SPS occurs more often in women, but both men and women can be affected (average age of symptom onset is 35 years) and develop progressive symptoms over several months or years. SPS is quite rare and exact epidemiologic data is lacking; the estimated prevalence is one in a million. It is most often an immunologically mediated disorder with the presence of anti-glutamic acid decarboxylase-65 (anti-GAD65) antibodies; it may coexist with other autoimmune disorders including type 1 diabetes mellitus (in at least 35% of patients with SPS), Hashimoto thyroiditis, Graves disease, pernicious anemia, vitiligo, and celiac disease. A paraneoplastic form of SPS accounts for about 5% of cases, most often associated with breast cancer but also reported with thyroid, renal, or colon
cancer. The disorder is extremely rare in children (eight cases identified older than 29 years at Mayo Clinic and 12 other case reports).

CNS γ-aminobutyric acid (GABA)-secreting neurons play a major role in the normal inhibition of excessive continuous motor activation. GABA synthesis from glutamic acid is catalyzed by the enzyme glutamic acid decarboxylase (GAD). The discovery of antibodies against the 65-kilodalton GAD protein in most patients suggests immunologically mediated dysfunction of inhibitory synapses. Figure 94.1 illustrates the inhibitory synapse and subcellular localization of antigenic targets of antibodies found in SPS. Reported association of SPS with autoimmune diseases as pernicious anemia, thyroid disease, type 1 diabetes mellitus, and others provides further support for the role of autoimmunity. The presence of anti-GAD65 antibodies with other neurologic disorders, including cerebellar ataxia (with or without coexisting SPS), epilepsy, or progressive encephalitis with rigidity and myoclonus (PERM) suggests a spectrum of pathology associated with neuronal disinhibition in which SPS is one subtype. Although there is often an association of anti-GAD65 antibodies and SPS, the direct pathogenic role of anti-GAD65 antibodies remains uncertain. One major puzzle is that the antigenic GAD65 enzyme is intracellular and therefore supposedly hidden from the offensive antibodies. Furthermore, unlike myasthenia gravis, another antibody-mediated autoimmune disease where antibodies are directed against surface nicotinic acetylcholine receptors, passive transmission of antibodies (e.g., in maternal placental transfer) does not confer the SPS.

It may be that other associated antibodies are the pathologic culprits as, for example, the anti-GABA receptor-associated protein (GABARAP) autoantibody. Dalmau and colleagues found that antibodies directed against the glycine receptor subunit alpha 1 (GlyRα1) IgG antibodies are present in 12% of SPS patients and are found in other hyperexcitable disorders affecting brain stem and spinal cord, most often PERM. Anti-GlyRα1 antibodies may predict good response to immunotherapy. Mutations in the gene encoding the GlyRα1 cause hyperekplexia or startle disease.

Over the years, a paraneoplastic subgroup form of SPS patients was identified. Many of those patients were positive for autoantibodies directed against other molecules in the inhibitory synapse such as amphiphysin (breast and small cell lung cancer) and gephyrin (mediastinal cancer).

Progressive stiffness and intermittent spasms of the axial musculature characterize the classic form of SPS, but distal limb muscles may also be affected. Aching discomfort and stiffness tend to predominate in the axial and proximal limb muscles, causing a hyperlordotic posture, with awkward gait and slowness of movements. Unlike tetanus, trismus does not occur, but facial and oropharyngeal muscles may be affected. In some cases, respiratory muscles are involved. The stiffness diminishes during sleep and under general anesthesia, differentiating it from other motor unit hyperexcitable syndromes such as neuromyotonia. The spasms may lead to joint deformities and are powerful enough to rupture muscles, rip surgical sutures, and fracture bones. Painful reflex spasms and falls occur in response to movement, sensory stimulation, or emotional changes. Fear of attacks elicited by environmental stimulation may lead to a debilitating avoidance of public places. Anxiety and taskspecific phobias can be dominant features in SPS and may contribute to the often observed delay in diagnosis or misdiagnosis.

Physical examination shows markedly increased axial and proximal muscle tone. However, strength, coordination, and sensation are preserved. Passive muscle stretch provokes an exaggerated reflex contraction that lasts several seconds. Table 94.2 highlights the dominant features of classic SPS. The startle reactions of SPS are similar to those in hyperekplexia.