1001/jamaneurol.2016.0133
      OpenUrlPubMed
    60. ↵
      2. Maramattom BV
      . Intrathecal baclofen pump implantation in a case of stiff person syndrome. Neurol India 2010;58:115–7. doi:10.4103/0028-3886.60420
      OpenUrlPubMed
    61. ↵
      2. Vaiyapuri A ,
      3. Kashyap P ,
      4. Kashyap N , et al
      . Is Stiff Person Syndrome Benefited by Physical Therapy Intervention? Summary of Case Reports. Biomed Res Int 2019;2019:5613680. doi:10.1155/2019/5613680
      OpenUrlPubMed

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    Footnotes

    • X @SmritiBose99194

    • Contributors Both authors have contributed equally to the concept, writing, revision and approval of the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests SJ has served as an international advisory board member for Alexion, Alnylam, Argenx, Immunovant, Janssen, Novartis, Regeneron and UCB pharmaceuticals, is currently an expert panel member of Myasthenia Gravis consortium for Argenx pharmaceuticals and has received speaker fees from Argenx, Eisai, Terumo BCT and UCB pharmaceuticals. He is also a board member (trustee) of the UK myasthenia patient charity, Myaware. None of these are relevant for the current manuscript.

    • Provenance and peer review Commissioned; externally peer reviewed by Jon Walters, Swansea, UK.

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