Case 11: Could This Be Guillain-Barré Syndrome?

Dana Cummings, MD, PhDPreceptor: Thomas Crawford, MD

Disclosures

February 22, 2002

In This Article

Discussion

Aysun and colleagues[6] reviewed 30 such patients who presented during a 14-year period. Eleven patients had ALL; 7 presented with back pain, difficulty walking, or weakness. Ten of the 30 were diagnosed with neuroblastoma, 4 with non-Hodgkin's lymphoma, 3 with rhabdomyosarcoma, 1 with Ewing's tumor, and 1 with Hodgkin's lymphoma.

In addition, Cabral and Tucker[7] reported on a series of patients with undiagnosed malignancies who presented to a rheumatology clinic. Of a total of 29 patients, 13 were ultimately diagnosed with leukemia. The feature suggestive of malignancy rather than rheumatologic disorder was nonarticular bone pain (present in 68% of the cases). In 28% of the patients, the ESR was discordant with platelet counts.

In childhood ALL, a large subset of patients present with bone pain as the initial symptom, in association with nearly normal hematologic indexes.[8] One hypothesis to explain this is that bone marrow expansion results in a diffuse, poorly localized syndrome of bone pain.

Anatomy of bone innervation. An extensive plexus of nerve fibers investing the periosteum and joints gives bone the lowest pain threshold of any of the deep tissues.[9] A-delta (small myelinated) fibers and C (small unmyelinated) fibers contain deep somatic nociceptors with free nerve endings. Deep somatic pain is usually described more as aching than sharp, and is less well localized than cutaneous somatic pain.[9]

Periosteal and cortical mediators of pain. In the human femur, all cortical Volkmann's and Haversian canals contain unmyelinated fibers, and some contain both myelinated and unmyelinated fibers.[10,11] Substance P, which mediates pain sensation, is localized to these fibers.[12]

Bone innervation in marrow. In rat and dog models, nerves in bone marrow have been found to be associated with venous sinuses. These are single fiber nerves, independent of the blood vessels in marrow,[13] that enter the Haversian canals from both periosteum and the marrow.

Autonomic/vasomotor innervation. Neuropeptide Y and tyrosine hydroxylase immunoreactivity is found almost exclusively in the blood vessel walls of the epiphyseal plate and in the Volkmann canals. By contrast, vasoactive intestinal polypeptide-positive fibers are predominantly present in the epiphysis and periosteum, but are seldom found near blood vessels[14] In deep somatic tissues, calcitonin gene-related peptide (CGRP) immunoreactivity is principally related to vasculature and the motor endplates of striated muscle; however, an extensive network of CGRP immunoreactive axons is found within bone, principally in the periosteum, and focally in the joint capsules.[15] This differentiation may be related to the specific functions of these substances in the regulation of bone and calcium metabolism.

Periosteal-encapsulated, pressure-sensitive nerve endings detect intraosseus or intramarrow hypertension. Periosteal complex free nerve endings produce pain resulting from the stretch that occurs with intraosseus hypertension. Intramarrow nociception may be induced by injury, baroreceptors, metabolism, and inflammatory processes. Abnormalities in intraosseus or intramarrow vasomotor autonomic tone could be responsible for lowering thresholds in any of these pathways.

Granulocyte colony-stimulating factor (G-CSF) administration causes "medullary bone pain" in up to 39% of patients in a dose-dependent fashion (see American Society for Clinical Oncology Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based Clinical Practice Guidelines). McCullough and colleagues[16] administered G-CSF to 261 healthy subjects and found bone pain to be a common dose-dependent side effect within 24 hours of administration (Table 1).

In a retrospective study, Jonsson and associates[8] found that 18% of a sample of 296 children with ALL experienced bone pain that was more prominent than other manifestations of the leukemia. Children in this group had hematologic values closer to normal than the other children in the sample, and had significantly lower uric acid and higher calcium levels compared with the other children. Thus, nociceptive pressure or pain transduction pathways may play a role in this symptom. Unique tumor cell biology with unique bone resorption and metabolic characteristics may account for the subset of children with ALL who present with bone pain as a prominent feature.

Summary

Children with undiagnosed systemic malignancies often present with neurologic complaints. Although our understanding of the neurochemistry and neuroanatomy of bony innervation has grown, the fundamentals of the functional neuroanatomy and neurophysiology of bony innervation remain speculative. Insight into the basic mechanisms of bone pain will enable the development of new treatments for complex disorders including cancer-related bone pain.

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