Stiff person syndrome

By Marcello Cherchi, MD PhD

For patients

Stiff person syndrome (SPS) is a rare disease.  It causes muscle stiffness in the trunk, limbs and sometimes the neck.  Many cases seem to due to an autoimmune problem.  A small number of cases may be related to cancer.  If your doctor suspects SPS, they may check several blood tests, and sometimes imaging, nerve-muscle tests, or other tests.  Treatment sometimes includes medications that work as muscle relaxants, or medications that alter the immune system.  The treatment of SPS is usually overseen by a neuromuscular specialist or (less commonly) a movement disorders specialist.

For clinicians

Overview

Stiff person syndrome (SPS) is a rare movement disorder that usually presents with muscle stiffness/rigidity of the trunk and limbs, that often has a chronic (baseline) component punctuated by episodic exacerbations. Less common features include ataxia, ocular motor abnormalities, autonomic dysfunction and psychiatric features. The majority of cases are associated with autoantibodies (usually anti-GAD65 antibodies, but numerous others have been reported), and a small percentage are paraneoplastic (with a variety of reported malignancies). The ocular motor findings (mainly reported in cases with anti-GAD65 antibodies) localize predominantly to the cerebellum. In cases with ataxia, brain MRI may show cerebellar atrophy. The muscular symptoms sometimes respond to GABA-ergic medications (such as benzodiazepines). In cases with autoantibodies, immunosuppression or immunomodulatory therapies may be considered.

Introduction

In 1956 Frederick Moersch and Henry Woltman reported a case series of 14 patients with progressive muscular rigidity of the trunk and thighs that they termed “stiff man syndrome” (Moersch and Woltman 1956). This was subsequently renamed stiff person syndrome (SPS), which is now usually classified as a movement disorder characterized by progressive, recurrent episodes of muscle stiffness variously involving the trunk, neck and extremities. Most cases have been associated with autoantibodies; a minority of cases appear to be idiopathic (i.e., unassociated with autoantibodies). Of the cases with an autoimmune etiology, some exhibit additional features such as ataxia, ocular motor abnormalities, or psychiatric symptoms.

Epidemiology

Stiff person syndrome is rare, estimated to affect 1 to 2 per million people; women are affected almost twice as often as men (Hadavi et al. 2011). About 5% of cases are found to be of paraneoplastic etiology (Nguyen et al. 2022).

Pathophysiological mechanism of disease

The hypothesis of an autoimmune mechanism of disease arose because of SPS occurring in the context of other autoimmune pathologies such as type 1 diabetes mellitus (Solimena et al. 1990), myasthenia gravis (Thomas et al. 2005), autoimmune thyroiditis (Nie et al. 2022), vitiligo, pernicious anemia and others.

Several different autoantibodies have been identified in SPS.

• The most common is antibodies to glutamic acid decarboxylase (GAD65), which is reported to account for 40% (Vincent et al. 1997) to 80% (Nguyen et al. 2022) of cases. Glutamic acid decarboxylase is an intracellular enzyme that catalyzes the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), so interference with this enzyme would effectively reduce the amount of available GABA.
• Antibodies have also been detected against the postsynaptic GABA_A receptor (Raju et al. 2006), thereby reducing the efficacy of existing GABA.
• Antibodies against amphiphysin, an intracellular protein that promotes cleavage of intracellular vesicles and would thus interfere with exocytosis of neurotransmitters. Anti-amphiphysin antibodies have been associated with breast cancer (Folli et al. 1993).
• Antibodies against the alpha-1 subunit of the glycine receptor has been reported in some patients whose SPS is of the “progressive encephalomyelitis with rigidity and myoclonus (PERM)” subtype (Martinez-Hernandez et al. 2016; McKeon et al. 2013). Glycine is an inhibitory neurotransmitter.
• Antibodies against thyroid peroxidase have been reported (Nie et al. 2022).
• Antibodies against acetylcholine receptors have been reported (Lester et al. 2020).
• Rare cases have been reported of patients positive for more than one autoantibody. Thomas and colleagues reported a patient who tested positive for anti-GAD antibodies and anti-acetylcholine receptor antibodies (Thomas et al. 2005). Nguyen and colleagues reported a patient who tested positive for anti-GAD and anti-SOX1 antibodies (Nguyen et al. 2022).

Clinical presentation

Muscle stiffness is the common feature of this syndrome, produced by the involuntary co-contraction of agonist and antagonist muscles. This can have chronic and episodic components. These muscular symptoms are the presenting feature in 95% of patients, often beginning with leg stiffness, followed by paraspinal muscle rigidity and painful spasms (Rakocevic et al. 2019).

Some patients with SPS additionally exhibit what appears to be a cerebellar ataxia (Kono et al. 2001; Zivotofsky et al. 2006).

Patients with autoimmune-mediated SPS, particularly with anti-GAD65 antibodies, may exhibit a variety of ocular motor abnormalities.

Some patients exhibit neuropsychiatric features such as specific phobias (Ameli et al. 2005; Henningsen and Meinck 2003; Marano et al. 2020; Nasri et al. 2023; Souissi et al. 2020).

Some cases of sudden death have been reported in SPS. Various mechanisms for this have been considered (Goetz and Klawans 1983), such as respiratory failure from chest wall muscle rigidity (Bheemavarapu et al. 2023; Jachiet et al. 2016) or autonomic failure (in cases with anti-acetylcholine receptor antibodies) (Mitsumoto et al. 1991).

The reported variations in SPS presentation have proliferated, even when considering cases associated with a particular autoantibody. Because of this, some researchers have begun to view this as a “spectrum” of disorders. For example, SPS associated with anti-GAD65 antibodies has been reported to manifest variously with cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and ocular motor abnormalities. As such, some investigators have proposed classifying these as “GAD antibody spectrum disorders” (Bai et al. 2022; Dalakas 2022).

Physical examination

Muscle stiffness and rigidity in the trunk, and sometimes limbs and neck, is characteristic. This can fluctuate in intensity.

Ocular motor examination

Ocular motor abnormalities are sometimes observable on face-to-face examination, though in some cases this may only be discernible on instrumented testing. Thomas and colleagues described a SPS patient with anti-GAD antibodies (and eventually anti-acetylcholine receptor antibodies) who on face-to-face examination exhibited “variable alternating esotropia,” “bilateral abduction deficits,” a tendency towards slow horizontal saccades, and “slight endpoint nystagmus” (Thomas et al. 2005).

Testing: instrumented ocular motor studies

It is uncommon for a patient with stiff person syndrome to be referred for otoneurological evaluation; in such cases the usual clinical query is for ataxia or unsteadiness. A variety of ocular motor abnormalities have been described in association with SPS associated with anti-GAD65 antibodies; these are interesting, but not essential for the diagnosis.

• Ances and colleagues described spontaneous down beat nystagmus in a SPS patient with anti-GAD antibodies (Ances et al. 2005). They additionally reported appendicular ataxia.
• Economides and Horton described a SPS patient with anti-GAD antibodies who exhibited asymmetric low gain on horizontal smooth pursuit; hypometric horizontal saccades; and abnormal gaze-evoked nystagmus in all directions (Economides and Horton 2005).
• Hac and colleagues described a SPS patient with anti-GAD antibodies who exhibited spontaneous down beat nystagmus, gaze-evoked nystagmus in all directions; rebound nystagmus; centripetal nystagmus; and apogeotropic direction-changing positional nystagmus on Dix-Hallpike testing (Hac et al. 2023).
• Oskarsson and colleagues described a SPS patient with anti-GAD antibodies who exhibited progressively lengthening latencies of horizontal and vertical saccades; restricted range of horizontal pursuit (with normal gain), that fatigued to cessation; fatiguing optokinetic responses; and fatiguing vestibulo-ocular reflexes (Oskarsson et al. 2008).
• Tilikete and colleagues described a SPS patient with anti-GAD antibodies who exhibited periodic alternating nystagmus (Tilikete et al. 2005).
• Wang and colleagues reviewed 22 cases of SPS with anti-GAD antibodies and described abnormalities in vergence (divergence insufficiency), skew (alternating skew deviation), spontaneous down beat nystagmus (with or without fixation, sometimes increased by hyperventilation), saccadic abnormalities (both hypermetria and hypometria), pursuit abnormalities (largely saccadic), direction-changing positional nystagmus on Dix-Hallpike testing, and sometimes abnormalities on head impulse testing (Wang et al. 2021).
• Zivotofsky and colleagues reported a SPS patient with anti-GAD antibodies whose ocular motor abnormalities included abnormal vertical smooth pursuit (reduced gain, much more so in the downward direction), abnormal horizontal vertical saccades (amounting to a series of small saccades in a staircase-like fashion), spontaneous down beat nystagmus and square wave jerks (Zivotofsky et al. 2006). Additional features in this patient included cerebellar ataxia.

These ocular motor findings predominantly localize to the cerebellum (spontaneous down beat nystagmus; dysmetric saccades; abnormalities of saccadic latency; gaze-evoked nystagmus; abnormal gain on smooth pursuit; abnormal optokinetic responses; periodic alternating nystagmus; rebound nystagmus).

Other findings suggest brainstem involvement (e.g., vergence abnormalities). The decline of vestibulo-ocular reflexes (Oskarsson et al. 2008) is compatible with an impaired (or fatigable) velocity storage mechanism, which may result from interference with the function of commissural inhibition between the vestibular nuclei due to reduced GABA activity (Teggi et al. 2008).

Testing: vestibular

Teggi and colleagues (Teggi et al. 2008) reported on a SPS patient with anti-GAD antibodies who experienced recurrent vertiginous episodes during which there was spontaneous horizontal nystagmus. They identified a 58% right unilateral caloric weakness on caloric testing.

Testing: other

Cerebrospinal fluid analysis of SPS patients may identify oligoclonal bands for anti-GAD antibodies (Jarius et al. 2010).

Electrodiagnostic studies in patients with SPS usually show coactivation of agonist-antagonist muscles (Li and Thakore 2020), which may be continuous, and diminish (though not disappear) during sleep (Armon et al. 1990).

Imaging

Some studies of SPS patients report cerebellar atrophy on brain MRI (Economides and Horton 2005; Tilikete et al. 2005).

Histopathology

There are very few published autopsy studies of patients with SPS.

Mutsomoto and colleagues reported two cases of patients with SPS who had sudden death attributed to autonomic instability (Mitsumoto et al. 1991). In one patient there was perivascular gliosis of the spinal cord and brain stem. In the other patient there was lymphocytic perivascular infiltration in the spinal cord, brain stem and basal ganglia.

Meinck and colleagues (Meinck et al. 1994) reported one case in which there were “scattered lymphocyte cuffs around leptomeningeal, intracerebral, and particularly intraspinal vessels, suggesting a mild inflammatory process.”

Witherick and colleagues (Witherick et al. 2011) reported a case in which microscopic examination of the spinal cord showed vacuolation of motor neurons in the caudal segments; electron microscopy suggested that these vacuoles might have been “hyperswollen lysosomes.” Histology of dorsal root ganglion showed neuronal loss with macrophage infiltration and attack of ganglion cells. On immunohistochemical examination, CD68 showed microglial reaction in gray matter, GFAP showed marked gray matter gliosis.

Differential diagnosis

The differential diagnosis of SPS is broad, and depends on the presentation. When the syndrome presents exclusively with muscle stiffness/rigidity, then the differential may include myelopathies, muscular dystrophies and basal ganglionic disorders. When the syndrome includes ataxia, cerebellar disorders should be considered.

Treatment

Treatment of SPS is usually overseen by a specialist in neuromuscular disorders (less commonly movement disorders), sometimes in conjunction with immunology and (if paraneoplastic) oncology.

Muscle spasticity is often treated with benzodiazepines (often diazepam or clonazepam, less commonly lorazepam), though this has not been studied in randomized controlled trials. In cases that are unresponsive to benzodiazepines, baclofen may be considered.

In cases with identified autoantibodies, immunosuppression (often with steroids) or immunomodulatory therapies (intravenous immunoglobulin) may be considered.

For cases that are believed to be paraneoplastic, management should include treatment of the underlying malignancy.

Prognosis

A longitudinal study that followed patients for up to 8 years reported that SPS is a progressive disease leading to physical disability over time (Rakocevic et al. 2019).

References

Ameli R, Snow J, Rakocevic G, Dalakas MC (2005) A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 64: 1961-3. doi: 10.1212/01.Wnl.0000163984.71993.Fe

Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL (2005) Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol 140: 142-4. doi: 10.1016/j.ajo.2004.12.052

Armon C, McEvoy KM, Westmoreland BF, McManis PG (1990) Clinical neurophysiologic studies in stiff-man syndrome: use of simultaneous video-electroencephalographic-surface electromyographic recording. Mayo Clin Proc 65: 960-7. doi: 10.1016/s0025-6196(12)65157-x

Bai L, Ren H, Liang M, Lu Q, Lin N, Liu M, Fan S, Cui R, Guan H (2022) Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China. Front Neurol 13: 990553. doi: 10.3389/fneur.2022.990553

Bheemavarapu B, Singh A, Ranjini NJ, Abhilash Meda VS, Patil D (2023) Recurrent Acute on Chronic Respiratory Failure in Stiff Person Syndrome. Case Rep Neurol 15: 187-191. doi: 10.1159/000532093

Dalakas MC (2022) Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies. Neurotherapeutics 19: 832-847. doi: 10.1007/s13311-022-01188-w

Economides JR, Horton JC (2005) Eye movement abnormalities in stiff person syndrome. Neurology 65: 1462-4. doi: 10.1212/01.wnl.0000183068.42803.33

Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, Bates D, Cartlidge N, Bottazzo GF, Piccolo G, De Camilli P, et al. (1993) Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 328: 546-51. doi: 10.1056/NEJM199302253280805

Goetz CG, Klawans HL (1983) On the mechanism of sudden death in Moersch-Woltman syndrome. Neurology 33: 930-2. doi: 10.1212/wnl.33.7.930

Hac NEF, Murphy OC, Butala AA, Newsome SD, Gold DR (2023) Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder. Journal of Neuro-Ophthalmology: 1-5. doi: 10.1097/WNO.0000000000001774

Hadavi S, Noyce AJ, Leslie RD, Giovannoni G (2011) Stiff person syndrome. Pract Neurol 11: 272-82. doi: 10.1136/practneurol-2011-000071

Henningsen P, Meinck HM (2003) Specific phobia is a frequent non-motor feature in stiff man syndrome. J Neurol Neurosurg Psychiatry 74: 462-5. doi: 10.1136/jnnp.74.4.462

Jachiet V, Laine L, Gendre T, Henry C, Da Silva D, de Montmollin E (2016) Acute Respiratory Failure in a Patient with Stiff-Person Syndrome. Neurocrit Care 25: 455-457. doi: 10.1007/s12028-016-0296-0

Jarius S, Stich O, Speck J, Rasiah C, Wildemann B, Meinck HM, Rauer S (2010) Qualitative and quantitative evidence of anti-glutamic acid decarboxylase-specific intrathecal antibody synthesis in patients with stiff person syndrome. J Neuroimmunol 229: 219-24. doi: 10.1016/j.jneuroim.2010.07.019

Kono S, Miyajima H, Sugimoto M, Suzuki Y, Takahashi Y, Hishida A (2001) Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer. Intern Med 40: 968-71. doi: 10.2169/internalmedicine.40.968

Lester J, Cojab J, Kleriga E (2020) Stiff Person Syndrome and Acetylcholine Receptor Ganglionic Neuronal Antibodies. Case Rep Neurol 12: 24-26. doi: 10.1159/000505229

Li Y, Thakore N (2020) An Appraisal of Electrodiagnostic Studies in Stiff Person Syndrome. J Clin Neuromuscul Dis 22: 84-89. doi: 10.1097/CND.0000000000000302

Marano M, Motolese F, Lanzone J, Di Santo A, Rossi M, Bevacqua MG, Ranieri F, Capone F, Gatto EM, Di Lazzaro V (2020) Pseudoagoraphobia, a Diagnostic Clue in Stiff-Limb Syndrome. Mov Disord Clin Pract 7: 313-317. doi: 10.1002/mdc3.12911

Martinez-Hernandez E, Arino H, McKeon A, Iizuka T, Titulaer MJ, Simabukuro MM, Lancaster E, Petit-Pedrol M, Planaguma J, Blanco Y, Harvey RJ, Saiz A, Graus F, Dalmau J (2016) Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder. JAMA Neurol 73: 714-20. doi: 10.1001/jamaneurol.2016.0133

McKeon A, Martinez-Hernandez E, Lancaster E, Matsumoto JY, Harvey RJ, McEvoy KM, Pittock SJ, Lennon VA, Dalmau J (2013) Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 70: 44-50. doi: 10.1001/jamaneurol.2013.574

Meinck HM, Ricker K, Hulser PJ, Schmid E, Peiffer J, Solimena M (1994) Stiff man syndrome: clinical and laboratory findings in eight patients. J Neurol 241: 157-66. doi: 10.1007/BF00868343

Mitsumoto H, Schwartzman MJ, Estes ML, Chou SM, La Franchise EF, De Camilli P, Solimena M (1991) Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol 238: 91-6. doi: 10.1007/BF00315688

Moersch FP, Woltman HW (1956) 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 31: 421-7.

Nasri A, Gharbi A, Ouali U, Mrabet S, Souissi A, Jomli R, Gargouri A, Bendjebara M, Kacem I, Gouider R (2023) Psychiatric Symptoms in Stiff-Person Syndrome: A Systematic Review and a Report of Two Cases. J Acad Consult Liaison Psychiatry 64: 183-191. doi: 10.1016/j.jaclp.2022.07.005

Nguyen PM, Vu DD, Vu KD, Nguyen HT, Nguyen DV (2022) Stiff Person Syndrome: A Case Report with Sudden Onset and Coexistence of Sero-Positive Antibodies to Glutamic Acid Decarboxylase and Anti-SOX1 Antibodies. Case Rep Neurol 14: 237-244. doi: 10.1159/000523988

Nie DA, Abud A, Serrano-Gonzalez M, Harappanahally G, Patil R (2022) Pediatric stiff limb syndrome with polyautoimmunity of anti-GAD-65, anti-islet cell, and thyroid peroxidase antibodies: A case report and review of literature. J Neuroimmunol 367: 577865. doi: 10.1016/j.jneuroim.2022.577865

Oskarsson B, Pelak V, Quan D, Hall D, Foster C, Galetta S (2008) Stiff eyes in stiff-person syndrome. Neurology 71: 378-80. doi: 10.1212/01.wnl.0000319725.22925.b4

Raju R, Rakocevic G, Chen Z, Hoehn G, Semino-Mora C, Shi W, Olsen R, Dalakas MC (2006) Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 129: 3270-6. doi: 10.1093/brain/awl245

Rakocevic G, Alexopoulos H, Dalakas MC (2019) Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder. BMC Neurol 19: 1. doi: 10.1186/s12883-018-1232-z

Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P (1990) Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322: 1555-60. doi: 10.1056/NEJM199005313222202

Souissi MA, Bellakhal S, Gharbi E, Abdelkefi I, Douggui MH (2020) A Stiff Person Syndrome Misdiagnosed as a Psychiatric Illness: A Case Report. Curr Rheumatol Rev 16: 343-345. doi: 10.2174/1573397115666191116101240

Teggi R, Piccioni LO, Martino G, Bellini C, Bussi M (2008) Stiff-person syndrome with acute recurrent peripheral vertigo: possible evidence of gamma aminobutyric acid as a neurotransmitter in the vestibular periphery. J Laryngol Otol 122: 636-8. doi: 10.1017/s0022215107000205

Thomas S, Critchley P, Lawden M, Farooq S, Thomas A, Proudlock FA, Constantinescu CS, Gottlob I (2005) Stiff person syndrome with eye movement abnormality, myasthenia gravis, and thymoma. J Neurol Neurosurg Psychiatry 76: 141-2. doi: 10.1136/jnnp.2004.036558

Tilikete C, Vighetto A, Trouillas P, Honnorat J (2005) Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol 62: 1300-3. doi: 10.1001/archneur.62.8.1300

Vincent A, Grimaldi LM, Martino G, Davenport C, Todd I (1997) Antibodies to 125I-glutamic acid decarboxylase in patients with stiff man syndrome. J Neurol Neurosurg Psychiatry 62: 395-7. doi: 10.1136/jnnp.62.4.395

Wang Y, Tourkevich R, Bosley J, Gold DR, Newsome SD (2021) Ocular Motor and Vestibular Characteristics of Antiglutamic Acid Decarboxylase-Associated Neurologic Disorders. J Neuroophthalmol 41: e665-e671. doi: 10.1097/wno.0000000000001084

Witherick J, Highley JR, Hadjivassiliou M (2011) Pathological findings in a case of stiff person syndrome with anti-GAD antibodies. Mov Disord 26: 2138-9. doi: 10.1002/mds.23784

Zivotofsky AZ, Siman-Tov T, Gadoth N, Gordon CR (2006) A rare saccade velocity profile in Stiff-Person Syndrome with cerebellar degeneration. Brain Res 1093: 135-40. doi: 10.1016/j.brainres.2006.03.064