Case Report: Stiff-limb Syndrome and a Variant of Stiff-person Syndrome

Introduction

Stiff-person syndrome is a spectrum of rare autoimmune neurological disorders resulting in muscle rigidity and episodic muscle spasms. The classical case of stiff-man syndrome is characterized by persistent paraspinal and abdominal rigidity, with spams in these muscles triggered by emotional or environmental stimuli (Brown and Marsden, 1999[1]). This syndrome was first described in 1956 by Moersch and Woltman, who presented a disorder in 14 patients described as progressive muscle rigidity and spasms causing falls and gait disturbance (Moersch & Woltman, 1956). Stiff-limb syndrome has traditionally thought to be a subtype of Stiff-Man syndrome (Baizabal-Carvallo & Jankovic, 2015). However, the pathophysiology of both disorders remains poorly understood, and SLS may in fact be a distinct entity from SPS with overlapping features.

Various case reports and literature reviews on the topic have stated that these syndromes occur most often occurs in middle-aged women around 30-50 years in age. These debilitating disorders are usually acquired, progressive, fluctuating, and occur in young women aged 30-50.

Herein we present an atypical case of [REDACTED]. We include a literature review describing the epidemiology, pathophysiology, evaluation, treatment, and prognosis associated with stiff person syndrome, which we hope to assist in the management of this disease.

Case Report

[REDACTED] for patient privacy.

Note! Patient here is 79 with immediate onset. Oldest recorded patient from 2010-2015!

Discussion

The case described above is an atypical presentation because, as mentioned previously, this particular syndrome most often occurs in middle-aged women. The patient described was found to exhibit the anti-GAD antibody, which has been implicated with this disorder. Stiff-person syndrome and its variants such as Stiff-limb syndrome are suspected to be caused by auto-antibodies to the GAD enzyme (Ciccoto, Blaya, & Kelley, 2013; Levy, Dalakas, & Floeter, 1999; Raju and Hampe, 2008). GAD is responsible for converting the principal excitatory neurotransmitter glutamate into the principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). With increased accumulation of glutamate, clinical findings will include hyperreflexia and increased muscle tone. Benzodiazepines are GABA agonists which can assist in enhancing the GABA neurotransmitter at the GABA receptor resulting in muscle relaxation and therapeutic relief for the patient.

Diagnosis and Clinical Variants of SPS

Although the classic form of classic Stiff Person syndrome has no formally accepted criteria, In 2009 Dalakas published a set of criteria for diagnosis of SPS (Dalakas, 2009). [Figure 1]

In contrast to classic SPS, case reports describe patients with  anti-GAD antibodies, and stiffness confined to a single limb, typically one of the lower limbs.  This syndrome has since been described as stiff-limb syndrome (Barker et al.)[2] . One study of 99 patients with some form of stiff-person syndrome described 13 out of 99 patients as having the stiff-limb person subtype of SPS. This subtype tends to have lower levels of anti-GAD antibodies. The initial study found no differences in epidemiology in race or age between classic SPS and SLS. In contrast to classic SPS, which tends to worsen until eventually stabilizing, SLS has a relapsing-remitting course, with the stiffness eventually coming to involve the brainstem and upper limb after 2-3 years[3].

Progressive encephalomyelolitis with rigidity and myoclonus (PERM) is a subtype of SPS which carries the features of classic SPS, but with the addition of autonomic dysfunction and clinical signs of damage to the spinal cord or brainstem. This subtype of SPS tends to be progressive and carries a poorer prognosis[4].

Paraneoplstic SPS is characterized by antiampiphysin antibodies, which may be found in combination with anti-GAD antibodies, or in isolation. In contrast to the other types of SPS, paraneoplastic SPS patients tend to be older, with a median age of 60. (Baizabal and carval, 2015). Clinically, these patients are distinguished by involvement of the arms and cervical region.

In addition to these subtypes, “Jerky SPS” has been proposed by several authors.[5][6]

Epidemiology and Risk Factors

Classic SPS occurs most commonly in middle-aged females. It has been described as having average age of onset of 41.2 years, with a range of around 29-59 years being most commonly seen, and no apparent racial predilection (Murinson, 2004)[7]. Similar to other autoimmune disorders, it has a greater incidence in females compared to males, at a ratio of around 2:1 (Dalakas et al., 2000; Hadavi et al., 2011). Stiff-person syndrome has been described as a very rare disorder, with some sources reporting an incidence as low as around one in a million (Bhatti & Gazali, 2015). A review of the published literature yields a number of case reports showing stiff-person syndrome being diagnosed in younger patients, and one review suggested this disorder may be underreported and undertreated in the pediatric population (Clardy et al., 2013; Jun et al., 2015; Sanefuji et al., 2013). The demographics of patients affected by Stiff-limb syndrome is similar to that of classic SPS[8]. In contrast, paraneoplastic SPS patients tend to be older, with a median age of 59-60 (Baizabal and Carval, 2015; Sarva et al., 2016[9]).

Stiff-person syndrome is traditionally regarded as an autoimmune disorder with the stereotypic propensity to have increased incidence in those afflicted with other autoimmune conditions. Notably, 30% of SPS patients also have Type 1 Diabetes Mellitus, another autoimmune disorder in which anti-GAD antibodies are central to the pathogenesis of the disease (Manto et al., 2007)[10].

More recent case reports and literature reviews have established associations between this disorder and certain acquired conditions. Stiff-person syndrome with patients expressing positivity for autoantibodies against the GAD enzyme have recently been reported following infectious diseases with insect vectors such as Lyme borreliosis and West Nile virus (Martin et al., 1990; Requena et al., 1995; Hassin-Baer et al., 2004).

Paraneoplastic stiff-person syndrome is a phenomenon known to occur in cancer patients (McCabe et al., 2004; Badzek et al., 2013). It is estimated that paraneoplastic cases of stiff-person syndrome compose 1-2% of SPS patients. Anti-amphiphysin antibodies are known to occur in many types of cancer. It is a rare antibody. It is associated with a wide range of neurologic symptoms. Only  10% of women and 4% of men with anti-amphiphysin antibodies were diagnosed with stiff-person syndrome[11]. SPS was more likely in patients with isolated anti-amphiphysin antibodies. Typically the cancer associated with paraneoplastic SPS is breast cancer (Murinson and Guarnaccia, 2008; Folli et al., 1993[12])[13]. Other associated cancers include lung cancer, thymoma, and renal cell carcinoma. [Thymoma references here]

Get Help With Your Nursing Literature Review

If you need assistance with writing your nursing literature review, our professional nursing literature review writing service is here to help!

Nursing Literature Review Writing Service

Interestingly, the initial researchers who described it used the terminology ‘stiff-man syndrome’. The index case of this syndrome, described by Moersch and Woltman, was that of a male patient and some of the earlier literature reviews on the topic seem to portray and equal incidence in males and females (Moersch & Woltman, 1956; Ali et al., 2011). Over the several decades following the initial description of stiff-person syndrome in 1956, it became apparent that it had a significantly greater incidence in female patients. As a result, it came to be referred to as ‘stiff-person syndrome’ instead of ‘stiff-man syndrome’, the terminology initially used to describe it (Ali et al., 2011; Blum and Jankovic, 1991).

Pathophysiology

The GAD enzyme functions to convert glutamic acid into GABA. The most commonly accepted proposal for the mechanism of SPS involves autoantibodies to GAD, resulting in a paucity of GABA, impairing GABAergic pathways leading to the clinical symptoms of stiffness and spasm.  The GAD enzyme is found to occur in two isoforms, GAD65 and GAD67. The antibody associated with stiff-person syndrome specifically targets the GAD65 isoform, and is found in about 60% of patients diagnosed with this disorder (Ciccoto, Blaya, & Kelley, 2013; Solimena et al., 1990). Functionally, the GAD65 isoform appears to generate excess GABA when more than the basal amount provided by the GAD67 isoform is needed – for instance, during times of stress or exertion (Ciccoto, Blaya & Kelley, 2013). Given the ubiquitous role of GABA throughout the nervous system, it is not surprising to note that antibodies against enzymes producing GABA have also been implicated in other disorders, including progressive encephalomyelitis with rigidity and myoclonus (PERM) and limbic encephalitis (Dayalu and Teener, 2012).  It has been suggested that the presence of antibodies against GAD may exist in high levels in stiff-person syndrome, along with other disorders, which assists in diagnosis but their presence and concentration does not play a role in degree of disease severity or response to medication (Alexopoulos & Dalakas, 2013).

Treatment

There are three major categories of drugs used to treat SPS. GABA agonists, namely benzodiazapines and baclofen, attempt to stimulate GABA receptors which are putatively bereft of their ligands.

The first therapeutic agents used to combat stiff-person syndrome were the benzodiazepines. Diazepam was first used in the 1960s to relieve symptoms such as muscle rigidity and spasticity, which are associated with stiff-person syndrome (Howard, 1963; Bhatti & Gazali, 2015). Today, benzodiazepines such as diazepam and clonazepam along with other GABAergic options including gabapentin, valproate, and levetiracectam continue to be the preferred first-lien options due to their ability to control severe spasticity and rigidity. Along with oral diazepam, oral baclofen may also be used as a first-line option to reduce spasticity (Bhatti & Gazali, 2015). For particularly severe and refractory cases, intrathecal baclofen delivery has also emerged as a viable treatment option (Newton et al., 2013). More recent trials have proposed using rituximab, a monoclonal antibody against a B-lymphocyte structural component, for treatment of stiff-person syndrome as it is effective against other autoimmune disorders and certain types of cancers (Bhatti & Gazali, 2015). A number of recent case reports have detailed the utility of rituximab against refractory and sever cases of stiff-person syndrome (Fekete & Jankovic, 2012; Qureshi & Hennessy, 2012; Sevy et al., 2012; Zdziarski, 2015).

Treat hyperthyroid, some sx resolution[14]

Treat pituitary defecit, sx resolution[15]

GAD negative SLS -> check for cancer

Check for autoimmune disease in all SPS patients.

GAD testing, diazepam trial with EMG testing,  routine bloodwork + thyroid

Prognosis

1. With treatment, most patients with classic SPS disorder have good outcomes. A literature review of all case reports from 2010-2015 reveals that, of the 58 SPS cases with an underlying autoimmune etiology, 78.5% of patients treated showed signs of clinical improvement, 13% of patients remained stable, while 3% either worsened or died. Notably, the patients who worsened or died had either the PERM subtype of SPS or concomitant corticobasilar syndrome. Most patients were treated with one or a combination of benzodiazapines, IVIG, or baclofen. A third of the patients treated had some form of relapse. [16] Untreated, patients with SPS eventually develop progressive motor derangements that significantly impair their activities of daily living.
2. I have case reports from 2015-2019 in Endnote. Check prognosis for these, if it is felt necessary.

In contrast, SLS is more relapsing-remitting. PERM tends to result in rapid death.

Conclusion

References

• Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. 2011. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun, 37:79-87.
• Alexopoulos H, Dalakas MC. 2013. Immunology of stiff person syndrome and other GAD-associated neurological disorders. Expert Rev Clin Immunol, 9:1043-1053.
• Badzek S, Miletic V, Prejac J, Gorsic I, Golem H, Bilic E, Kekez D, Librenjak N, Plestina S. 2013. Paraneoplastic stiff person syndrome associated with colon cancer misdiagnosed as idiopathic Parkinson’s disease worsened after capecitabine therapy. World J Surg Oncol, 11:224.
• Baizabal-Carvallo JF, Jankovic J. 2015. Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry, 86:840-848.
• Bhatti AB, Gazali ZA. 2015. Recent advances and review on treatment of stiff person syndrome in adults and pediatric patients. Cureus, 7:e427.
• Blum P, Jankovic J. 1991. Stiff-person syndrome: an autoimmune disease. Mov Disord, 6:12-20.
• Ciccoto G, Blaya M, Kelley RE. 2013. Stiff person syndrome. Neurol Clin, 31:319-328.
• Clardy SL, Lennon VA, Dalmau J, Pittock SJ, Jones HR Jr, Renaud DL, Harper CM Jr, Matsumoto JY, McKeon A. 2013. Childhood onset of stiff-man syndrome. JAMA Neurol, 70:1531-1536.
• Dalakas MC, Fujii M, Li M, McElroy B. 2000. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology, 28:1531-1535.
• Dayalu P, Teener JW. 2012. Stiff Person syndrome and other anti-GAD-associated neurologic disorders. Semin Neurol, 32:544-549.
• Fekete R, Jankovic J. 2012. Childhood stiff-person syndrome improved with rituximab. Case Rep Neurol, 4:92-96.
• Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. 2011. Stiff person syndrome. Pract Neurol, 11:272-282.
• Hassin-Baer S, Kirson ED, Shulman L, Buchman AS, Bin H, Hindiyeh M, Markevich L, Mendelson E. 2004. Stiff-person syndrome following West Nile fever. Arch Neurol, 61:938-941.
• Howard FM Jr. 1963. A new and effective drug in the treatment of the stiff-man syndrome: preliminary report. Proc Staff Meet Mayo Clin, 38:203-212.
• Jun HO, Yum MS, Kim EK, Lee YJ, Seo JJ, Ko TS. 2015. A rare case of childhood stiff person syndrome associated with pleuropulmonary blastoma. Peadtr Neurol, 53:448-451.
• Levy LM, Dalakas MC, Floeter MK. 1999. The stiff-man syndrome: an autoimmune disorder affecting neurotransmission of gamma-immunobutyric acid. Ann Intern Med, 131:522-530.
• Martin R, Meink HM, Schulte-Mattler W, Ricker K, Mertens HG. 1990. Borrelia burgdorferi myelitis presenting as a partial stiff man syndrome. J Neurol, 237:51-54.
• McCabe DJ, Turner NC, Chao D, Leff A, Gregson NA, Womersley HJ, Mak I, Perkin GD, Schapira AH. 2004. Paraneoplastic “stiff person syndrome” with metastatic adenocarcinoma and anti-Ri antibodies. Neurology, 62:1402-1404.
• 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, 31:421-427.
• Newton JC, Harned ME, Sloan PA, Salles SS. 2013. Trialing of intrathecal baclofen therapy for refractory stiff-person syndrome. Reg Anesth Pain Med, 38:248-250.
• Qureshi A, Hennessy M. 2012. Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J Neurol, 259:180-181.
• Raju R, Hampe CS. 2008. Immunobiology of stiff-person syndrome. Int Rev Immunol, 27:79-92.
• Requena I, Arias M, Pardo J, Portela M, Alvarez JA. 1995. Syndromes of continuous muscular activity: report of a central case (stiff-man) and a peripheral case (neuromyotonia) associated with neuroborreliosis [article in Spanish]. Rev Neurol, 23:129-133.
• Sanefuji M, Torisu H, Kira R, Yamashita H, Ejima K, Shigeto H, Takada Y, Yoshida K, Hara T. 2013. A case of childhood stiff-person syndrome with striatal lesions: a possible entity distinct from the classical adult form. Brain Dev, 35:575-578.
• Sevy A, Franques J, Chiche L, Pouget J, Attarian S. 2012. Successful treatment with rituximab in a refractory Stiff-person syndrome. Rev Neurol (Paris), 168:375-378.
• 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, 322:1555-1560.
• Zdziarski P. 2015. A case of stiff person syndrome: immunomodulary effect of benzodiazepines: successful rituximab and tizanidine therapy. Medicine (Baltimore), 94:e954.

[1] Brown, P., and C. D. Marsden. “The stiff man and stiff man plus syndromes.” Journal of neurology 246.8 (1999): 648-652.

[2] Barker, R. A., 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.” Journal of Neurology, Neurosurgery & Psychiatry 65.5 (1998): 633-640.

[3] McKeon, Andrew, et al. “Stiff-man syndrome and variants: clinical course, treatments, and outcomes.” Archives of Neurology 69.2 (2012): 230-238.

[4] Brown, P., and C. D. Marsden. “The stiff man and stiff man plus syndromes.” Journal of neurology 246.8 (1999): 648-652.

[5] Leigh PN, Rothwell JC, Traub M, et al. A patient with reflex myoclonus and

muscle rigidity: “jerking stiff-man syndrome”. J Neurol Neurosurg Psychiatry

1980;43:1125–31.

[6] Alberca RA, Romero M, Chaparro J. Jerking stiff-man syndrome. J Neurol

Neurosurg Psychiatry 1982;45:1159–60.

[7] Murinson B.B.: Stiff-person syndrome. Neurologist 2004; 10: pp. 131-137

[8] McKeon, Andrew, et al. “Stiff-man syndrome and variants: clinical course, treatments, and outcomes.” Archives of Neurology 69.2 (2012): 230-238.

[9] Sarva, Harini, et al. “Clinical spectrum of stiff person syndrome: a review of recent reports.” Tremor and Other Hyperkinetic Movements 6 (2016).

[10] Manto, Mario‐Ubaldo, et al. “Effects of anti–glutamic acid decarboxylase antibodies associated with neurological diseases.” Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 61.6 (2007): 544-551.

[11] Pittock, Sean J., et al. “Amphiphysin autoimmunity: paraneoplastic accompaniments.” Annals of neurology 58.1 (2005): 96-107.

[12] Folli, Franco, et al. “Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer.” New England Journal of Medicine 328.8 (1993): 546-551.

[13] Murinson, Beth B., and Joseph B. Guarnaccia. “Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease.” Neurology 71.24 (2008): 1955-1958.

[14] https://www.ncbi.nlm.nih.gov/pubmed?term=14006194

[15] https://www.ncbi.nlm.nih.gov/pubmed?term=6325914

[16] Sarva, Harini, et al. “Clinical spectrum of stiff person syndrome: a review of recent reports.” Tremor and Other Hyperkinetic Movements 6 (2016).