Development of CRPS after shingles: it's all about location.

Although the goal of medicine is to cure disease, effective treatment of the symptoms that the patient notices requires that the clinician identify their underlying cause – namely the diagnosis. Without a diagnosis, clinicians can only palliate the symptoms and hope that the actual disease resolves on its own. The 20th century brought great advances in understanding disease pathophysiology. For instance, we learned that seemingly identical coughs can have causes as diverse as infection, cancer, heart failure, or asthma, each requiring different diagnostic and therapeutic responses. Moving beyond symptoms to pathogenic diagnosis enabled development of diagnostic tests and disease-modifying treatments of such efficacy that prescribing cough syrup became irrelevant. In the 21st century diagnostic accuracy looms even larger as treatment decisions become increasingly complex, factoring in clinical-trial and data-mining results, not to mention cost considerations. As we enter the era of individualized medicine, in which computers will be necessary to perform these multivariate treatment decisions, accurate diagnosis will be paramount (viz. ‘‘garbage in (to the computer), garbage out’’). However fundamental it may be, diagnosis can be challenging when the major symptom is pain. Given pain’s subjective nature and widespread expression, the causes of pain symptoms are often uncertain. The same pain can signal conditions ranging from trivial to fatal. One of the most elusive pain syndromes is complex regional pain syndrome (CRPS), previously known as causalgia and reflex sympathetic dystrophy. CRPS consists of chronic limb pain that is disproportionate in severity and duration to the causal injury. For CRPS, the Freudian-era attribution of unexplained symptoms to psychopathology lingered to the end of the 20th century – surprising given that CRPS includes not only pain but also hard-to-fake objective signs including edema, abnormal bone metabolism, and disordered sweating. Pathophysiological understanding of CRPS began in the early 21st century with recognition that peripheral nociceptive axons (‘‘small-fibers’’) have efferent and trophic actions in addition to pain signaling function, as demonstrated in the small-fiber-predominant polyneuropathies [9]. Discovering small-fiber-predominant axonal injuries in CRPS-I patients explicated many of the non-pain as well as pain features of CRPS [1,11,15] and invalidated the distinction between CRPS-II (with known nerve injury) and CRPS-I (without known nerve injury) [10]. Discovering the prevalence of motor-system and brain dysfunction provided additional evidence that CRPS is a neuropathic disorder caused by neurological injury [7,12]. The role of microvasculopathy also came into focus–not only as an independent pain generator, but also for causing tissue hypoxia and malnutrition, which hinders recovery and spreads CRPS. Contributions of inflammation and immunity were also recognized, initially as caused by neurogenic inflamma-