THORACIC OUTLET SYNDROME

AS A DISORDER OF

NEUROGENIC INFLAMMATION

 

                         Wladislaw Ellis M.D.

         

                               510-849-4703                                

ABSTRACT

Neurogenic thoracic outlet syndrome continues to be controversial largely, because the pathophysiology remains undefined. The analysis of the progression of symptoms in 1500 patients coupled with the discovery of innervated fibrotic tissue adherent to the trunks of the brachial plexus and secreting proinflammatory peptides, prompted the following hypothesis.

Stretch activates nervi nervorum to discharge inflammatory peptides and to degranulate resident mast cells producing vasospasm, ischemia, swelling and leukocyte recruitment with a resultant, localized, neural compartment syndrome. Repeated injury initiates a vicious cycle of increasing neural sensitization to neuropeptide expression, symptom intensification and spread, and evolving innervated fibrosis. This proposed cascade is sufficient to account for the pleiotropic symptoms and contended findings in this disorder


KEY WORDS

Thoracic outlet syndrome, nerve entrapments, innervated fibrosis, mast cells, pain.


BACKGROUND

Neurogenic thoracic outlet syndrome (TOS) continues to be controversial.  Its variable symptomatology, a paucity of “objective” clinical findings, together with its varied and often intermittent course, may be confusing and viewed with skepticism by many examining physicians [1]. The lack of a clearly defined and effective treatment strategy is a major factor in the progression of symptoms and ensuing disability in affected patients.


This may occur because the pathophysiology of this disorder remains undefined. Symptom onset commonly follows single force cervical flexion/extension (whiplash) injury or repetitive trauma associated with poor upper extremity positioning in the work place. Related predisposing factors in this predominantly female population in their third and fourth decades include musculoskeletal abnormalities, fibrous bands and post traumatic mal-positioning of the plexus roots in the scalene triangle. However, the presence of these same factors observed in normal individuals during routine autopsy, and the absence of clinical symptoms in numerous individuals who have experienced similar traumatic events are not easily reconciled and underscore their insufficiency as explanations [2]. The accurate diagnosis and a better understanding of the actual disease mechanisms becomes increasingly important in the face of a  growing incidence of individuals experiencing hand, shoulder, and arm pain as well as paraesthesias referable to the brachial plexus.


HYPOTHESIS

Based on the evaluation and treatment of over 1500 patients exhibiting brachial plexus irritability, the following pathophysiological mechanism is proposed. The plexus roots, following contusive or repetitive trauma, develop a neurogenically induced inflammation  and innervated fibrosis which provide a cytokine based mechanism for continued,  repetitive neural inflammation without demyelinization or frank neuronal death. This would explain the lack of findings on electrodiagnosis or imaging modalities given the small size of the fibrotic lesions (see below) [3].


JUSTIFICATION

The typical time course of symptom formation is instructive.  Distal paresthesias usually begin to occur following prolonged repetitive work with the arms outstretched.    Paresthesias are paradigmatic for neural ischemia.


Aching pain follows with increasing use of the arm(s), or as an initial result of contusive injury, improving with rest.  As the upper extremities, shoulders, and neck continue being used in ways that increase traction on the trunks of the brachial plexus, symptoms begin to increase over time and take longer to improve with rest.  At some point, often three to six months after their initial appearance, symptoms become constant.  This course argues for the increasing sensitization of the nerves involved.


This sensitization of the nerves is further evidenced by the spread of symptoms. Swelling in the dorsi of the hands, as well as supraclavicularly becomes a common occurrence. Pain analogous to that of “sympathetically mediated disorders”, namely burning, lancing pains with areas of hyper- and hypoesthesia makes its appearance.  Intermittent motor weakness becomes a frequent accompaniment of these increasing symptoms, as does symmetrically contralateral involvement.


This symptom spread is not mononeural, nor restricted to myotomes or dermatomes, although frequently there is preponderance of ulnar involvement.  Within a year or so of symptom onset, the clinical presentation commonly progresses to involve all three trunks. Double and triple crush injuries are common. Mirror symptoms follow. This spread also activates the cervical plexus (paravertebral neck pain), the greater occipital nerves (radiating headaches), and often  vagal (GI symptoms) and recurrent laryngeal (hoarseness) nerves. Raynaud’s phenomenon frequently occurs with exposure to temperature extremes, implying the involvement of sympathetic and nocifensive C-fibers.


Another important observation, besides symptom spread, that needs explanation is that symptoms increase in a highly time variable fashion. Pain can increase in seconds with abrupt arm abduction or in many hours following five minutes of writing. This argues for a time differential release or induction of algesic compounds.


This symptom sequence, whether initiated by either of the principal traumatic mechanisms, implies a process which, over time, involves nerves adjacent to the brachial plexus and, ultimately, the central nervous system (CNS). This pattern of accelerated neural re-injury may explain the increase in symptom formation with use.


The direct observation of the scalene triangle and its contents, exposed during supraclavicular decompression procedures, helps clarify this seemingly confusing panorama.  Fibrous bands, and persistent adhesions are visualized which limit the normal movement of the plexus and impose  deformation and  swelling, adhering it to adjacent structures [4].  Most important, in terms of the pathophysiology and continued symptom formation, is the occurence of richly innervated small (<1cm. sq.) perineural adhesions.   Careful resection of these perineural adhesions results in the normalization of blood flow in the appropriate dermatomes with resolution of the distal vasospasm as confirmed thermographically. The relief of these symptoms and signs of vasospasm following  neurolysis implies that they originated in the relevant plexus roots [5]. 

In over one hundred cases utilizing intraoperative thermography, decompressive surgery documented the presence of both directly mechanical (fibrous bands, fibrotically transformed muscle, adhesions) and neurogenic (small perineural adhesions) mechanisms for neural constriction, inflammation, and distal vasospasm. Substance P (SubP) and calcitonin gene related peptide (CGRP), present in the resected perineural adhesions as substantiated by histological immunoassay provide the basis for neurogenic inflammation [5]. Re-operation underscores the relevance of these perineural adhesions by the observed presence of exuberant recurrence.


Evidence from similar disorders in ulnar and median nerve entrapments provides corroborating evidence for the primacy of fibrosis in initiating and continuing symptomatology in these disorders.  Surgical decompressions of the ulnar and median nerves in the elbow, forearm, wrist, and hand all note the presence of significant fibrosis, occurring both peri- and endoneurally.  Endoneural fibrosis was felt to be most damaging because of its primary appearance and more direct effect on nerves and blood vessels [6].


Based on our own intraoperative findings of highly innervated perineural fibrosis secreting inflammatory factors, it is highly likely that the endoneural fibrosis is similarly innervated.  Neuropeptides expressed by this innervated fibrosis are well recognized as important mast cell activators [7]. Mast cells reside in significant numbers endoneurally, clustering at C-fiber convolutions, synaptic junctions of the nervi nervorum, and peri-vascularly about the vasa nervorum [8]. Their activation is biphasic with either explosive extrusion of granules which can volume increase by a factor of 1000 in milliseconds or by a slow tonic release lasting hours to days [9]. Messengers include histamine, proteoglycans, proteases, leukotrienes, prostaglandins, interleukins, interferon gamma, tumor necrosis factor (TNF) alpha and tryptases which initiate fibroblast proliferation and collagen deposition [10, 11].


These mast cell mediators, coupled with the direct effect of neuropeptides in the vasa nervorum produce loosening of endothelial junctions, localized edema, and  recruitment of lymphocytes and monocytes [12]. The result is a localized compartment syndrome inside the relatively rigid perineurium. The tortuous arrangement of fascicles in peripheral nerves embedded in a fibrous matrix of resident mast cells, macrophages,  Schwann cells, and perineural cells is made to order for the mechanical propagation of this, neurogenically induced local compartment syndrome [13]. Lengthy symptom occurrence, as well as fibroblast proliferation and fibrosis follow.


This fibrosis, spreading perineurally with reinjury, fixes the nerve, which is normally free to travel significant distances, focally increasing the mechanical strain on the nerve, and thus causing vasospasm of the vasa nervorum [14].  Delayed symptom occurrence could be explained by the slow tonic release of vasospastic mast cell mediators noted above. In and of itself, this facilitates the creation of intermittent symptoms, much like a pressure cuff.  What is more worrisome, and certainly more debilitating over time, is the consequent proliferative response, which worsens symptoms, the ease with which they arise, and lengthens any recuperative processes.  What is originally a neurogenically induced localized inflammation with it’s consequent pain begins to spread both endoneurally and perineurally, most likely via cytokine mediated mechanisms promoting adhesions, their innervation and, ultimately, the activation of  the CNS.


Neural ischemia gives rise to yet another dimension of  injury: ischemia-reperfusion, which has been shown to produce entrapment symptomatology even with minimal ischemia as long as it is repetitive [15]. This could augment and consolidate the above tissue changes


 Additionally, pharmacological manipulations corroborate the primacy of neurogenic inflammation in TOS.


 Mu  receptor agonists are minimally effective in controlling the chronic pain of TOS, producing a generalized numbness, but little amelioration of the more intense symptoms.  This is characteristic of neuropathic/neurogenic disorders [16].  Interestingly, nalbuphine, a kappa and sigma agonist, is consistently more effective and has minimal side effects.


Octreotide, a somatostatin analog which quickly down regulates neuropeptide production (SubP, CGRP, VIP, etc.}, is effective during early flare-ups, corroborating the importance of neurogenic peptides in initiating symptoms [17].  Octreotide labeled positron emission tomography is a potential diagnostic method because of its ability to image localized neurogenic inflammation.  


Topical nitroglycerin can lessen pain significantly, more so than opiates. This points to the importance of endothelial factors that are  nitric oxide mediated as well as the importance of vascular integrity [18].


Anti-inflammatory agents modulating cyclo-oxygenases  show little symptomatic benefit, possibly quieting the effects of direct mechanical irritation.


 

Substantiating the importance of TNF-alpha, a major cytokine of mast cells, Etanercept, a TNF-alpha blocker, eliminates the diffuse and spreading pain accompanying flare ups (personal communication) [19].


More dramatically, low-dose heparin produces relief, lasting weeks to months.  Heparin is a complicated mix of glycose aminoglycans with pleiotropic functions.  Only 3% of the heparin functional sites are dedicated to anticoagulation.  The rest regulate the extracellular matrix, cytokines, chemokines, growth factors, normalize the endothelium, leukocyte migration, cellular junctions, and  stabilize mast cells.  Its tissue half life in the extracellular matrix is on the order of several weeks [20].  Heparin has been shown to reduce: post-radiation neuropathy, inflammation and  pain  in severe burns,  asthmatic bronchoconstriction, the symptoms of irritable bowel syndrome, and  the pain of nerve entrapments by its direct action on peripheral nerves [21, 22].

 

CONCLUSION

Stretch and micromovement activate nervi nervorum to discharge inflammatory neuropeptides with consequent vasospasm and ischemia.  These neuropeptides (SubP, CGRF and others) can also produce sudden mast cell degranulation with acute symptoms, or, alternatively, a more gradual release, increasing symptomatology over time and explaining the clinically observed time variable symptom formation. These cytokines and vaso-active compounds, released by mast cells and nervi nervorum (primarily nocifensive C-fibers), result in increased neural irritability and sensitivity, progressively involving the local microvasculature with increased vasospasm, initiating endothelial dysjunction, edema, leukocyte and macrophage migration with a resulting endoneural compartment syndrome [23]. Fibroblast and mast cell migration follow as does growth factor (NGF, BDNF, FGF, etc.) induced innervated fibrosis [24, 25]. Reinjury occurs easily in these sensitized nerves , the fibrosis spreads,  resulting in a  vicious cycles of progressive neuronal activation, edema, stasis, and more extensive, innervated fibrosis. Given the relatively rigid perineurium, and the sinuous and interdigitating course of the fascicles, a compartment syndrome results Continued cytokine elaboration is sufficient to  evoke symptom spread, the establishment of double or triple crush injuries, CNS sensitization as well as  the appearance of a mirror syndrome [26, 27]. Kindling, hypo/hyperesthesia, allodynia, and Raynaud’s phenomenon follow.


Based on the well-documented etiology of TOS in the workplace, constant stretch and small movements are enough to set off this vicious cycle. Repetitive non deforming stretch (e.g. keyboarding) has been shown to induce neural ischemia and bleb formation, sensitizing the nerves and providing the initial insult for the neurogenic cascade described above [28].


Direct traumatic onset (excessive flexion/extension and seatbelt contusions during motor-vehicle accidents, clavicular fractures, thrombi or aneurysms) can initiate enough of an inflammatory response through tissue necrosis, to also allow the above perturbations to take hold [29]. 


Neurogenically induced perineural inflammation could induce scalene muscle fibrosis and transformation as well as initiate or enhance the pathological effect of existing interdigitations or fibrous bands  [30]. The current etiologic explanation for TOS of volume increase in the scalene triangle and consequent compression of the trunks of the plexus is insufficient to account for the late onset of symptoms and the consequent progression and elaboration of symptoms [31]. Direct irritation of the plexus is certainly important but it is not sufficient. Neurogenic inflammation with its cascade of swelling, cellular recruitment and fibrosis provides a more comprehensive explanation.


This description of pathological events and their consequences explains much of the often cryptic  initiation and clinical progression of  TOS. The spread of innervated fibrosis with continued reinjury presents a mechanism for increasing symptoms, the involvement of sympathetic and motor nerves, as well as distal, proximal and adjacent neural sensitization. Reflection extends this process to other entrapments as indicated by the prevalence of intraoperative reports of localized fibrosis, perineural thickening, and edema.  Idiopathic low back pain, postoperative pain, and sacrococcygeal syndrome, among others, could have similar pathophysiologies.


This hypothesis allows for greater diagnostic and clinical clarity and redefines the direction of treatment. Long term mast cell stabilizing agents, cytokine and neuropeptides inhibitors, and endothelium stabilizing agents  can offer the hope of better treatment in the future.


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