Wladislaw Ellis

ABSTRACT:

NTOS frequently becomes chronic with spreading and migrating sensory, motor and autonomic dysfunctions that are poorly understood. Intraoperative thermography, microscopy and cytokine staining revealed " innervated fibrosis" of brachial plexus nerve trunks leading to the local presence of pro-inflammatory cytokines. Because similar abnormal, actively secreting growths have been reported in a wide variety of chronic, painful disorders, indicating a commonality, we propose a model involving potentially de-differentiated neurites, Schwann cells as well as activated mast cells, macrophages and fibroblasts to account for symptom formation, progression, and intransigence. This conceptual structure suggests new strategies for better symptom control, including thorough brachial plexus neurolysis at the time of operation, perineural anti-inflammatory treatment, and systemic anti-inflammatory modulation.

KEY WORDS: Innervated fibrosis, neurogenic inflammation, cytokine spread, mirror symptoms, neurolysis

Any practitioner who treats patients with neurogenic Thoracic Outlet Syndrome (NTOS) for any length of time, is aware of the wide variety, spread and intermittency of reported symptoms. In addition, many patients with apparently optimal thoracic outlet decompressions and non-operative therapy do not improve. Inflammation has been implicated in an increasing number and wide variety of problems in the human body. For all these reasons we have explored the potential role of inflammation in patients with NTOS.

We have closely analyzed the small foci of adherent fibrous tissue shown to be neurologically active using intra-operative thermography and removed during neurolysis of the brachial plexus and cervical roots while operating for NTOS. Histological examination showed that these  irritating fibrous foci were richly innervated with both myelinated and unmyelinated nerve fibers. Many of these  were immature and secreting Calcitonin Gene Related Peptide and Substance P, proinflammatory neuropeptides involved in pain, hyperesthesia and autonomic dysfunction, and existing in an extracellular matrix richly populated by macrophages, mast cells and fibroblasts (1). This finding of such cellular and molecular substrates may help explain the evolution and spread of painful, disabling symptomatology in NTOS (2,3). Interestingly, this same perpetuating mechanism of "innervated fibrosis" spreading both locally and distantly via neurogenic inflammatory mechanisms is operant in multiple other disorders ranging from endometriosis to varieties of migraine (4,5).

Events that initiate NTOS are thought to be those that directly traumatize the brachial plexus,  most commonly a  seatbelt,  flexion-extension, or acute stretch trauma during a motor vehicle accident (MVA) (6). The consequent inflammatory edema activates neuropeptides and cytokines initiating a plethora of various  growth  and inflammation stimulating cascades (cytokine, interleukine, chemokine, many growth factors, and, importantly, a minimal arachidonic acid cascade limiting steroid effectiveness) with potential long term consequences (7,8). This situation leads to an environment suitable for the initiation of recurrent neurogenic inflammation caused by Schwann cell activation resulting in neurite ingrowth from nervi nervorum (perhaps from or associated with investing fibrosis) at first intra and then peri- neurally becoming macroscopic "innervated fibrosis" over time (9). Mechanosensitivity of both neural and glial (Schwann) cells, probably due to continued neuritic de-differentiation, leads to further generation of  inflammatory and trophic factors perpetuating and extending the pathology and creates the groundwork for double, triple crush injuries as well as scalene hypertrophy and fibrous interdigitations (10,11). De-differentiation explains not only the continued hyperesthesia and paresthesias but also easy re-injury, therapeutic unresponsiveness, spread, continued disability and an excellent response to terminal differentiation as induced by erythropoietin.

A second proposed major category of initiating events for NTOS is constant mechanical  tension (for example: repetitive work injury) of the brachial plexus and its rami (12). The primary problem seems to lie not with the nerve itself but with the supporting  Remak Schwann cells which, in response to tension or ischemia, initiate local neuronal sprouting and neurite ingrowth by decreasing myelin associated glycoprotein expression (13). Continued mechanosensitivity facilitates the progression of the innervated fibrosis described above leading to the evolution of general, shared symptoms over time, despite varied initial presentations. Why some, mainly women, become affected with chronic, progressive symptoms while others recover remains unanswered but there are hints that it lies in the genome (14).

In over half of these patients, initial symptoms are pain in the shoulder arm and hand. Following initial injury symptoms originate locally and then spread both distally and centrally, driven by the released cytokines (15). Patients with repetitive work injury usually develop hand pain initially followed by proximal spread of symptoms. Many of these patients therefore receive carpal tunnel decompressions with no benefit, but then do receive significant relief from thoracic outlet decompressions, underscoring the importance of the brachial plexus lesion as the underlying cause of the referred pain in the forearm, wrist, and hand.

Headaches, especially those suboccipital, radiating, and migranoid in nature, have been long recognized as a presenting sign of NTOS (16). Ulnar paresthesias, severe episodic left chest and arm pain, cold sensitivity, hyperhidrosis, varied gastrointestinal and genitourinary symptoms, and episodes of hyperesthesia or allodynia can all precede clinical diagnosis of  NTOS or accompany its development (17).

It is likely that the products of nerve driven inflammation not only change the involved nerves themselves but also diffuse to involve nearby structures such as the stellate ganglion, vagus, laryngeal or phrenic nerves. In addition this process could  affect  the dorsal root ganglion and spinal dorsal horn, producing motor symptoms that seem unrelated but are , in fact, driven by the basic pathophysiology of NTOS (18, 19, 20). Central sensitization and mirror symptomatology occur with time after repeated re-injuries of the already sensitized nerves and account for much of the subsequent spread and additional dysfunction (21).     

In summary, evidence suggests that trauma, overt or subtle, leads to small intra- and peri-neural foci of inflammation and neural ingrowth as part of the fibrosis around the brachial plexus and adjacent structures. This leads to a wide variety of pain and sensory symptoms, but also explains autonomic and motor disturbances depending on the location, combination, and concentration of inflammatory substances expressed. Recurrent and or self-perpetuated activation of this process, driven probably by immature neuro-glial elements, results in spreading pathology and symptoms for what is, essentially, aberrant wound healing.

This formulation, although conjectural, explains the varied clinical and tissue findings, and lack of response to many therapies. In addition, it suggests new interventions. Most importantly it implies that aggressive neurolysis of the brachial plexus during operation may be of benefit, coupled with  directed local or systemic pharmacologic interventions, one of which, erythropoietin, acts by inducing terminal differentiation in immature neurites and Schwann cells (22, 23).

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