Stiff person spectrum disorder (ORPHA:3198)
A rare neurological disorder comprising fluctuating trunk and limb stiffness, painful muscle spasms, task-specific phobia related to walking, an exaggerated startle response, and often ankylosing deformities such as fixed lumbar hyperlordosis.
Epidemiology
The prevalence is estimated at about 1/1,000,000. Approximately 2/3 of patients are female.
Clinical description
The most common form of stiff person spectrum disorders (SPSD) is classic stiff person syndrome (SPS). Age of onset peaks around 45 and symptoms develop over months or years. Progressive muscle stiffness renders the trunk and hips immobile, and the gait becomes stiff and awkward. Superimposed painful spontaneous or reflex-induced muscle spasms may cause serious falls. A specific fear of crossing open spaces (pseudo-agoraphobia) may induce freezing of gait, sudden spasms, and falls. Focal neurological signs are absent. Clinical variants of SPSD include the stiff limb syndrome (SLS) where symptoms affect only one limb, and progressive encephalomyelitis with rigidity and myoclonus (PERM) where stiffness and myoclonic spasms are associated with focal neurological signs. Many patients with SPSD have insulin-dependent diabetes mellitus (30%), autoimmune thyroiditis (10%), atrophic gastritis with pernicious anemia (5%), and some have tumors of the breast, lung, colon or thymus.
Etiology
The presence of antibodies against glutamic acid decarboxylase (GAD-Abs; ~70-80%), glycine receptors (GlyR-Abs; ~10-20%), amphiphysin (~5%) and other, rarer antibodies (e.g. DPPX) in most of cases suggests an autoimmune pathogenesis. The exact immunopathophysiology (idiopathic vs. paraneoplastic; T-cell mediated vs. antibody mediated) varies amongst the different antibody subgroups. In particular for GAD-antibody associated autoimmunity there seems to be a certain genetic predisposition with an association of certain HLA haplotypes (DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype and DRB1*04:01 allele), and genetic variants in genes relevant for immune regulation as risk factors.
Diagnostic methods
Diagnosis essentially relies on clinical examination, and is substantiated by detection of associated antibodies in serum and cerebrospinal fluid (CSF), and by characteristic electromyographic abnormalities. Scans of the spinal cord can help to exclude mechanical causes such as a cyst or disc compression of the spinal cord.
Differential diagnosis
Differential diagnosis includes an atypical manifestation of a spinal cord disease (e.g. multiple sclerosis; tumors), axial dystonia, tetanus, neuromyotonia, acquired hyperekplexia (startle disease), and functional movement disorders.
Management and treatment
Benzodiazepines and baclofen are standard drugs for symptomatic treatment. Immunomodulating therapies (corticosteroids, intravenous immunoglobulin, plasmapheresis, rituximab, cyclophosphamide, autologous hematopoietic stem cell transplantation) have been proposed with variable results. Treatments help to control symptoms in the majority of patients affected by SPSD. PERM is a potentially lethal variant and requires early and consequent immunotherapy. GlyR-antibody mediated disease is often associated with thymomas, which need to be removed. In amphiphysin antibodies-associated SPSD or other paraneoplastic forms, the treatment of the underlying malignancy is of paramount importance.
Prognosis
The prognosis varies widely and depends greatly on the immunological and clinical subtype. While there are monophasic forms (e.g. GlyR-antibody related PERM) in which patients may make a good recovery with adequate treatment, the most common GAD-antibody related form is chronic. Many patients lose their ability to walk independently, and stiffness spreads, leading to an overall decline in the functional status and quality of life. In paraneoplastic SPSD, the prognosis is mainly determined by the underlying malignancy.

                            Last update: 
                            August 2023


                            - Expert reviewer(s): 
                            Pr Bettina BALINT