Marinos C. Dalakas, MD
Corresponding author Marinos C. Dalakas, MD Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and Neuromuscular Division, Thomas Jefferson University, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA. E-mail: marinos.dalakas@jefferson.edu Current Neurology and Neuroscience Reports 2008, 8:4855 Current Medicine Group LLC ISSN 1528-4042 Copyright 2008 by Current Medicine Group LLC
prototypic CNS disorders in which autoantibodies exert a functional blockade on inhibitory neurotransmitters. This article focuses on recent advances in the diagnosis, immunopathogenesis, and treatment of SPS.
Advances in the clinical diagnosis, prognosis, pathogenesis, and therapies for stiff person syndrome (SPS), based on observations in more than 50 consecutive patients, are presented. The syndrome varies from mild to severe, but if untreated it can be progressive and disabling. SPS remains a largely underdiagnosed condition. Antiglutamic acid decarboxylase (GAD) antibodies provide an excellent diagnostic marker, but their role in disease pathogenesis is uncertain. Research focused on identifying new autoantigens has provided evidence that -aminobutyric acid (GABA)A receptorassociated protein (GABARAP), a 14-kD protein localized at the postsynaptic regions of GABAergic synapses, is a new antigenic target. In up to 65% of SPS patients, there are circulating anti-GABARAP antibodies that inhibit the GABAA receptor expression on GABAergic neurons. This review examines the diagnostic criteria for SPS, SPS variants, common errors in diagnosis, and a step-by-step therapeutic approach, including new advances in therapy.
Introduction
Stiff person syndrome (SPS) is an uncommon, but also overlooked, disorder of the central nervous system (CNS). Based on the number of patients referred to us at the National Institutes of Health in clinical practice (approximately one new patient per month), SPS is not as rare as previously thought. The recognition of SPS is important because early initiation of therapy prevents long-term disability. From the pathogenetic point view, SPS can be considered one of the
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autoimmune disorder or autoantibodies, especially type 1 diabetes and anti-thyroglobulin or antiparietal cell antibodies, should raise the clinical suspicion of SPS in a patient with the aforementioned symptoms. There is also a strong immunogenetic association with the DR 1 locus (0301, 0101 alleles) and DQ 1 locus (0201, 0203, and 0205 alleles).
antibodies cause a functional blockade of GABAergic interneurons rather than cell destruction.
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High Anti-GAD Antibody Titers in Other Neurologic Conditions and Their Pathogenic Role
Low-titer antibodies against GAD, the presynaptic enzyme responsible for the synthesis of GABA, were first described in patients with diabetes, where GAD is a major autoantigen in islet cells [20]. In contrast to type 1 diabetes, however, where the titers are elevated up to 10 times above baseline [4], in SPS the anti-GAD antibody titers are very high, at least 50 times above baseline. Furthermore, in type 1 diabetes, the GAD antibodies recognize conformational epitopes, whereas in SPS they recognize linear epitopes detected on Western blots [21]. Although high anti-GAD antibody titers are specific markers for SPS, they can be seen occasionally in patients with other neurologic manifestations without SPS, such as myoclonus, epilepsy, cerebellar ataxia, abnormal eye movements, and neuromyotonia [12,2225]. Rarely, some of these disorders may co-exist with SPS (SPS-plus) [26]. GAD antibodies have also been seen in some patients with neurologic complications of thymoma and, rarely, in lung and breast carcinomas, suggesting a paraneoplastic association [27]. High-titer GAD antibodies have been also observed in Battens disease, a juvenile neuronal ceroid lipofuscinosis of autosomal recessive inheritance due to deletions in the CLN3 gene [28]. CLN3 knockout mice, the animal model of Battens disease, also develop anti-GAD antibodies. Differences in recognition of GAD epitopes could explain the spectrum of symptomatology that varies from SPS alone to SPS with cerebellar involvement, cerebellar dysfunction alone, myoclonus, or seizures [11]. It has been hypothesized that the anti-GAD antibodies may be pathogenic because anti-GADspecific IgG from SPS patients inhibits GAD activity and GABA synthesis in vitro [29]. The degree of inhibition, although dose dependent, is unrelated to GAD titers, however [30]. The anti-GAD antibodies are also produced intrathecally, but there is no correlation between the cerebrospinal fluid GAD-specific IgG index and disease severity or duration, even within individual patients that we have followed over time [31]. Therefore, monitoring anti-GAD antibody titers during the course of SPS is not meaningful. The anti-GAD65 antibodies do not transfer the disease from mothers to infants [32], and GAD-specific T cells are inconsistently present in only a small number of SPS patients (Raju and Dalakas, Unpublished data). Most importantly, GAD65, like the two other autoantigens identified in paraneoplastic SPS (amphiphysin and gephyrin) [15,16], are cytosolic (Fig. 1), and the mechanism by which these antibodies gain access to GABAergic interneurons to recognize cytosolic antigens is unknown. Collectively, the aforementioned observations cast doubt on the causative role of anti-GAD antibodies in disease pathogenesis, prompting us to search for other responsible autoantigens.
Dysfunction of GABAergic Pathways and the Identification of GABA A Receptorassociated Protein as a New Autoantigen
Using magnetic resonance spectroscopy, we have noted a selective reduction of GABA in the motor cortex but not the occipital cortex [19]. Dysfunction of GABAergic pathways was also noted with positron emission tomography scan [33]. Because GABA is the brains predominant inhibitory neurotransmitter, reduction of GABA could explain the patients symptoms of muscle hyperactivity and is consistent with the motor cortex hyperexcitability noted by the electrophysiologic studies [8,18]. Passive transfer of some SPS symptomatology was possible from a patient with paraneoplastic SPS and anti-amphiphysin antibodies to experimental rats [33], suggesting that an antibody or a humoral factor may be responsible for the reduction of brain GABA. To search for molecules with biologic relevance that could distinguish SPS from other neurologic disorders, we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to obtain a proteomic profile in the sera from 25 GAD-positive SPS patients and 25 controls [34]. A significant decrease was found in the level of a protein corresponding to GABA A receptorassociated protein (GABARAP), which is responsible for the stability and surface expression of the GABA A receptors (Fig. 1) [35]. Anti-GABARAP antibody titers were significantly elevated in up to 70% of the SPS patients compared with controls [34]. Further, the GABARAP IgG from SPS patients, but not the IgG from controls, significantly inhibited the surface expression of GABA A receptors, suggesting that in SPS the circulating anti-GABARAP antibodies can impair GABAergic transmission and play a role in the clinical symptoms [34]. Unlike gephyrin, the other postsynaptic cellular protein involved in paraneoplastic SPS [16], GABARAP is expressed not only within the intracellular compartment but also on the axonal processes, and it may be more accessible to circulating antibodies. As shown in Figure 1, GABARAP is localized at the postsynaptic membrane and interacts with the 2 subunit of the GABA A receptors, linking the receptors to the microtubules of the cytoskeleton [33]. GABARAP also promotes the recruitment of gephyrin to plasma membrane and organizes the clustering of GABA A receptors by linking them to gephyrin [36]. Clustering of neurotransmitter receptors at the postsynaptic membrane is a critical requirement for efficient neurotransmission because defects in GABA A receptor clustering are associated with cellular dysfunction and anxiety in mice [36]. Although the pathogenic target antigen in SPS remains elusive [37], the new observation offers the possibility that GABARAP may be an autoantigen of pathogenic significance because GABARAP-positive IgG inhibits GABA A receptor expression on the axonal processes and impairs the stability of GABA A receptors.
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GA
VGABA-T
Microtubules
Figure 1. Autoantigens associated with -aminobutyric acid (GABA)ergic transmission in stiff person syndrome (SPS) patients include two presynaptic and two postsynaptic proteins. The presynaptic antigens are glutamic acid decarboxylase (GAD) (1), the rate limiting enzyme for GABA synthesis, and amphiphysin (2), a synaptic vesicle protein responsible for endocytosis (retrieving vesicle membrane from the axonal terminals plasma membranes after exocytosis of GABA). Postsynaptically, the two target antigens are gephyrin (3) and GABAA receptorassociated protein (GABARAP) (4). Gephyrin is a large tubulin-binding protein needed for clustering of the two inhibitory neurotransmitters (the glycine receptors in the spinal cord and the GABAA receptors in the brain). Although gephyrin binds directly to glycine receptors, it requires GABARAP to bind to GABAA receptors. Clusters of GABAA receptors are held together through tethering of the intracellular loop of the 2 subunit to an intracellular membrane scaffold that includes gephyrin. GABARAP is a linker protein between gephyrin and GABA A receptors and promotes the recruitment of gephyrin and organization of the GABA receptors [37]. The most common autoantigen in SPS is GAD, which is seen in 85% of patients, followed by GABARAP, which is seen in 65%. Amphiphysin is seen in 5% of patients, and gephyrin has been seen in only one case.
sedation that sometimes limits the patients activities more than the disease itself [2,6]. The clinical efficacy of diazepam has been supported by concomitant electromyographic studies showing that continuous, uninhibited motor unit activity at rest is abolished or greatly attenuated after intravenous administration of the drug. The daily doses needed vary from patient to patient and range from 5 to 100 mg/d in divided doses every 3 to 6 hours. In our experience, the average total daily dose required and tolerated is 20 to 60 mg/d. Other similar compounds include clonazepam, alprazolam, lorazepam, and tetrazepam, with the average maintenance dose being 4 to 6 mg/d (Table 1). Antiepileptic drugs Although no controlled study has ever been conducted, antiepileptic drugs that enhance the brains GABAergic transmission have been helpful in improving symptoms in SPS patients when used alone or concurrently with one of the benzodiazepines mentioned previously. The most effective ones include 1) vigabatrin, a structural analogue of GABA, which acts by irreversible inhibition of GABA-transaminase (the enzyme responsible for
GABA-enhancing drugs
Sedative anxiolytics Among these agents, diazepam is the first therapeutic option for SPS. Diazepam not only helps most of the patients for a period of time, but it is often used to support the diagnosis [38]. Although the response to diazepam is gratifying, the required doses are often so high that they cannot be tolerated due to excessive
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Table 1. Most commonly used therapies for patients with stiff person syndrome
Therapy type GABA-enhancing drugs Sedative-anxiolytics Diazepam Clonazepam Alprazolam Lorazepam Antiepileptic drugs Valproate Gabapentin Levetiracetam Tiagabine Antispasticity agents Baclofen Tizanidine Dantrolene Botulinium toxin A Immunotherapies Corticosteroids Immunosuppresive agents Azathioprine Methotrexate Mycophenolate Plasmapheresis IV immunoglobulin Rituximab 2.53 mg/kg/d 1520 mg 23 g 56 passes 2 g/kg 2 g (in two divided doses) Immunosuppression/modulation Immunosuppression/modulation Immunosuppression/modulation Immunosuppression/modulation Immunosuppression/modulation B-cell depletion 1060 mg 6 mg 200400 mg GABAB agonist Central
2
Dose
Central GABA A agonist Central GABA A agonist Central GABA A agonist Central GABA A agonist Augments GABA transmission Structurally related to GABA but mechanism of action unknown Facilitates inhibition of GABAergic transmission Blocks GABA reuptake
Dissociates excitation-contraction coupling and blocks release of Ca++ from the sarcoplasmic reticulum NMJ blocking; prevents acetylcholine exocytosis
the breakdown of GABA), at doses of 2 to 3 g/d [39]; 2) tiagabine, an inhibitor of GABA catabolism, which can be helpful at doses up to 6 g/d [40]; 3) gabapentin, a GABA analogue, which can be used at daily doses up to 3600 mg; and 4) levetiracetem, a GABAergic inhibitor, which can be used at doses up to 2000 mg/d [41].
myogram activity compared with placebo [42]. However, serious complications have been observed, such as a catheter rupture resulting in severe spasms, catheter dislocation causing root symptoms, malfunction of the pump resulting in inaccurate dosing or transient comalike state, and sudden pump failure resulting in acute withdrawal reactions or even death. Tizanidine Tizanidine is a centrally acting 2 adrenergic receptor agonist that is a useful antispasticity agent. Daily doses up to 12 mg have been tried, but the drug was poorly tolerated because of adverse effects, notably drowsiness and fatigue. Dantrolene Dantrolene is a locally acting muscle relaxant that can be given in quantities up to 400 mg/d. It can be helpful, and in our opinion it is underutilized.
Antispasticity drugs
Baclofen Baclofen is a GABA B agonist. It is the second most useful drug (after diazepam) for the symptomatic treatment of SPS. Doses start at 5 to 10 mg/d and can be titrated up to a total of 40 to 60 mg/d. The combination of diazepam with baclofen has been helpful, although the high doses needed are hampered by the disabling cognitive effects (sedation, vertigo, cognitive clumsiness) [6]. In a controlled study, intrathecal administration of baclofen using a pump has shown a quick, objective, and statistically significant improvement in the reflex electro-
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Botulinum toxin A Botulinum toxin A can be useful in difficult cases for relieving stiffness, but expertise is required. Injections need to involve both agonist and antagonist muscles. Benefits may last up to 4 months [43]. The efficacy and indications of botulinum toxin A in patients with SPS have not yet been explored.
conducted a controlled trial and the results are being analyzed. A single case report demonstrated efficacy [45].
Immunotherapy
Regardless of whether GAD or GABARAP antibodies are pathogenic, their presence at high titers and the frequent association of SPS with autoimmune diseases provide the rationale to apply immunotherapy with corticosteroids, immunosuppressants, plasmapheresis, intravenous immunoglobulin (IVIg), or rituximab. However, controlled studies have been conducted only with IVIg and rituximab [44]. Corticosteroids Corticosteroids, up to 60 mg/d, have been used with variable and, in our experience, rather disappointing results. Whether IV methylprednisolone can be effective in severe acute spasms remains untested. Azathioprine, methotrexate, and mycophenolate The benefits of azathioprine, methotrexate, and mycophenolate, based on our experience, are minimal. Plasmapheresis Plasmapheresis has been beneficial in up to 40% of patients. The degree of response varies. We have not observed any dramatic improvement, however. IVIg IVIg, given at 2 g/kg divided into two daily doses, is the only medication that has been tested in a controlled trial. It reduced the mean number of stiff areas significantly 3 months after therapy compared with placebo [44]. Statistically significant reduction of the stiffness was noted in the trunk (P < 0.001), abdomen (P < 0.001), and face (P < 0.001). Patients who improved became able to walk unassisted, stopped falling, were able to appear in public, socialize, cross streets without help, shower without spasms, and assume work or household chores. Their phobias for open spaces diminished. Considering that the other immunotherapies mentioned here are not very effective, IVIg is the preferred treatment among the immunotherapeutic options. Improvement may last from 1 to 4 months, and repeated infusions are required if there is benefit after the first infusion. Because approximately 30% of patients do not respond to IVIg or their response is minimal and short lived, there is a need for more effective therapies. Rituximab Rituximab, a B celldepleting monoclonal antibody, is a promising therapy for a number of antibody-mediated autoimmune neurologic disorders. On this basis, we
Conclusions
Although progress has been made in understanding and treating SPS, the disease remains underdiagnosed, delaying treatment. Increased awareness of SPS among practicing physicians is necessary to recognize the disease early and prevent permanent disability. In SPS, there is impairment of GABAergic pathways and reduction of brain GABA, the brains predominant inhibitory neurotransmitter, resulting in the clinical manifestation of stiffness, spasms, and phobias. GAD is the most common target antigen in the GABAergic system, but whether anti-GAD antibodies are pathogenic remains unclear. Recent work has identified that GABARAP is a new autoantigen, and GABARAP antibodies are detected in up to 65% of patients. Because patients anti-GABARAP IgG inhibits the surface expression of the GABA A receptor, these antibodies may be of pathogenic significance. Most patients with SPS respond to GABA-enhancing drugs, but the high doses required cause unacceptable adverse effects. The disease clearly responds
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to IVIg, but repeated infusions are needed to maintain response. New agents are being explored for difficult cases and to induce long-lasting remissions.
Disclosure
No potential conflict of interest relevant to this article was reported.
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Liguori R, Cordivari C, Lugaresi E, et al.: Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome. Mov Disord 1997, 12:10601063. 44. Dalakas MC, Fujii M, Li M, et al.: High-dose intravenous immunoglobulin for stiff-person Syndrome. N Engl J Med 2001, 345:18701876. 45. Baker MR, Das M, Isaacs J, et al.: Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry 2005, 76:9991001. 46. Bouw J, Leendertse K, Tijssen MA, Dzoljic M: Stiff person syndrome and anesthesia: case report. Anesth Analg 2003, 97:486487. 47. Ledowski T, Bromilow J, Paech MJ, et al.: Skin conductance monitoring compared with Bispectral Index to assess emergence from total i.v. anaesthesia using propofol and remifentanil. Br J Anaesth 2006, 97:817821. 48. Elkassabany N, Tetzlaff JE, Argalious M: Anesthetic management of a patient with stiff person syndrome. J Clin Anesth 2006, 18:218220. The potential difficulties with anesthesia in SPS patients are raised.