Stiff-Person Syndrome and Related Disorders: A Comprehensive, Practical Guide

By Pichet Termsarasab, Thananan Thammongkolchai and Bashar Katirji

This comprehensive title covers all of the broad aspects of stiff-person spectrum disorders (SPSD), ranging from clinical features and laboratory investigations to the basic scientific roles of neuroimmunology and genetics that aid clinicians in understanding the pathogenesis of this disorder.

Organized across 15 chapters, this highly practical book begins with a thorough account of the history and clinical phenomenology of SPSD.  Subsequent chapters then delve into the differential diagnoses of the disorder, as well as its electrophysiology, immunopathogenesis, and neurochemistry. Following this is an analysis of each subtype of SPSD including classic stiff-person syndrome and its variants, correlations between clinical phenotypes and antibodies, as well as SPSD in the pediatric population. Finally, the book concludes with an examination of the various SPSD diagnostic approaches, treatments, and potential emergencies seen in clinical practice.

Developed by a renowned multidisciplinary authorship, Stiff-Person Syndrome and Related Disorders is an indispensable contribution to the clinical literature and will be of great interest to both clinicians and basic science researchers.

• Language: English
• Publisher: Springer
• Release date: May 27, 2020
• ISBN: 9783030430597

Book preview

© Springer Nature Switzerland AG 2020

P. Termsarasab et al.Stiff-Person Syndrome and Related Disordershttps://doi.org/10.1007/978-3-030-43059-7_1

1. Historical Background of Stiff-Person Spectrum Disorders

Pichet Termsarasab¹  , Thananan Thammongkolchai¹   and Bashar Katirji²  

(1)

Division of Neurology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

(2)

Department of Neurology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA

Pichet Termsarasab (Corresponding author)

Thananan Thammongkolchai

Bashar Katirji

Keywords

Stiff-person syndromeStiff-man syndromeMoersch-Woltman syndromeAnti-GADCriteriaHistory

Historical Background

In the summer of 1924, two American neurologists at the Mayo Clinic in Rochester, Minnesota, Drs. Frederick P. Moersch and Henry V. Woltman (Fig. 1.1 [1, 2]), saw a farmer from Iowa, aged 49 years, who presented with muscle stiffness and difficulty in walking. His symptoms began insidiously 4 years prior and had worsened to the point that he could no longer work. The patient had episodes of tightening of the muscles of his neck. Gradually these attacks had increased in frequency, in severity and in duration. After a fall in 1923, they wrote, His muscular condition had worsened. His neck muscles had remained rigid most of the time and his head could be brought forward only with great effort. Also, the abdominal muscles and, to a lesser degree, those of the lower part of the back and those of the thighs had partaken of this same stiffness or tightness. Moreover, the rigidity had been punctuated by intermittent and moderately painful spasms. His neurological examination did not add much to the history, as they wrote, Nothing helpful to diagnosis was learned from routine physical examination. On neurologic examination, the cranial nerves were found to be intact. The head was pulled down rigidly between the shoulders and, with the taut pectoral muscles, imparted an odd, hunched-over posture and an awkward, waddling gait. Both voluntary and passive movements of the trunk or lower extremities often precipitated, in the abdomen and legs abrupt spasm that might last minutes or even an hour. Intrinsic muscular strength was intact but was not always manageable. Muscle-stretch reflexes were normal; the plantar responses were flexor and sensation was unimpaired.

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Fig. 1.1

Frederick P. Moersch, MD and Henry W. Woltman, MD. These two authors originally described stiff-person syndrome in 1956. (Photograph of Moersch reprinted from Amadio [1], Copyright 1992, with permission from Elsevier. Photograph of Woltman reproduced with permission from Corbin and Kernohan [2])

The patient’s sedimentation rate, blood, and urine were normal. Cerebrospinal fluid was normal. His head X-rays were normal, and spine X-rays showed moderate hypertrophic arthritis and some kyphosis in the thoracic region.

Drs. Moersch and Woltman remarked, We could not make a diagnosis but the unusual condition interested us no end and, to associate it with a memorable and descriptive term that could not be taken by anyone to be final, we nicknamed it the stiff-man syndrome.

They had very little to offer for treatment. They wrote, In the absence of a diagnosis, and without knowledge of specific treatment, we observed the effects of bromides, of intramuscular administration of magnesium sulfate and of sedation with barbiturates, but these helped only temporarily. Warm baths, massage and passive exercises, the patient said, increased his comfort in walking and the length of time that he could walk. He was advised to continue physical therapy at home.

They did not see or examine this patient again but they communicated with him in 1927. They marked in their report that there had been slight periods of improvement but, if anything, his condition had worsened and he no longer left his home for a walk. The spasms had increased in frequency and he had difficulty in feeding himself. They last communicated with him in 1932. Per the patient report, they transcribed: the stiffness had lessened and muscular spasms were fewer than they had been. He could be on his feet but he was weak and could take only a few steps unassisted [3].

In 1956, Drs. Moersch and Woltman reported this patient and 13 others seen at the Mayo Clinic in the Proceedings of the Staff Meetings of the Mayo Clinic. The title of the publication was progressive fluctuating muscular rigidity and spasms (stiff-man syndrome): Report of a case and observations in 13 other cases [3]. Prior to 1956, Ornsteen had reported one case of stiff-man presentation, a man with stiffness at the age of 40 [4]. Intermittent pain and disability were noted. However, Ornsteen did a muscle biopsy and concluded the diagnosis of myositis fibrosa instead.

In 1991, Blum and Jankovic suggested the preferred name, stiff-person syndrome (SPS), instead of stiff-man syndrome, since the disease affects both men and women. Since then, the name SPS has become the accepted name for this entity [5]. The timeline of historical events in SPS is shown in Fig. 1.2 [3, 6–18].

../images/472471_1_En_1_Chapter/472471_1_En_1_Fig2_HTML.png

Fig. 1.2

Timeline of significant discovery in stiff-person spectrum disorders [3, 6–18]. PERM progressive encephalomyelitis with rigidity and myoclonus, anti-GAD anti-glutamic acid decarboxylase antibodies, SPS stiff-person syndrome, PLEX plasma exchange, IVIG intravenous immunoglobulin, SLS stiff-limb syndrome, anti-GABARAP anti-GABAA receptor associated protein antibodies, anti-DPPX dipeptidyl-peptidase-like protein-6

SPS remains a relatively novel entity. Patients with SPS suffer from muscle rigidity, especially of axial muscle, causing pain and significant disability. Most of the patients were previously labeled as having psychogenic or functional disease owing to relatively normal physical examination, laboratory, and imaging.

Criteria Evolution

After the first reported series in 1956, there were more than 100 cases reported with stiff-man syndrome, reflecting an increase in the awareness of this disease among physicians. The first criteria were proposed by Gordon et al. in 1967 [7]. They included clinical and, neurophysiological criteria, as well as laboratory findings from literature in the 10-year period after Moersch and Woltman’ initial publication. However, anti-glutamic acid decarboxylase (anti-GAD) antibody, which was not discovered by that time, was not included in the laboratory findings. Gordon et al. also clarified in more detail the neurophysiological findings reported in the literature. They defined it as persistent tonic contraction reflected in constant firing even at rest. This electrical and contractile activity would disappear after myoneural block, motor nerve block, or general anesthesia. They highlighted that the changes occurring after neurologic blocking agents are essential, because Isaacs described a similar case with muscle rigidity and stiffness; however, motor unit action potentials were not abolished with general anesthesia and not totally with motor nerve block. Later, several authors called the finding as continuous motor unit activity (CMUA) [19]. This activity had been described by Moersch, Woltman, Gordon, and others [3, 6, 7, 20–22].

Lorish et al. proposed another criteria in 1989 that included seven clinical, physical examination, and neurophysiological criteria [10]. Even though the data of anti-GAD antibody from Solimena et al. were published in 1988 [9], these criteria did not include laboratory criteria, concluding at that time that there were insufficient data since they report antibody from only one patient.

During that period, clinicians identified patients who did not fit Gordon’s or Lorish’s criteria, often referring to them as atypical stiff-person syndrome. In 1997, Brown and Marsden reported cases of focal stiff-person syndrome or stiff-limb syndrome [23]. Barker et al. reported case series and different categories of stiff-person syndrome in 1998 [24]. They divided the spectrum into typical stiff-person syndrome, progressive encephalopathy with rigidity and myoclonus (PERM), and stiff-limb syndrome (or a focal form of the disorders). In 1999, Brown and Marsden published their case series and included clinical, immunological, and pathological features. They also proposed another similar classification (see Chap. 2), defined into classic form and stiff-man plus syndromes, which was further divided into two subgroups: subacute (PERM) and chronic (brainstem form including jerking stiff-man syndrome) and spinal form (stiff-limb syndrome) [25]. In 2009, Dalakas classified clinical features of SPS [17]. His clinical criteria are shown in Table 1.1.

Table 1.1

Comparison between criteria by Gordon, Lorish, and Dalakas [7, 10, 17]

History of Variants in Stiff-Person Syndrome

Progressive Encephalomyelitis with Rigidity and Myoclonus

In 1971, Kasperek reported a case with stiffness and painful spasm initially similar to description in SPS; however, the patient worsened with gaze palsies and peripheral polyneuropathy [8]. Despite of the diazepam trial, patient unfortunately died 11 months after onset of stiffness. Autopsy showed evidence of subacute encephalomyelitis affecting the lower brainstem and spinal cord. In 1973, Lhermitte reported additional two cases with similar presentation and raised the possibility of a new entity [26]. In 1976, Whiteley reported another two cases and proposed the term progressive encephalomyelitis with rigidity (PER) [27]. Whiteley found that Campbell and Garland had reported patients with PER presentation in 1956 and named the disorder subacute myoclonic spinal neuronitis instead [28]. The pathology in these cases was striking and different from classic stiff-person syndrome. All of them reported evidence of inflammation, initially concerned for viral infection, in the lower brainstem. Neuroimaging data was not well described until the late 1900s. In 1989, McCombe reported T2 hyperintensity on MRI throughout the length of the cervical cord and lower brainstem, correlating with T1 hypointensity in the same regions, in a patient with progressive encephalomyelitis with rigidity [29]. This patient underwent biopsy in the area of MRI changes, which showed perivascular cuffing with mononuclear cells, accompanied by destruction of myelin and axon. This finding was consistent with an inflammatory process which supported the theory of autoimmune disorder at that time. Meinck et al. first added myoclonus in the name of PER to become progressive encephalomyelitis with rigidity and myoclonus (PERM) [30]. However, the name was interchangeably called either PER or PERM, mostly PER, until 2010 when PERM has become the more popular and preferred term. Barker et al. first lumped SPS and related disorders including PER together [24]. Similar classification was also reported by Brown and Marsden in 1999 [25].

Stiff-Limb Syndrome

Focal SPS was first reported by Brown in 1997 [23]. They described four cases with stiffness confined to the lower extremity only. The term stiff-leg syndrome was suggested as a variant of SPS based on clinical and electrodiagnostic evidences. In 1998, Barker reported a case series of 23 patients with SPS [24]. Of them, 13 had stiffness only in either upper or lower extremity without truncal stiffness and named stiff-limb syndrome. In the same year, Saiz et al. also reported two cases with stiff-leg syndrome [31], while Fiol et al. in 2001 published on focal stiff-person syndrome [32]. Since then stiff-limb syndrome has been recognized as a focal form of SPS.

Discovery of Antibodies

Anti-GAD antibody was first discovered by Solimena et al. in 1988 [9]. This was based on the hypothesis of continuous alpha motor unit activity in SPS and the impairment of the suprasegmental or spinal inhibitory systems which is mediated through γ-aminobutyric acid (GABA). The authors obtained serum and Cerebrospinal fluid (CSF ) from one patient with SPS and type 1 diabetes mellitus and tested for immunochemistry in association with GABA-ergic neuron. They identified the autoantibody to glutamic acid decarboxylase (GAD), the enzyme responsible for the biosynthesis of GABA in the serum and CSF, and confirmed staining patterns in mouse brains by patient’s antibodies. They also identified similar positive staining to GAD in the pancreatic beta cells. In 1990, Solimena and De Camilli et al. published a larger series of patients [33]. They confirmed that anti-GAD was found in up to 60% of SPS patients. Anti-GAD was also found in the stiff-person variants. In 1991, Burn et al. reported a case with PERM phenotype with positive anti-GAD antibody [34]. Anti-GAD was identified in two distinct isoforms : GAD65 and GAD67. These two proteins are translated from two different genes and both are expressed in the brain [35]. In 1993, Butler et al. found that antibodies in SPS selectively recognized GAD65 isoform [36].

In 1993, Folli et al., from the same group of Solimena and De Camilli, reported antibody linked to paraneoplastic SPS [12]. At that time, they identified a 128-kd based antibody in the CSF of three patients with breast cancer and SPS. In all three patients, anti-GAD antibody was negative. In 1993, De Camilli et al. uncovered that this 128-kd based antibody is anti-amphiphysin [37]. Since then, it is estimated that 5% of patients with SPS have a strong association with cancer, especially breast cancer.

In 2000, Butler found another antibody which was later called anti-gephyrin in paraneoplastic stiff-person syndrome [14]. Since 2000, multiple antibodies had been identified in association with SPS, e.g., anti-GABAA receptor-associated protein (anti-GABARAP) [15], anti-glycine receptor [16], and anti-dipeptidyl-peptidase-like protein 6 (anti-DPPX) antibodies [18]. Although anti-glycine receptor antibody is the main antibody associated with PERM, it may also be positive in classic SPS. For example, Carvajal-Gonzales et al. found 2 out of 45 patients (4%) with SPS with positive anti-glycine receptor antibody [38]. Despite these important discoveries , the most common antibody associated with SPS remains the anti-GAD65 antibody.

Treatment History

The first successful treatment of SPS with diazepam was published by Howard in 1963 (Fig. 1.2) [6]. He reported significant improvement in stiffness and spasms. This finding supported the hypothesis for pathophysiology of stiff-person syndrome as either hyperexcitation of central catecholaminergic neurons or inhibition of GABA-ergic neurons. In 1989, Vicari et al. reported one patient with SPS who was successfully treated with plasma exchange [11]. However in the same year, Harding et al. reported two patients who did not improve with plasma exchange [39]. In 1994, Amato et al. and Karlson et al. reported separately that intravenous immunoglobulin (IVIG) improved both subjective and functional outcomes in their three patients combined [13, 40]. Karlson’s patients were bedridden and were able to walk after IVIG therapy. In the past decade, multiple case reports described the use of immunosuppressive therapies in SPS including rituximab with variable outcome. Eventually, in 2017 Dalakas et al. published a double-blind, placebo-controlled trial of rituximab in stiff-person syndrome which demonstrated no significant difference compared to placebo [41]. This will be discussed futher in detail in Chap. 12.

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