Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes

Abstract

Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.

Figure 1

Reciprocal inhibition between antagonist muscles. The upper pair of traces shows needle EMG recordings from a pair of antagonist muscles in a patient with SPS, with involuntary MUP firing in the agonist muscle (top trace). Volitional contraction of the antagonist muscle (arrow) does not silence the agonist MUP firing (asterisk). In contrast, in the lower pair of traces, contraction of the antagonist muscle (arrow) silences the voluntary contraction (asterisk) in a healthy control subject voluntarily contracting the agonist muscle.

Figure 2

Increased reflex excitability in SPS patients. A. Flexor reflex of the leg. Stimulation of the sural nerve with 4 pulses elicits contraction of the two flexor muscles (tibialis anterior, hamstrings) and spreads abnormally to extensor (quadriceps) and paraspinal muscles. B. Hyperexcitability of the blink reflex in an SPS patient following paired stimulation of the contralateral supraorbital nerve at 16 mA with an interstimulus interval of 160 ms. Four stimulation trials are shown. The first stimulus of each pair elicits a response (R2a) with normal latency, although the first trial produced a prolonged response. The R2 response (R2b) to the second stimulus of the pair should normally be fully inhibited at this interval, but instead a robust and prolonged blink occurs.

Figure 3

Components of the inhibitory synapse recognized by known antibodies in Stiff Person Syndrome. The pre-synaptic glutamic acid decarboxylase (GAD) (1) is the rate-limiting enzyme in GABA synthesis; amphiphysin (2) is a cytosolic, pre-synaptic vesicle-associated protein responsible for endocytosis of vesicle plasma membranes following GABA release. The post-synaptic target antigens in SPS are gephyrin (3), and GABA-A-receptor-associated protein (GABARAP) (4). Gephyrin is a cytosolic, tubulin-binding protein involved in clustering the glycine and GABA-A receptors in the spinal cord and the brain. GABARAP is a linker protein between gephyrin and GABA-A receptors and promotes recycling and organization of the GABA receptors. The most common autoantigen in SPS is GAD, which is seen in 85 % of patients, followed by GABARAP, which is found in 65 % of patients. Amphiphysin is detected in 5 % of patients, while gephyrin has been seen only in one case. (From reference with permission).