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Movement disorders
Review
Stiff-person syndrome: insights into a complex autoimmune disorder
  1. José Fidel Baizabal-Carvallo,
  2. Joseph Jankovic
  1. Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr José Fidel Baizabal-Carvallo, Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, The Smith Tower, Suite 1801, 6550 Fannin, Houston, TX 77030, USA; baizabaljf{at}hotmail.com

Abstract

Stiff-person syndrome (SPS) is characterised by progressive rigidity and muscle spasms affecting the axial and limb muscles. Since its initial description in 1956, marked progress has been made in the clinical characterisation, understanding of pathogenesis and therapy of this disorder. SPS can be classified according to the clinical presentation into classic SPS and SPS variants: focal or segmental-SPS, jerking-SPS and progressive encephalomyelitis with rigidity and myoclonus. Most patients with SPS have antibodies directed against the glutamic acid decarboxylase, the rate-limiting enzyme for the production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Antibodies directed against GABAA receptor-associated protein, and the glycine-α1 receptor can also be observed. Paraneoplastic SPS is commonly associated with antiamphiphysin antibodies and breast cancer. Treatment of SPS with drugs that increase the GABAergic tone combined with immunotherapy can improve the neurological manifestations of these patients. The prognosis, however, is unpredictable and spontaneous remissions are unlikely.

  • MOVEMENT DISORDERS
  • STIFF MAN SYNDROME

https://doi.org/10.1136/jnnp-2014-309201

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    Introduction

    Stiff-person syndrome (SPS) was first reported by Moersch and Woltman in 1956 who described 14 patients with fluctuating, but progressive rigidity, and painful-muscle spasm leading to gait difficulties, falls and a ‘wooden-man’ appearance, leading the authors to use the term ‘stiff man syndrome’.1 The term ‘stiff-person syndrome’ was first used in 1991 by one of the authors (JJ) to draw attention to its frequent occurrence in women.2 Subsequent studies established SPS as an autoimmune disorder, most frequently associated with antibodies against glutamic acid decarboxylase (GAD).3

    Epidemiology and clinical variants

    SPS has an estimated prevalence of 1–2 cases per million with an incidence of 1 case per million per year.4 Most patients present between the ages of 20 and 50. Classical SPS affects women two to three times more often than men. Several classifications have been proposed for SPS according to the severity or distribution of the stiffness, related neurological findings, and association with neoplasia (table 1).5–9

    View this table:
    Table 1

    Main features of stiff-person syndrome

    Clinical manifestations of classic SPS

    The onset of classic SPS is usually insidious, with intermittent muscle tightness or aching, eventually evolving into objective hypertonia or rigidity associated with sustained cocontraction of antagonist groups of muscles, leading to a restricted range of motion, slow voluntary movements (resembling parkinsonism), muscle hypertrophy and abnormal postures with the characteristic lumbar hyperlordosis (see online supplementary video 1). The rigidity/hypertonia usually progresses from the trunk to the proximal and then to the distal limb muscles, affecting gait and balance (see online supplementary video 2). Patients may experience frequent falls, which appear as ‘statue-like’ or ‘log-like’, without the usual reflexive manoeuvers to soften the impact and prevent injury.2 The generalised rigidity may lead to dyspnoea and poor exercise tolerance and early satiety due to restricted chest and abdominal expansion, respectively. Patients also develop muscle spasms that may be triggered by emotional upset, startle (precipitated by tactile, auditory and visual stimuli) or by sudden movements generated by muscle contractions of adjacent muscles (overflow spasms). The muscle spasms are variable in intensity, distribution and duration, but usually present in bouts.10 The spasms may be preceded by jerky muscle contractions (myoclonus) and tend to resolve gradually.10 Besides the spasms, some patients experience chronic muscle pain. Muscle weakness and sensory disturbances are not part of classic SPS.

    Patients with SPS may exhibit other neurological abnormalities. Oculomotor disturbances including dysconjugate gaze, horizontal and vertical supranuclear gaze palsy, hypometric and slow saccades, impaired smooth pursuit, nystagmus and abduction deficits have been described in patients with SPS.11 ,12 Exaggerated startle responses, abnormally-enhanced extereoceptive reflexes and disinhibition of brainstem reflexes such as the head-retraction reflex are not uncommon features of SPS.13 Paroxysmal dysautonomic crisis, manifested by high blood pressure, tachycardia, hyperthermia and diaphoresis are not uncommon and may accompany muscle spasms.14

    In addition to neurological abnormalities, depression, anxiety and alcohol abuse are frequently present in patients with SPS.15 In one study, 44% of the 43 patients with SPS reported agoraphobia and other situation-specific phobias.16 These psychiatric features along with the uncommon motor manifestations could lead to an erroneous diagnosis of a psychogenic disorder. Patients with SPS may develop severe life-threatening complications, particularly if untreated (table 1). Most patients with classic SPS have antibodies directed against the enzyme GAD and can be used to support the diagnosis of SPS.

    Paraneoplastic SPS

    Paraneoplastic variants represent less than 10% of all patients with SPS.17 Antiamphiphysin antibodies are the most common markers of this variant. However, the prevalence of antiamphiphysin antibodies among patients with paraneoplastic disorders is low, with only 71 patients among 120 000 evaluated for a paraneoplastic disorder.18 Although neuropathy and encephalopathy were the most common neurological manifestations in patients with antiamphiphysin antibodies, other paraneoplastic antibodies have been implicated as a cause of these manifestations. In contrast, patients with isolated antiamphiphysin antibodies more frequently exhibited stiff-person phenomena or myelopathy.18 Patients with stiffness associated with antiamphiphysin antibodies are typically women with breast cancer, who may also have low titres of anti-GAD65 antibodies.18 These patients often exhibit a rostrocaudal distribution of stiffness with more frequent neck and upper limb stiffness, in contrast to classic non-paraneoplastic SPS which presents more frequently with spine and lower limb involvement.17 This pattern differs from the one observed in a rat model with passive transfer of human antiamphiphysin antibodies, which produced more truncal and hind-limb stiffness rather than fore-limb stiffness.19 Rhabdomyolysis in patients with antibodies recognising the brain and muscle isoforms of amphiphysin is a potential complication.20 Anti-gephyrin antibodies have been reported in a single patient with a mediastinal undifferentiated neoplasm.21 Paraneoplastic SPS has been also associated with anti-GAD and anti-Ri (ANNA-2; antineuronal nuclear autoantibody type 2) antibodies.22

    Progressive encephalomyelitis with rigidity and myoclonus

    Progressive encephalomyelitis with rigidity and myoclonus (PERM) was first described by Campbell and Garland in 1956 in three patients exhibiting axial and limb rigidity, with prominent myoclonus, accompanied with profuse sweating and hyperthermia.23 Most patients with PERM present in the fifth or sixth decades of their life with insidious onset and a relapsing-remitting course, manifested by prominent brainstem dysfunction, dysautonomia, besides SPS phenomenon. Anti-glycine-α1 receptor (anti-GlyR) antibodies are typically found, although some patients also have anti-GAD antibodies.9 ,24 ,25 An associated tumour is documented in about 20% of cases.9 One-quarter of the patients require mechanical ventilation and mortality can be as high as 40%.24 Although PERM may represent a continuum from the classic SPS, the presence of anti-GlyR antibodies in the absence of anti-GAD antibodies in some patients suggests the possibility that PERM is a separate autoimmune disorder with overlapping features with SPS. Patients with PERM usually respond to immunotherapy but relapses are frequent, particularly when these medications are stopped or the dose has been reduced.

    Pathogenesis and pathophysiology

    The cardinal manifestations of SPS have been attributed to dysfunction of inhibitory mechanisms within the central nervous system (CNS). A major breakthrough in our understanding of the pathogenesis of SPS occurred in 1988, when an association between anti-GAD antibodies and SPS was first reported by Solimena et al.26 GAD is the rate-limiting step in the decarboxylation of L-glutamate to γ-aminobutyric acid (GABA). Neurons contain two isoforms of GAD: a cytoplasmic, constitutively active 67 kDa form (GAD67) that provides a steady production of GABA, and a synaptic membrane-associated form of 65 kDa (GAD65) which supplies pulses of GABA under circumstances demanding rapid postsynaptic inhibition.27 These isoforms are encoded by different genes, GAD1 and GAD2, located on chromosome 2q31.1 and 10p12, respectively.28 Antibodies reacting to GAD, mainly the 65 kDa isoform, are found in high titres (>1000 U/mL) in 60–80% of patients with classic SPS.29 Patients with other disorders such as type 1 diabetes mellitus (T1D), Batten disease, autoimmune polyendocrine syndrome type 1, cerebellar ataxia, drug-refractory epilepsy and palatal myoclonus also have been associated with anti-GAD antibodies.30 ,31 T1D is observed in as many of 30% of patients with SPS; however, only 1 in 10 000 patients with T1D is affected by SPS.32 In patients with SPS, anti-GAD antibodies are found in the blood and cerebrospinal fluid (CSF), but these antibodies are only seen in the blood of patients with T1D, although they may reach the CNS in cases of dysfunction of the blood-brain-barrier.

    The GAD isoforms are divided into three functional domains (figure 1). Patients with SPS have anti-GAD antibodies recognising discontinuous segments of the middle and C-terminal part of GAD65, which represents epitopes influenced by molecular conformation.33 ,34 The antibodies directed against the C-terminal part of the GAD seem to block the activity of the enzyme by a non-competitive mechanism. However, this effect does not occur in patients with T1D with anti-GAD65 antibodies.31 ,35 Additionally, patients with SPS have anti-GAD65 antibodies directed against a linear epitope in the N-terminal segment, especially within the first 100 amino acids of the protein, not found in patients with T1D.33 ,36 This segment of GAD is exposed during synaptic transmission, but whether these antibodies are pathogenic is unknown.37 Despite these differences, a significant overlap in epitope recognition between patients with SPS and T1D has been recognised.33 Some authors propose that the difference in pathogenicity is related to the higher titre of anti-GAD antibodies in SPS rather than differences in epitope recognition.38

    Figure 1
    Figure 1

    Molecular conformation of glutamic acid decarboxylase (GAD) enzymes 65 and 67. The two GAD isoforms have 65% amino acid (aa) sequence homology differing in middle, C-terminal and N-terminal segments. GAD65 is activated when bound to pyridoxal 5′-phosphate (PLP). The N-terminal contains the domain that anchors the enzyme to the synaptic vesicle, and the proteolytic cleavage site that separates this from the enzymatic region. Antibodies are directed to different segments of both GAD isoenzymes. The main location of GAD65 is in the synaptic vesicles of neurons, but it is also encountered in the pancreatic β-cells, testes and oviducts. Between 50% and 60% of Stiff-person syndrome (SPS) patients have antibodies against GAD67, whereas these antibodies are only seen in about 10% of patients with type-1 diabetes (T1D) and are believed to represent cross-reactivity from anti-GAD65 antibodies.27

    The inhibitory effect of anti-GAD antibodies on GABA synthesis has been observed in the experimental models using extracts of cerebellar rat tissue, exposed to serum or CSF from patients with SPS with anti-GAD65 antibodies.35 ,39 An increase in postsynaptic inhibitory potentials has been found in hippocampal cultured neurons exposed to anti-GAD antibodies.40 Transfer of serum from patients with SPS syndrome to animal models has been shown to reproduce some of the motor and neuropsychiatric manifestations of SPS (table 2).19 ,41–47 However, the pathogenic role of anti-GAD antibodies has been questioned as the serum and CSF titres do not necessarily correlate with clinical fluctuations or severity of SPS, suggesting lack of specificity (table 3).48 Furthermore, the intracellular location of GAD makes this antigen relatively inaccessible, casting doubts on the pathogenicity of anti-GAD antibodies in SPS. To address this issue, it has been suggested that an epitope of GAD be exposed during a synaptic-vesicle release allowing antibodies to bind to the cell surface and disrupt normal-cellular mechanisms.4 Alternatively, using immunohistochemistry, it has been demonstrated that anti-GAD antibodies colocalise with GAD in permeabilised cultured cerebellar GABAergic neurons without actually binding to the epitopes located in the neuronal-cell surface, suggesting that other antibodies bind to the surface of non-permeabilised cells.38

    View this table:
    Table 2

    Animal studies assessing the effect of anti-GAD and antiamphiphysin antibodies

    View this table:
    Table 3

    Arguments for and against pathogenic role of anti-GAD antibodies in SPS

    Antibodies directed against the 14 kDa postsynaptic GABAA receptor-associated protein have been detected in almost 70% of patients with non-paraneoplastic SPS.49 This protein interacts with gephyrin enabling the assembly of GABAA-receptor into the plasma membrane (figure 2). IgG from patients with SPS inhibited the surface expression of GABAA receptors on the neuronal membrane, perhaps interfering with the cellular trafficking and expression of GABAA receptors.49 No antibodies against the GABAB receptor were found in 77 patients with neurological syndromes associated with anti-GAD antibodies.50 Antibodies against the 80 kDa enzyme 17β-hydroxysteroid dehydrogenase type 4 have been identified in 12% of patients with SPS but their pathogenic role is unknown.51 Anti-GlyR antibodies, most commonly associated with PERM, can be found in 10–15% of patients with SPS.52 ,53 Interestingly, these patients seem to have more prominent anxiety and emotional excitability,53 although the exact role of anti-GlyR antibodies in the clinical manifestations of SPS is yet to be clarified. Recently, low titres of antibodies directed against the GABAA receptors were detected in the serum of four patients with SPS: one with seizures and one with limbic encephalitis.54 While patients with high serum and CSF titres of these antibodies tend to have a severe form of encephalitis with seizures, the role of these antibodies in the pathogenesis of SPS pathogenesis is unknown.54

    Figure 2
    Figure 2

    Immunopathogenesis of stiff-person syndrome (SPS) and main components of inhibitory synapses. (A) Pathogenic roles of T cells and B cells in SPS are not well defined, neurons are not antigen presenting cells, but microglia and B cells can perpetuate the activity of T-cells within the central nervous system by presenting glutamic acid decarboxylase (GAD)65 or GAD67 antigens to T cells. B cells produce an oligoclonal population of antibodies. (B) Relevant components of inhibitory synapses. GAD65 reversibly binds to the membrane of synaptic vesicles. Amphiphysin is involved in the endocytosis process in the presynaptic membrane. γ-Aminobutyric acid (GABA)A receptor-associated protein and gephyrin are microtubule binding proteins with a role in clustering and anchoring of GABAA receptors facilitating their binding to the synaptic cytoskeleton. RAP, receptor-associated protein.

    Antibodies directed against the 128 kDa protein amphiphysin have been documented in patients with paraneoplastic SPS, particularly associated with breast cancer.55 ,56 Amphiphysin is an intracellular protein that promotes cleavage of clathrin-coated vesicles by binding its Src homology 3 (SH-3)-domain to dynamin, supporting endocytosis at synapses by the formation of dynamin rings around clathrin vesicles (figure 2).19 ,57 Internalisation of antiamphiphysin antibodies into the intracellular domain has been demonstrated in an experimental model with neurons of rats.42 Furthermore, an activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic potentials may explain its pathogenic role.42 However, it is unclear why these antibodies affect predominantly GABAergic inhibitory synaptic transmission, as amphiphysin is found in synapses of several neuronal types.

    The immunoglobulin isotype IgG1 is the main antibody found in patients with T1D and SPS. However, other isotypes including IgG2, IgG3, IgG4, and IgE have been detected in lower quantities in patients with SPS.24 ,27 ,32 Oligoclonal bands (OCB) are frequently encountered in the CSF of patients with SPS; these OCBs have a higher frequency and intensity in the CSF than in the serum and are conformed by various subsets of antibodies directed against different GAD epitopes.31 ,58 This oligoclonal production of intrathecal antibodies is estimated to be 10-fold higher in the CNS than in peripheral tissues.48 Differences in epitope recognition of anti-GAD65 antibodies when serum and CSF samples from the same patient are compared, suggests a strong intrathecal production by active B cells.31 However, it is unclear what mechanisms sustain the antibody production by B cells within the CNS.45

    The role of T cells has recently been investigated more thoroughly in patients with SPS. It is generally accepted that T-cell activation targeting neural antigens takes place in lymphoid organs outside the CNS.59 Although some of these T cells can cross the blood-brain barrier, only those reactivated in the CNS seem to remain intrathecally.59 It is uncertain what triggers peripheral T-cell activation, but viral infections such as West Nile virus, coxsackievirus and cytomegalovirus have been observed preceding the onset of an SPS.60 This activation can occur either through bystander activation or cross-recognition of viral epitopes (molecular mimicry). It has been shown that GAD65-specific T-cells cross-react with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein, furthermore an hCMV-derived epitope can be processed by dendritic cells and recognised by GAD65-reactive T cells.61 Patients with SPS have peripheral lymphocytes that react to GAD, but detection of these cells has proven difficult.62 These peripheral T-cells react to GAD regions 81–171 and 313–403, which contrasts with their counterparts in patients with T1D that react mainly to GAD regions 161–243 and 473–555.63 Other studies have demonstrated a T-cell response to GAD region between 339 and 565 in patients with SPS.62 ,64 ,65 Attempts to detect and clone the T-cells responding to GAD65 have been more successful using CSF than peripheral lymphocytes from patients with SPS.65 Also, an evidence of interferon γ (IFNγ) and interleukin 4 (IL-4) production by T cells suggests a combined Th1 and Th2 response in patients with SPS, which differs from the predominant Th1 response in patients with T1D.63 ,66 Some of the T-cell clones in SPS produce Th2 cytokines supporting an antigen-driven collaboration between T and B cells leading to a sustained intrathecal production of oligoclonal anti-GAD IgG antibodies.65 Furthermore, a Th2 anti-inflammatory response in SPS has been proposed as a protective mechanism against the development of T1D in the majority of patients with SPS.67 The T-cell response in patients with SPS seem to be different from those with cerebellar ataxia and anti-GAD antibodies, with the latter having higher IFNγ production and lower proliferative response to GAD65 by T-cells.67 It is unclear what mechanisms are involved in the reactivation of T cells, once inside the CNS. It has been proposed that antigen-presenting cells such as macrophage/microglia, dendritic cells and B cells can support T-cell reactivation, retaining them inside the CNS and perpetuating the autoimmune response (figure 2).65 Finally, the direct pathogenic effects of T-cells in the CNS is controversial. However, an experimental model showed that mice possessing monoclonal GAD65-specific CD4(+) T cells may develop an encephalomyelitis-like response.68

    Immunogenetics

    A genetic susceptibility linked to the human-associated leucocyte-antigen has been reported in SPS. The alleles DQB1*0201 and DRB1*0301 are present in about 70% of patients with SPS, compared to 37% of controls, these alleles also increase the susceptibility for T1D and other autoimmune disorders; whereas, the DQB1*0602 allele seem to confer a protective effect for T1D in patients with SPS.69 ,70

    Neurophysiological studies and functional imaging

    Muscle stiffness in SPS is caused by the continuous firing of motor neurons, involving agonists and antagonist muscles. Electromyography (EMG) shows a continuous motor-unit activity, despite attempted relaxation.5

    Neurophysiological studies have shown a normal Hmax/Mmax ratio suggesting a premotor neuronal origin of increased-motor activity. Enhanced H-reflex recovery and reduced vibration-induced H-reflex inhibition are observed in patients with SPS, both believed to be mediated by GABAergic interneurons producing presynaptic inhibition of stretch reflex afferents.10 ,71 However, a non-altered presynaptic period of reciprocal inhibition in most patients with SPS suggests some functional preservation of GABAergic interneurons.71 Besides GABAergic system, glycinergic neurons may also play a role in SPS. Antibodies directed against the α-1 subunit of the glycine receptor have also been identified in 10–15% of cases of SPS.53

    Monosynaptic reflexes were normal in a group of patients with SPS.72 However, a stereotyped-motor response to peripheral-nerve stimulation consisting of a sequence of 1–3 synchronous myoclonic bursts with a 60–70 ms latency, followed by a decrescendo tonic-muscle activity and habituation has been termed ‘spasmodic reflex myoclonus’.10 An exaggerated response to exteroceptive (somatosensory and acoustic) stimuli with short-transmission times and abnormal excitatory-reflex phases on the face, arms and legs, suggest a widespread decrease in CNS inhibitory mechanisms.72 Little or no response to visual and vestibular stimuli was recorded.72 Further evidence of altered supraspinal-inhibitory mechanisms has been reported with brainstem reflexes frequently showing increased excitation with hyper-synchronisation of multiple muscles, decreased inhibition and short-response latencies with a pattern similar to that observed in patients with hyperekplexia.73 An enhanced recovery cycle in the late (R2) component of the blink reflex is another feature of brainstem hyperexcitability in patients with SPS.74

    Support for altered GABAergic inhibitory mechanisms in the brain have been observed in vivo in patients with SPS. For example, the GABA/creatine ratio was reduced 29–36% in the motor cortex bilaterally in a group of eight patients with SPS compared to controls studied with MR spectroscopy.75 The GABA levels were also reduced in the CSF of patients with SPS as compared to participants with other autoimmune disorders.76 Enhanced motor-cortex excitability using transcranial magnetic stimulation (TMS) in untreated patients with SPS has been reported to correlate with the anti-GAD titre of the CSF.77 ,78 A study using a paired-pulse TMS paradigm aimed to assess intracortical circuitry, showed excessive facilitation of the MEP. This evidence, along with shorter intracortical silent periods suggests altered cortical-inhibitory mechanisms in patients with SPS.78 A lack of facilitation of H-reflexes in this study argued against spinal mechanisms as being responsible for the MEP changes.78 Furthermore, a global decrease in the benzodiazepine receptor binding in the brains of three patients with SPS assessed by [11C]flumazenil positron emission tomography has been documented, with significant clusters in the premotor and motor cortex.79 ,80 This latter finding suggests an altered postsynaptic cortical-inhibitory mechanism as the benzodiazepine receptors colocalise with the GABAA receptors. In summary, widespread altered inhibitory mechanisms have been documented in patients with SPS; with evidence supporting a predominant premotor and supraspinal mechanisms driving the increased-motor activity.

    Pathology

    Pathological studies of tissues from patients with SPS have found chromatolysis and vacuolisation of anterior horn cells, more commonly in the caudal levels of the spinal cord,81–83 and a loss of α-motor, γ-motor neurons and spinal interneurons with gliosis.14 ,84 Despite these changes, EMG studies classically do not show signs of denervation, except in selected cases.81 Neuronal degeneration with macrophage/microglia infiltrates in the dorsal-root ganglia of the spinal cord has also been documented.83 Vacuolation of spinal cord motor neurons is thought to be related to hyper-swollen lysosomes.83 These pathological changes, although thought to be pathogenically relevant, show little or no correlation with clinical manifestations.83 ,84 Furthermore, some autopsy studies of patients with SPS show no inflammatory infiltrates or other important pathological changes.5

    Encephalitis with perivascular lymphocytic cuffing at different levels of the CNS is a pathological feature of PERM, but has also been reported in patients with SPS and brainstem signs, suggesting an overlap or continuum between both the disorders; with PERM being on the more-severe end of the spectrum.85 Accumulation of CD8+ cytotoxic T cells and proliferation of CD68 microglial cells in the anterior horns is another feature of PERM.81 A similar inflammatory infiltrate, predominantly in the mesial temporal lobes, brainstem, spinal cord and dorsal-root ganglion has also been reported in patients with paraneoplastic SPS, associated with antiamphiphysin antibodies.18 ,86

    Differential diagnosis

    The diagnosis of SPS is based on the recognition of the cardinal manifestations and supported by EMG, antibody testing and response to diazepam (table 1).4 Associated autoimmune disorders should be actively searched in all patients with SPS (table 1).87 Differential diagnosis of SPS is wide and includes: parkinsonian syndromes, focal and generalised dystonia, hereditary spastic paraparesis, motor neuron disease, myelopathies, tetanus, neuromyotonia (Morvan's and Isaac's syndrome), ankylosing spondylitis, psychogenic, among several other disorders.3–7 ,87

    Treatment

    Therapy is aimed at symptomatic relief and modulation of the autoimmune process. GABA agonists such as diazepam (type-A receptors) and oral baclofen (type-B receptors) alone or combined are usually effective for rigidity and muscle spasms.6 ,88 In one study of 99 patients with SPS, diazepam (median dosage 40.0 mg/day) provided sustained improvement in nearly all patients.6 Although a symptomatic benefit is experienced by most patients with these medications, progressively higher doses may be required, sometimes leading to intolerable side effects such as drowsiness. A small cross-over randomised trial of levetiracetam showed the benefit of this drug as compared to placebo.89 Other oral agents have been reported in isolated case reports as effective for symptomatic relief of SPS with a benzodiazepine sparing effect (table 4). Intrathecal baclofen can be used as a rescue therapy for severe SPS and PERM.90 ,91 However, catheter malfunction is not uncommon and caution should be taken as sudden interruption of the intrathecal supply may lead to severe symptomatic withdrawal and even death from dysautonomia.91 Spinal cord stimulation may provide relief of painful muscle spasms.92 Intravenous or subcutaneous opiates are sometimes needed to relieve severe pain crises; whereas, botulinum toxin may be useful for severe rigidity.93

    View this table:
    Table 4

    Therapeutic options in patients with stiff-person syndrome

    Immunotherapy should be considered in most patients with SPS. Intravenous immunoglobulin (IVIg) showed efficacy as compared to a placebo in a randomised-crossover trial in 16 patients with SPS.94 The IVIg (or placebo) was given for 3 months, followed by 1 month of washout before switching to the alternative therapy. A marked improvement in muscle spasms, mobility, frequency of falls and activities of daily living and reduction of anti-GAD titres was observed with IVIg. The benefit lasted between 6 weeks and 1 year.94 Plasmapheresis has a variable efficacy in patients with SPS.95 Some authors have advocated the chronic monthly use of this therapy as a means of maintaining symptomatic relief.95 ,96 The B-cell depleting monoclonal anti-CD20 antibody rituximab has been used with variable success in patients with SPS.97–99 PERM or patients with SPS with positive anti-GAD or antiamphiphysin antibodies and lack of response to other immunotherapies, including steroids and IVIg may benefit from a trial of rituximab.100–102 Patients with SPS have been found to harbour populations of rituximab-sensitive and rituximab-resistant B cells; the latter may be represented by long-lived plasma cells not expressing the CD20-antigen in the cellular membrane.103 Other immunotherapies have been tried alone or in combination with variable success (table 3).

    Prognosis

    Prognosis is variable and largely depends on the initial-clinical presentation. Unfortunately, many patients experience symptoms and disability despite the combination of multiple symptomatic and immunological therapies. The quality of life is severely affected in patients with SPS, with depression having an important role in reported scores.104

    Conclusions

    SPS is clinically heterogeneous in presentation and likely in pathogenesis. Although anti-GAD antibodies are excellent biomarkers of the disease, their role in the pathogenesis is still unclear. Other antibodies have been detected in patients with SPS and further studies with transfer of these antibodies to animals may help to clarify their pathogenic role. Also, a better understanding of the role of B cells and T cells may help to define better therapeutic strategies for this disorder.

    Acknowledgments

    The authors wish to thank the National Parkinson Foundation for their support to the Baylor College of Medicine Center of Excellence.

    References

    1. ↵
      1. Moersch FP,
      2. 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
    2. ↵
      1. Blum P,
      2. Jankovic J
      . Stiff-person syndrome: an autoimmune disease. Mov Disord 1991;6:12–20.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Baizabal-Carvallo JF,
      2. Jankovic J
      . Movement disorders in autoimmune diseases. Mov Disord 2012;27:935–46.
      OpenUrlCrossRefPubMed
    4. ↵
      1. Dalakas MC
      . Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol 2009;11:102–10.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Barker RA,
      2. Revesz T,
      3. 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.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. McKeon A,
      2. Robinson MT,
      3. McEvoy KM, et al
      . Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–8.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Leigh PN,
      2. Rothwell JC,
      3. Traub M, et al
      . A patient with reflex myoclonus and muscle rigidity: “jerking stiff-man syndrome”. J Neurol Neurosurg Psychiatry 1980;43:1125–31.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Alberca RA,
      2. Romero M,
      3. Chaparro J
      . Jerking stiff-man syndrome. J Neurol Neurosurg Psychiatry 1982;45:1159–60.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Mas N,
      2. Saiz A,
      3. Leite MI, et al
      . Antiglycine-receptor encephalomyelitis with rigidity. J Neurol Neurosug Psychiatry 2011;82:1399–401.
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Meinck HM,
      2. Ricker K,
      3. Hulser PJ, et al
      . Stiff man syndrome: neurophysiological findings in eight patients. J Neurol 1995;242:134–2.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Economides JR,
      2. Horton JC
      . Eye movement abnormalities in stiff person syndrome. Neurology 2005;65:1462–4.
      OpenUrlCrossRef
    12. ↵
      1. Oskarsson B,
      2. Pelak V,
      3. Quan D, et al
      . Stiff eyes in stiff-person syndrome. Neurology 2008;71:378–80.
      OpenUrlCrossRef
    13. ↵
      1. Berger C,
      2. Meinck HM
      . Head retraction reflex in stiff-man syndrome and related disorders. Mov Disord 2003;18:906–11.
      OpenUrlCrossRefPubMed
    14. ↵
      1. Mitsumoto H,
      2. Schwartzman MJ,
      3. Estes ML, et al
      . Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol 1991;238:91–6.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Tinsley JA,
      2. Barth EM,
      3. Black JL, et al
      . Psychiatric consultations in stiff-man syndrome. J Clin Psychiatry 1997;58:444–9.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Henningsen P,
      2. Meinck HM
      . Specific phobia is a frequent non-motor feature in stiff man syndrome. J Neurol Neurosurg Psychiatry 2003;74:462–5.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Murinson BB,
      2. Murinson JB
      . Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008;71:1955–8.
      OpenUrlCrossRef
    18. ↵
      1. Pittock SJ,
      2. Lucchinetti CF,
      3. Parisi JE, et al
      . Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96–107.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Sommer CA,
      2. Wishaupt A,
      3. Brinkoff J, et al
      . Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365:1406–11.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Petzold GC,
      2. Marcucci M,
      3. Butler MH, et al
      . Rhabomyolysis and paraneoplastic stiff-man syndrome with amphiphysin autoimmunity. Ann Neurol 2004;55: 286–90.
      OpenUrlCrossRefPubMed
    21. ↵
      1. Butler MH,
      2. Hayashi A,
      3. Ohkoshi N, et al
      . Autoimmunity to gephyrin in stiff-man syndrome. Neuron 2000;26:307–12.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Thümen A,
      2. Moser A
      . An uncommon paraneoplastic Ri-positive opsoclonus-myoclonus-like syndrome and stiff-person syndrome with elevated glutamate/GABA ratio in the cerebrospinal fluid after breast cancer. J Neurol 2010;257:1215–17.
      OpenUrlCrossRefPubMed
    23. ↵
      1. Campbell AM,
      2. Garland H
      . Subacute myoclonic spinal neuronitis. J Neurol Neurosug Psychiatry 1956;19:268–74.
      OpenUrlFREE Full Text
    24. ↵
      1. Duddy ME,
      2. Baker MR
      . Stiff person syndrome. Front Neurol Neurosci 2009;29:147–65.
      OpenUrl
    25. ↵
      1. Piotrowicz A,
      2. Thümen A,
      3. Leite MI, et al
      . A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings. J Neurol 2011;258:2268–70.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Solimena M,
      2. Folli F,
      3. 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.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. Ali F,
      2. Rowley M,
      3. Jayakrishnan B, et al
      . Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun 2011;37:79–87.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Erlander MG,
      2. Tillakaratne NJ,
      3. Feldblum S, et al
      . Two genes encode distinct glutamate decarboxylases. Neuron 1991;7:91–100.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Solimena M,
      2. Folli F,
      3. 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.
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Saiz A,
      2. Blanco Y,
      3. Sabater L, et al
      . Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131:2553–63.
      OpenUrlAbstract/FREE Full Text
    31. ↵
      1. Raju R,
      2. Foote J,
      3. Banga JP, et al
      . Analysis of GAD65 autoantibodies in stiff-person syndrome patients. J Immunol 2005;175:7755–62.
      OpenUrlAbstract/FREE Full Text
    32. ↵
      1. Chéramy M,
      2. Hampe CS,
      3. Ludvigsson J, et al
      . Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals. Clin Exp Immunol 2013;171:247–54.
      OpenUrlCrossRefPubMed
    33. ↵
      1. Daw K,
      2. Ujihara N,
      3. Atkinson M, et al
      . Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J Immunol 1996;156:818–25.
      OpenUrlAbstract
    34. ↵
      1. Butler MH,
      2. Solimena M,
      3. Dirkx R Jr., et al
      . Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med 1993;178:2097–106.
      OpenUrlAbstract/FREE Full Text
    35. ↵
      1. Dinkel K,
      2. Meinck HM,
      3. Jury KM, et al
      . Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998;44:194–201.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Kim J,
      2. Namchuk M,
      3. Bugawan T, et al
      . Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. J Exp Med 1994;180:595–606.
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Richter W,
      2. Shi Y,
      3. Baekkeskov S
      . Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc Natl Acad Sci USA 1993;90:2832–6.
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Chang T,
      2. Alexopoulos H,
      3. McMenamin M, et al
      . Neuronal surface and glutamic acid decarboxylase autoantibodies in nonparaneoplastic stiff person syndrome. JAMA Neurol 2013;70:1140–9.
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      1. Mitoma H,
      2. Song SY,
      3. Ishida K, et al
      . Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 2000;175:40–4.
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      1. Vianello M,
      2. Bisson G,
      3. Dal Maschio M, et al
      . Increased spontaneous activity of a network of hippocampal neurons in culture caused by suppression of inhibitory potentials mediated by anti-gad antibodies. Autoimmunity 2008;41:66–73.
      OpenUrlCrossRefPubMed
    41. ↵
      1. Manto MU,
      2. Laute MA,
      3. Aguera M, et al
      . Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol 2007;61:544–51.
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      1. Geis C,
      2. Weishaupt A,
      3. Hallermann S, et al
      . Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010;133:3166–80.
      OpenUrlAbstract/FREE Full Text
    43. ↵
      1. Geis C,
      2. Weishaupt A,
      3. Grünewald B, et al
      . Human stiff-person syndrome IgG induces anxious behaviour in rats. PLoS ONE 2011;6:e16775.
      OpenUrlCrossRefPubMed
    44. ↵
      1. Geis C,
      2. Grünewald B,
      3. Weishaupt A, et al
      . Human IgG directed against amphiphysin induces anxiety behaviour in a rat model after intrathecal passive transfer. J Neural Transm 2012;119:981–5.
      OpenUrlCrossRefPubMedWeb of Science
    45. ↵
      1. Manto MU,
      2. Hampe CS,
      3. Rogemond V, et al
      . Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J Rare Dis 2011;6:3.
      OpenUrlCrossRefPubMed
    46. ↵
      1. Hampe CS,
      2. Petrosini L,
      3. De Bartolo P, et al
      . Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats. Orphanet J Rare Dis 2013;8:82.
      OpenUrlCrossRefPubMed
    47. ↵
      1. Hansen N,
      2. Grünewald B,
      3. Weishaupt A, et al
      . Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. Exp Neurol 2013;239:202–9.
      OpenUrlCrossRefPubMed
    48. ↵
      1. Rakocevic G,
      2. Raju R,
      3. Dalakas MC
      . Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: correlation with clinical severity. Arch Neurol 2004;61:902–4.
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      1. Raju R,
      2. Rakocevic G,
      3. Chen Z, et al
      . Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 2006;129:3270–6.
      OpenUrlAbstract/FREE Full Text
    50. ↵
      1. Boronat A,
      2. Sabater L,
      3. Saiz A, et al
      . GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 2011;76:795–800.
      OpenUrlCrossRef
    51. ↵
      1. Dinkel K,
      2. Rickert M,
      3. Möller G, et al
      . Stiff-man syndrome: identification of 17 beta-hydroxysteroid dehydrogenase type 4 as a novel 80-kDa antineuronal antigen. J Neuroimmunol 2002;130:184–93.
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      1. McKeon A,
      2. Martinez-Hernandez E,
      3. Lancaster E, et al
      . Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 2013;70:44–50.
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      1. Alexopoulos H,
      2. Akrivou S,
      3. Dalakas MC
      . Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders. Neurology 2013;81:1962–4.
      OpenUrlCrossRef
    54. ↵
      1. Petit-Pedrol M,
      2. Armangue T,
      3. Peng X, et al
      . Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterization of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276–86.
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      1. Folli F,
      2. Solimena M,
      3. Cofiell R, et al
      . Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993;328:546–51.
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      1. De Camilli P,
      2. Thomas A,
      3. Cofiell R, et al
      . The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. J Exp Med 1993;178:2219–23.
      OpenUrlAbstract/FREE Full Text
    57. ↵
      1. Wigge P,
      2. McMahon HT
      . The amphiphysin family of proteins and their role in endocytosis at the synapse. Trends Neurosci 1998;21:339–44.
      OpenUrlCrossRefPubMedWeb of Science
    58. ↵
      1. Jarius S,
      2. Stich O,
      3. Speck J, et al
      . Qualitative and quantitative evidence of anti-glutamic acid decarboxylase-specific intrathecal antibody synthesis in patients with stiff person syndrome. J Neuroimmunol 2010;229:219–24.
      OpenUrlCrossRefPubMed
    59. ↵
      1. Hickey WF,
      2. Hsu BL,
      3. Kimura H
      . T-lymphocyte entry into the central nervous system. J Neurosci Res 1991;28:254–60.
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      1. Hassin-Baer S,
      2. Kirson ED,
      3. Shulman L, et al
      . Stiff-person syndrome following West Nile fever. Arch Neurol 2004;61:938–41.
      OpenUrlCrossRefPubMed
    61. ↵
      1. Hiemstra HS,
      2. Schloot NC,
      3. van Veelen PA, et al
      . Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase. Proc Natl Acad Sci USA 2001;98:3988–91.
      OpenUrlAbstract/FREE Full Text
    62. ↵
      1. Schloot NC,
      2. Batstra MC,
      3. Duinkerken G, et al
      . GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. J Autoimmun 1999;12:289–6.
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      1. Lohmann T,
      2. Hawa M,
      3. Leslie RD, et al
      . Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus. Lancet 2000;356:31–5.
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      1. Hänninen A,
      2. Soilu-Hänninen M,
      3. Hampe CS, et al
      . Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff-person syndrome but without type 1 diabetes. Diabetes Metab Res Rev 2010;26:271–9.
      OpenUrlCrossRefPubMed
    65. ↵
      1. Skorstad G,
      2. Hestvik AL,
      3. Vartdal F, et al
      . Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome. J Autoimmun 2009;32:24–32.
      OpenUrlCrossRefPubMed
    66. ↵
      1. Lohmann T,
      2. Londei M,
      3. Hawa M, et al
      . Humoral and cellular autoimmune responses in stiff person syndrome. Ann N Y Acad Sci 2003;998:215–22.
      OpenUrlCrossRefPubMed
    67. ↵
      1. Costa M,
      2. Saiz A,
      3. Casamitjana R, et al
      . T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity. Clin Exp Immunol 2002;129:471–8.
      OpenUrlCrossRefPubMedWeb of Science
    68. ↵
      1. Burton AR,
      2. Baquet Z,
      3. Eisenbarth GS, et al
      . Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J Immunol 2010;184:4863–70.
      OpenUrlAbstract/FREE Full Text
    69. ↵
      1. Pugliese A,
      2. Solimena M,
      3. Awdeh ZL, et al
      . Association of HLA-DQB1*0201 with stiff-man syndrome. J Clin Endocrinol Metab 1993;77:1550–3.
      OpenUrlCrossRefPubMedWeb of Science
    70. ↵
      1. Dalakas MC,
      2. Fujii M,
      3. Li M, et al
      . The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55: 1531–5.
      OpenUrlCrossRef
    71. ↵
      1. Floeter MK,
      2. Valls-Solé J,
      3. Toro C, et al
      . Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome. Neurology 1998;51:85–93.
      OpenUrlCrossRef
    72. ↵
      1. Meinck HM,
      2. Ricker K,
      3. Conrad B
      . The stiff-man syndrome: new pathophysiological aspects from abnormal exteroceptive reflexes and the response to clomipramine, clonidine, and tizanidine. J Neurol Neurosurg Psychiatry 1984;47:280–7.
      OpenUrlAbstract/FREE Full Text
    73. ↵
      1. Khasani S,
      2. Becker K,
      3. Meinck HM
      . Hyperekplexia and stiff-man syndrome: abnormal brainstem reflexes suggest a physiological relationship. J Neurol Neurosurg Psychiatry 2004;75:1265–9.
      OpenUrlAbstract/FREE Full Text
    74. ↵
      1. Molloy FM,
      2. Dalakas MC,
      3. Floeter MK
      . Increased brainstem excitability in stiff-person syndrome. Neurology 2002;59:449–51.
      OpenUrlCrossRef
    75. ↵
      1. Levy LM,
      2. Levy-Reis I,
      3. Fujii M, et al
      . Brain gamma-aminobutyric acid changes in stiff-person syndrome. Arch Neurol 2005;62:970–4.
      OpenUrlCrossRefPubMedWeb of Science
    76. ↵
      1. Dalakas MC,
      2. Li M,
      3. Fujii M, et al
      . Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780–4.
      OpenUrlCrossRef
    77. ↵
      1. Koerner C,
      2. Wieland B,
      3. Richter W, et al
      . Stiff-person syndromes: motor cortex hyperexcitability correlates with anti-GAD autoimmunity. Neurology 2004;62:1357–62.
      OpenUrlCrossRef
    78. ↵
      1. Sandbrink F,
      2. Syed NA,
      3. Fujii MD, et al
      . Motor cortex excitability in stiff-person syndrome. Brain 2000;123:2231–9.
      OpenUrlAbstract/FREE Full Text
    79. ↵
      1. Perani D,
      2. Garibotto V,
      3. Moresco RM, et al
      . PET evidence of central GABAergic changes in stiff-person syndrome. Mov Disord 2007;22:1030–3.
      OpenUrlCrossRefPubMed
    80. ↵
      1. Galldiks N,
      2. Thiel A,
      3. Haense C, et al
      . 11C-flumazenil positron emission tomography demonstrates reduction of both global and local cerebral benzodiazepine receptor binding in a patient with Stiff Person Syndrome. J Neurol 2008;255:1361–4.
      OpenUrlCrossRefPubMed
    81. ↵
      1. Holmøy T,
      2. Skorstad G,
      3. Alvik KM, et al
      . Stiff person syndrome associated with lower motor neuron disease and infiltration of cytotoxic T cells in the spinal cord. Clin Neurol Neurosurg 2009;111:708–12.
      OpenUrlCrossRefPubMed
    82. ↵
      1. Saiz A,
      2. Minguez A,
      3. Graus F, et al
      . Stiff-am syndrome with vacuolar degeneration of anterior horn motor neurons. J Neurol 1999;246:858–60.
      OpenUrlCrossRefPubMedWeb of Science
    83. ↵
      1. Witherick J,
      2. Highley JR,
      3. Hadjivassiliou M
      . Pathological findings in a case of stiff person syndrome with anti-GAD antibodies. Mov Disord 2011;26:2138–9.
      OpenUrlCrossRefPubMed
    84. ↵
      1. Ishizawa K,
      2. Komori T,
      3. Okayama K, et al
      . Large motor neuron involvement in Stiff-man syndrome: a qualitative and quantitative study. Acta Neuropathol 1999;97:63–70.
      OpenUrlCrossRefPubMed
    85. ↵
      1. Warren JD,
      2. Scott G,
      3. Blumbergs PC, et al
      . Pathological evidence of encephalomyelitis in the stiff man syndrome with anti-GAD antibodies. J Clin Neurosci 2002;9:328–9.
      OpenUrlCrossRefPubMed
    86. ↵
      1. Poh MQ,
      2. Simon NG,
      3. Buckland ME, et al
      . Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti-amphiphysin antibodies. J Neurol Sci 2014;337:235–7.
      OpenUrlCrossRefPubMed
    87. ↵
      1. Baizabal Carvallo JF,
      2. Jankovic J
      . Movement disorders of autoimmune origin. In: Poewe W, Jankovic J, eds. Movement disorders in neurologic and systemic diseases. UK: Cambridge University Press, 2014:179–242.
    88. ↵
      1. Miller F,
      2. Korsvik H
      . Baclofen in the treatment of stiff-man syndrome. Ann Neurol 1981;9:511–12.
      OpenUrlCrossRefPubMedWeb of Science
    89. ↵
      1. Sechi G,
      2. Barrocu M,
      3. Piluzza MG, et al
      . Levetiracetam in stiff-person syndrome. J Neurol 2008;255:1721–5.
      OpenUrlCrossRefPubMedWeb of Science
    90. ↵
      1. Silbert PL,
      2. Matsumoto JY,
      3. McManis PG, et al
      . Intrathecal baclofen therapy in stiff-man syndrome: a double-blind, placebo-controlled trial. Neurology 1995;45:1893–7.
      OpenUrlCrossRef
    91. ↵
      1. Stayer C,
      2. Tronnier V,
      3. Dressnandt J, et al
      . Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus. Neurology 1997;49:1591–7.
      OpenUrlCrossRef
    92. ↵
      1. Ughratdar I,
      2. Sivakumar G,
      3. Basu S
      . Spinal cord stimulation to abort painful spasms of atypical stiff limb syndrome. Stereotact Funct Neurosurg 2010;88:183–6.
      OpenUrlCrossRefPubMed
    93. ↵
      1. Davis D,
      2. Jabbari B
      . Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. Mov Disord 1993;8:371–3.
      OpenUrlCrossRefPubMed
    94. ↵
      1. Dalakas MC,
      2. Fujii M,
      3. Li M, et al
      . High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;345:1870–6.
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      1. Harding AE,
      2. Thompson PD,
      3. Kocen RS, et al
      . Plasma exchange and immunosuppression in the stiff man syndrome. Lancet 1989;2:915.
      OpenUrlPubMedWeb of Science
    96. ↵
      1. De la Casa-Fages B,
      2. Anaya F,
      3. Gabriel-Ortemberg M, et al
      . Treatment of stiff-person syndrome with chronic plasmapheresis. Mov Disord 2013;28:396–7.
      OpenUrlCrossRefPubMed
    97. ↵
      1. Fekete R,
      2. Jankovic J
      . Childhood stiff-person syndrome improved with rituximab. Case Rep Neurol 2012;4:92–6.
      OpenUrlCrossRefPubMed
    98. ↵
      1. Venhoff N,
      2. Rizzi M,
      3. Salzer U, et al
      . Monozygotic twins with stiff person syndrome and autoimmune thyroiditis: rituximab inefficacy in a double-blind, randomised, placebo controlled crossover study. Ann Rheum Dis 2009;68:1506–8.
      OpenUrlFREE Full Text
    99. ↵
      1. Baker MR,
      2. Das M,
      3. Isaacs J, et al
      . Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry 2005;76:999–1001.
      OpenUrlAbstract/FREE Full Text
    100. ↵
      1. Dupond JL,
      2. Essalmi L,
      3. Gil H, et al
      . Rituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus and autoimmune thyroiditis. J Clin Neurosci 2010;17:389–91.
      OpenUrlCrossRefPubMed
    101. ↵
      1. Qureshi A,
      2. Hennessy M
      . Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J Neurol 2012;259:180–1.
      OpenUrlCrossRefPubMed
    102. ↵
      1. Kyskan R,
      2. Chapman K,
      3. Mattman A, et al
      . Antiglycine receptor antibody and encephalomyelitis with rigidity and myoclonus (PERM) related to small cell lung cancer. BMJ Case Rep 2013;2013:pii: bcr2013010027
      OpenUrlAbstract/FREE Full Text
    103. ↵
      1. Rizzi M,
      2. Knoth R,
      3. Hampe CS, et al
      . Long-lived plasma cells and memory B cells produce pathogenic anti-GAD65 autoantibodies in Stiff Person Syndrome. PLoS ONE 2010;5:e10838.
      OpenUrlCrossRefPubMed
    104. ↵
      1. Gerschlager W,
      2. Schrag A,
      3. Brown P
      . Quality of life in stiff-person syndrome. Mov Disord 2002;17:1064–7.
      OpenUrlCrossRefPubMed

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    Footnotes

    • Contributors JFB-C involved in the research project conception, organisation, execution, writing of the first draft, review and critique. JJ involved in the research project conception, organisation, execution, review and critique.

    • Competing interests JFB-C: Research Support: Medtronic and Merz Pharmaceuticals. Contributions: Medlink: Neurology. JJ: Research Support: Allergan, Inc; Allon Therapeutics; Biotie; Ceregene, Inc; Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation; EMD Serono; Huntington's Disease Society of America; Huntington Study Group; Impax Pharmaceuticals; Ipsen Limited; Lundbeck Inc; Medtronic; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Institutes of Health; National Parkinson Foundation; Neurogen; St. Jude Medical; Teva Pharmaceutical Industries Ltd; University of Rochester; Parkinson Study Group. Consultant or Advisory Committee Member: Allergan, Inc; AstraZeneca, Chelsea Therapeutics; EMD Serono; Lundbeck Inc; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; Neurocrine Biosciences, Inc; Teva Pharmaceutical Industries Ltd. Editorial Boards: Elsevier; Medlink: Neurology; Neurology in Clinical Practice; Neurotoxin Institute; Scientiae; UpToDate. Financial Disclosure/Competing interests concerning the research related to the manuscript: None for all authors.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.