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.
Pichet Termsarasab, MDFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok, Thailand Thananan Thammongkolchai, MDFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok, Thailand
Bashar Katirji, MDAcademic affiliation: Professor of Neurology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
1. Historical background of stiff-person syndrome* The original description by Moersch and Woltman* Timeline of discoveries of antibodies* Treatment advances in the field
2. Clinical phenomenology (including diagnostic criteria) of stiff-person syndrome and stiff-person syndrome variants* How to differentiate stiffness in stiff-person syndrome from other phenomenologieso Spasticity/hypertoniao Dystoniao Cramps* Clinical features of classic stiff-person syndromeo Core featureso Associated features including associated autoimmunity* Diagnostic criteria of stiff-person syndrome and its limitation* Clinical features of stiff-person syndrome variantso Stiff-limb syndrome (SLS)o Progressive encephalomyelitis with rigidity and myoclonus (PERM)o Overlapping syndromeso Hyperekplexia: A stiff-person syndrome variant or distinguished entity?o Confusion about terminology in clinical practice* Clinical pearls and pitfalls in the diagnosis of stiff-person syndrome
3. Differential diagnosis of stiff-person syndrome* Central hyperexcitabilityo Focal spinal cord lesionso Toxic/parainfectious causeso Autoimmune causes e.g. LGI-associated faciobrachial dystonic seizureso Paroxysmal movement disorders Paroxysmal kinesigenic dyskinesia (PKD) Paroxysmal non-kinesigenic dyskinesia (PNKD) Paroxysmal exercise dystonia (PED) Secondary paroxysmal kinesigenic dyskinesias* Paroxysmal tonic spasm in multiple sclerosis* Other structural spinal cord lesions Episodic ataxia* Peripheral hyperexcitability (overview here with further dedicated information on this subtopic in chapter 14)o Peripheral nerve hyperexcitability syndromeso Disorders of skeletal muscle membrane hyperexcitability
4. Electrophysiology of stiff-person syndromes* Electrophysiologic techniques in studying stiff-person syndromeo Needle electromyography vs. surface electromyographyo Special techniques* Key electrophysiologic findings in stiff-person syndromeo Continuous motor unit activity (CMUA)o Loss of vibration-induced inhibition of H-reflexo Enhanced exteroceptive reflexes including blink reflexeso Co-contraction of agonist and antagonist muscles
5. Neurochemistry of inhibitory synapses and clinical applications in stiff-person syndromes* GABA-ergic synapses* Antigenic targets of GABA-ergic synapses in stiff-person syndromeo Glutamic acid decarboxylase (GAD)o Amphiphysin o GABAA receptor (GABA AR)o GABAA receptor-associated protein (GABARAP)* Glycinergic synapses* Antigenic targets of glycinergic synapses in stiff-person syndromeo Glycine receptoro Glycine transporter 2 (GlyT2)o Gephyrin
6. Immunopathogenesis of stiff-person syndromes* GAD-65 vs. GAD-67In each subtopic below, we will discuss the controversies and current supporting and arguing evidence.* Is GAD-65 pathogenic or epiphenomenon?* Cell-mediated immunity vs. humoral immune response* Role of T-cell vs. B-cell* Future directions of research in stiff-person syndromes
7. Antibodies in stiff-person syndrome and their correlations with clinical phenotypes* Eight main antibodies: anti-GAD, anti-amphiphysin, anti- GABA AR, anti-GABARAP, anti-glycine, anti-GlyT2, anti-gephyrin, anti-dipeptidylpeptidase (anti-DPPX)* Prevalence of these antibodies in stiff-person syndrome and its variants* Complex correlations between clinical phenotypes and immunophenotypes* Oncological association/Paraneoplastic stiff-person syndrome
8. Anti-glutamic acid decarboxylase 65 (GAD65)-associated syndromes* Phenotypic Spectrum of anti-GAD65 antibody syndromeso Anti-GAD65-associated stiff-person syndromeo Anti-GAD65 and diabetes mellituso Anti-GAD65-associated ataxiao Anti-GAD65-associated epilepsyo Other neurologic syndromes associated with anti-GAD65* Laboratory aspects of anti-GAD65o Positive high vs. positive low titero An issue and caveat about non-unity of reported unitso Laboratory techniques Radio-immunoassay (RIA) Enzyme-linked immunoassay (ELISA) Western blot Immunofluorescence* Oncological association of anti-GAD-65 antibodies: Is paraneoplastic work-up required?* Treatment response and prognosis
9. Progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome* Brief history (already discussed in detail in chapter 1)* Clinical features* Electrodiagnostic findings* Associated antibodieso Anti-glycineo Anti-DPPX * Prognosis and treatment responses
10. Emergencies in stiff-person syndrome In each topic below, we will discuss clinical features, how to recognize and treatment. These features, if not recognized and treated promptly and appropriately, can lead to morbidity and mortality. This topic is particularly important to clinicians managing stiff-person syndrome in the inpatient setting.* Paroxysmal dysautonomia* Respiratory issues* Status spasticus* Treatment-related emergencies: Baclofen withdrawal syndrome
11. Diagnostic approach in stiff-person syndrome and its variants* Complexity between immunophenotypes and antibodies* Targeted approach vs. shotgun approacho Pros and conso Current status of antibody testingo Issues with existing diagnostic algorithms* Proposed diagnostic algorithm* Future directions
12. Treatment of stiff-person syndrome For each treatment modality, we will review current evidence in the literature including clinical trials (if any), discuss our experience and provide a practical guide in clinical practice. Doses and routes of administration will also be provided, likely in a tabulated form.* Symptomatic therapieso Benzodiazepineso Baclofeno Other medications* Immunotherapieso Steroidso Intravenous immunoglobulins (IVIg) Randomized controlled trial o Plasma exchange (PLEX)o Rituximab Randomized controlled trial o Other immunomodulatory agents including azathioprine, mycophenolate mofetilo Proposed treatment algorithmo Future directions
13. Pediatric stiff-person syndrome* Prevalence* Reported cases in the literature* Clinical features* Difference between pediatric vs. adult stiff-person syndrome* Treatment outcome * Caveats in management of pediatric stiff-person syndrome
14. Peripheral hyperexcitability syndromesClinical features, differential diagnoses, how to distinguish from the stiff-person syndrome, investigations and brief discussion about treatment of each entiity will be discussed in this chapter.* Peripheral nerve hyperexcitability syndromeso Neuromyotonia including Isaac and Morvan syndromeso Cramp-fasciculation syndrome* Disorders of skeletal muscle membrane hyperexcitabilityo Myotonic dystrophieso Myotonia congenitao Paramyotonia congenitao Myotonia in periodic paralysis o Schwartz-Jampel syndromeo Rippling muscle disease
15. Hyperekplexia* Clinical features* How to distinguish from stiff-person syndromes and other startle syndromeso Culture-specific startle syndromes e.g. Latah, Jumping Frenchmen, Miryachit* Genetic basis of hereditary hyperekplexia* Investigations* Treatment