Reduced spinal GABA presumably creates an imbalance between the spinal inhibitory (gabanergic) input and the excitatory input to alpha motor neurons. This interpretation is supported by the fact that the spasms worsen under the influence of drugs that enhance aminergic activity, thereby facilitating long-latency spinal reflexes, or that inhibit catecholaminergic or gabanergic transmitters. An autoimmune mechanism is further suggested by the high incidence of insulin-dependent diabetes (present eventually in almost all the cases under our care) with detectable antibodies to islet cells; a few patients have thyroiditis, pernicious anemia, or immune-mediated vitiligo.
There are rare paraneoplastic varieties of stiff man syndrome, mostly accompanying breast cancer and associated in some cases with circulating antibodies directed against amphiphysin or gephyrin, proteins associated with synaptic GABA receptors. Some of the cases related to the antiamphiphysin antibodies also display more conventional types of paraneoplastic neurologic disorder such as encephalopathy or opsoclonus (see Chap. 30). Also reported, perhaps not surprising, have been instances of a variable cerebellar syndrome with stiff-man and high titers of anti-GAD antibodies (Rakoevic et al).
The stiff man syndrome must be distinguished from tetanus (see “Tetanus” in Chap. 41 and further on), Isaacs syndrome, and the rare syndrome of subacute myoclonic spinal neuronitis, described in Chaps. 32 and 42. In both the stiff man syndrome and myoclonic spinal neuronitis, the intense spasms and stiffness of muscles are a result of disinhibition of interneurons in the gray matter of the spinal cord.
The syndromes of continuous muscle activity are usually distinguishable clinically and electromyographically from extrapyramidal and corticospinal abnormalities such as dystonia, dyskinesia, and rigidity, although early phases of axial dystonic disorders and stiff man syndrome have similarities.
In the stiff man syndrome, diazepam in doses of up to 50 to 250 mg/d, increased gradually, is most effective; clonazepam, vigabatrin, or baclofen is sometimes effective as well. In keeping with the presumed autoimmune mechanism of most cases, plasma exchange, high-dose corticosteroids, or intravenous gamma globulin are helpful in some patients, albeit for only several weeks or months before another infusion is required. Several of our patients have required intravenous gamma globulin for several years at intervals of 6 to 12 weeks but nevertheless became disabled if the dose of diazepam was reduced below 100 mg/d. A small randomized trial of intravenous immune globulin conducted by Dalakas and colleagues has demonstrated the efficacy of this treatment; in their study, the benefits varied in duration from 6 weeks to 1 year. The typical dose is 0.4 mg/kg daily for 4 or 5 consecutive days. Immunosuppression with rituximab is being used increasingly, on the basis of case reports and small series but a small randomized trial has been negative (Dalakas et al, 2017). For intractable cases, particularly when 1 limb is involved, propofol has been anecdotally effective in doses that do not produce sedation (Hattan et al).