Clinical Information

Stiff-person spectrum disorders include classical stiff-person syndrome, focal stiff-person forms (stiff-limb and stiff-trunk), and a severe encephalomyelitic form known as progressive encephalomyelitis with rigidity and myoclonus (PERM). Paraneoplastic and idiopathic autoimmune causes may be differentiated by a neuronal IgG antibody profile. The unifying clinical and electrophysiologic characteristic is central nervous system hyperexcitability. Clinical manifestations include stiffness, spasms, heightened startle responses, and falls. For the classical stiff-person form, the low back and lower extremities are principally affected. The stiff-limb phenotype may affect one or more limbs without truncal involvement. Truncal manifestations include low back spasms and deformity, with sudden chest wall spasms and breathing difficulties. In addition, patients with PERM have encephalopathy (often with seizures), myoclonus (muscle jerking), and dysautonomia. The most common IgG biomarker detected in stiff-person spectrum is glutamic acid decarboxylase 65 (GAD65) antibody. These patients generally have a classical or limited stiff-person form, almost always have antibody values above 20.0 nmol/L, have accompanying non-neurological autoimmune disease in 50% (type 1 diabetes and thyroid disease being most common), and almost always without accompanying cancer. Amphiphysin-IgG positivity is most frequently encountered in patients with occult breast adenocarcinoma presenting with limb stiffness and spasms; neurogenic changes are usually detectable on clinical exam and electromyography. Patients with glycine receptor (GlyR [alpha1 1 subunit]) autoimmunity present more commonly with PERM or stiff-limb phenotype rather than the classical stiff-person form. Associated neoplasms in patients who are GlyR antibody positive include thymoma, but a general search for age- and sex-pertinent cancers should also be undertaken. Dipeptidyl-peptidase-like protein-6 (DPPX) antibody is associated with diverse central and autonomic presentations, including PERM. B-cell blood dyscrasias should be tested for in DPPX-IgG positive cases. All patients with stiff-person spectrum, both seropositive and seronegative, may be immune therapy responsive. GlyR-IgG may be predictive of immune therapy response, including in patients with coexisting GAD65 antibody.