J Manipulative Physiol Ther 1999 (Jun); 22 (5): 333–340 ~ FULL TEXT
Joel Alcantara, DC, David M. Steiner, DC, Gregory Plaugher, DC, Joey Alcantara
This study was funded by Palmer College of Chiropractic West,
San Jose, California and the Gonstead Clinical Studies Society,
Mount Horeb, Wisconsin.
OBJECTIVE: The chiropractic management of a patient with myasthenia gravis and vertebral subluxation is described. We discuss the pathophysiology, clinical features, and treatment of patients with these diseases.
CLINICAL FEATURES: The 63–year-old male patient suffered from complaints associated with the disease myasthenia gravis along with signs of vertebral subluxation. The patient had an initial complaint of dysphagia. In addition, the patient experienced swelling of the tongue, nausea, digestive problems, weakness in the eye muscles, difficulty breathing, myopia, diplopia, and headaches. Balance and coordination problems resulted in walking difficulties.
INTERVENTION AND OUTCOME: Contact specific, high-velocity, low-amplitude adjustments were applied to sites of patient subluxation. Myasthenia gravis is no longer debilitating to the patient; he is medication free and has resumed a "normal life."
CONCLUSION: The clinical aspects of the disease, including the possible role of chiropractic intervention in the treatment of patients suffering from myasthenia gravis, are also discussed. This case study encourages further investigation into the holistic approach to patient management by chiropractors vis-a-vis specific adjustments of vertebral subluxation.
From the Full-Text Article:
Myasthenia gravis is an autoimmune disorder that affects the skeletal muscles. The pathophysiology of the disease involves the presynaptic nerve terminal and structures located in the postsynaptic skeletal muscle membrane. In a simplistic approach, we provide the following description of the disease. For a more extensive discussion on the topic, we refer the reader elsewhere. [9–11] Calcium entry into the nerve terminal at a neuromuscular junction triggers the release of acetylcholine (ACh) from storage vesicles within the nerve terminal.  Each synaptic vesicle releases about 10,000 ACh molecules into the synaptic cleft,  where it diffuses rapidly throughout. At the postsynaptic membrane, acetylcholine receptors (AChR) line the primary synaptic clefts. The membrane itself contains depressions resulting from membrane in-folding to increase membrane surface area. The AChR is a transmembrane glycoprotein structure composed of 5 subunits that is cation-selective and ligand gated.  In a possible ligand-receptor interaction put forth, the binding of ACh may somehow cause the AChR subunits to move and portions of the transmembrane protein may form a gate that opens.  Opening of these gates is a requisite for ion permeability, membrane depolarization, and a resultant action potential for muscle contraction. In myasthenia gravis antibodies generated by the immune system attack the AChR. The resultant antibody-receptor structure may result in receptor blockade. The main immunogenic regions are located close to but distinct from the subunit of the AChR. [14, 15] Another possibility from an antibody-receptor interaction perspective is that the AChR structure may be altered, resulting in poor affinity of the ACh for the receptor. The resultant size or duration of a single channel current because of the ion permeability or the duration of opening burst of the receptor gates may thus be affected. [14, 16] Overall, regardless of the specific effect of AChR binding by antibodies, the result is an inadequate response to ACh release and therefore muscle response.
Myasthenia gravis is a common disease of the neuromuscular junction and is considered fairly stereotypical. For example, most patients have ptosis, ophthalmoplegia, dysarthria, and dysphagia. Myasthenia gravis is known as the “great imitator” because it may mimic cranial nerve palsies and brainstem diseases, myopathies, and anterior horn cell disease.  It is beyond the scope of this writing to delve into great detail with respect to diagnosis, and the reader is referred elsewhere.  The demonstration of weakness with continued use and improvement in strength with a short rest is diagnostic. The patient may be referred to a medical doctor for the Tensilon test, which is readily available. However, some caveats are worth mentioning, because this test has associated risks. The drug may be dangerous and life threatening, particularly to the elderly, those with heart disease, and individuals with obstructive lung disease. Also the test may be difficult to interpret and difficult to tell from placebo, especially when the complaint of weakness is mild.  Immunologic testing for the AChR is very reliable. However, false-positive results may occur in some patients, such as those with systemic lupus erythematosus.  Finally, electrophysiological testing may also be performed, and the reader is referred elsewhere for a more complete discussion  on the topic.
The goal of any treatment regimen, medical or otherwise, is to produce normal function. The ideal therapy should have rapid onset with minimal side effects, be easy to administer, and have low cost. The following is a cursory overview of some of the medical approaches to the disease, based on the work by Massey.  Cholinesterase inhibitors are usually used as the initial therapy. They provide symptomatic improvement for a time by hindering the hydrolysis of acetylcholine at the neuromuscular junction. However, this approach alone is rarely sufficient. Pyridostigmine bromide (Mestinone) and neostigmine bromide (Prostigmine) are the most commonly used agents. Common side effects are gastrointestinal hyperactivity and increased upper and respiratory secretions, as well as bradycardia. Thymectomy is another approach to treatment, although no prospective blinded study has ever been performed nor is the association between the thymus and the pathogenesis of myasthenia gravis fully understood. There are reports that more than 50% of patients undergoing thymectomy experience sustained improvement. The use of immunosuppressant drugs is another treatment choice. However, because of the increased risk of infection as a result of the immunosuppression, as well as the potential side effects of the individual drugs, this route of care must be used with caution. The treatment is dependent on the rate of progression and the severity of weakness in patients' symptoms and the potential side effects of the medication. Immunosuppressant agents used are corticosteroids, azathioprine, cyclosporine, and cyclophosphamide. Other forms of therapy include plasmapheresis, intravenous immunoglobulin, total body radiation, splenectomy, thoracic duct lymph drainage, and anti-thymocyte globulin.
This is the second citation in the scientific literature describing the chiropractic management of a patient with myasthenia gravis. Araghi  reported in a conference proceedings the chiropractic care of a 2–year-old female patient in whom myasthenia gravis developed after a motor vehicle collision. She had the following symptoms after injury: otitis media, ptosis of the right eye (developed 8 days after trauma), lethargy, lower extremity weakness, bilateral toe-in foot flare, and a moderate left head tilt. The patient had a positive Tensilon test result and electromyogram. The patient was adjusted at S2, atlas, and occiput, with the Gonstead technique. Her symptoms were nearly completely resolved after 5 months of care. The patient presented in this case report was also managed with the Gonstead technique. The technique is an established method of patient management and is highly used within the practice of hiropractic.  The management approach with respect to examination findings (ie, inspection, palpation, range of motion, spinography and x-ray marking, and Nervoscope instrumentation) and treatment approach (ie, adjustments with respect to patient position, doctor's stance, patient and doctor's contact point, line of drive, line of correction, and torque) are well described in the Gonstead reference text by Plaugher and Lopes.  The patient was treated during a total of 80 visits over a period of approximately 2 years. The main subluxation findings were at C7 PLS, T4 PRI-T, and L5 PL.
To delineate the possible role of chiropractic intervention in the treatment of patients suffering from a myriad of conditions, we will examine the effects of treatment from three possible perspectives with respect to patient improvement. One reason why a patient's condition may improve is due to the natural history of the disease or regression to the mean. That is, regardless of the treatment the patient may receive, the patient's problems resolve. Regression to the mean refers to the phenomenon in which the patient's symptoms are to the extreme on first examination and then return to their more natural or typical state, which are not so severe. According to Massey,  because of 22% of untreated patients achieving remission and another 18% experiencing marked improvement, it is difficult to sort out the effects of any therapeutic improvement on myasthenia gravis from the natural history of the disease. The role of the natural history of this disease is confounded by the patient's thymectomy some 6 years after being diagnosed with the disease if one is of the opinion that 6 years is not ample time to decide that the disease will not improve. In addition, approximately 30% of patients with myasthenia gravis will experience weakness in the respiratory muscles, and approximately 15% to 20% will experience myasthenia crisis. Myasthenia crisis is defined as respiratory failure requiring mechanical ventilation. 
A study by Durelli et al  examined the occurrence of remissions in 400 patients who had myasthenia gravis with thymectomy. These patients had an overall stable remission of 27%. Incidentally, Durelli et al  caution that, in the absence of a concurrent control group of nonthymectomized patients, no definitive conclusions about the effectiveness of thymectomy can be drawn from the study. The patient in this case report underwent a thymectomy approximately 22 years before presenting to the chiropractor. After the surgery the patient indicated some improvement in ambulation and breathing but still experienced symptoms of the disease. We can only assume that the patient's condition was not improving after he was diagnosed with the disease and, hence, the decision then to perform a thymectomy. With respect to the thymectomy, Durelli et al  found in their study groups that those patients without thymoma and not requiring additional immunosuppressive therapy had the highest stable remission rate occurring at 2 years after thymectomy. Those treated with immunosuppressive drugs had the highest stable remission rate 5 years after surgery. This patient reported stable remission some 22 years after the thymectomy. Is the patient's improvement to be credited to the thymectomy after 22 years? We do not believe this is the case. According to Massey,  “although the onset and extent of improvement are unpredictable with thymectomy, any weakness that is persistent for one year after thymectomy is unlikely to remit.” Arguably, one may say that time alone could account for the recovery of the patient described in this report. By the same token, one may also argue that if the passage of time was the significant clinical difference in this patient, then why did this patient's condition not improve at 3, 5, 10, or 15 years after diagnosis. Because this is a case report, it is not the purpose of this writing to prove but rather to illustrate a clinical scenario of a chiropractic patient with myasthenia gravis, the patient's possible response to chiropractic treatment (recovery), as well as a theoretical exposition of the mechanisms of the chiropractic intervention.
Another possibility for patient improvement may be due to the specific effects of the treatment applied. Myasthenia gravis is an autoimmune disorder. Chiropractors for the most part adhere to the principle of the “supremacy of the nervous system,” and theories exist with regard to the possible effects of the spinal adjustment on the immune system. [27–29] The neurodystrophic hypothesis  states that neural dysfunction (ie, subluxation) is stressful to visceral and other body structures, resulting in lowered body resistance to disease. This decreased resistance results in modified nonspecific and specific immune responses and alters the trophic function of the involved nerves. Chiropractic theories posit that through spinal adjustments, neural dysfunction may be alleviated or corrected, thereby promoting the body toward wellness in the biologic spectrum of health.
What are the anatomic and physiological evidence pointing to a neural-immune interaction? The discussion below provides a sampling to address the above question. Sympathetic noradrenergic innervation of lymphoid organs exists.  Postganglionic sympathetic axons arborize widely to organs of the immune system and in association with smooth muscle compartments, as well as in the parenchyma, give rise to various sites of release for target cells of the immune system. For example, noradrenergic nerve fibers have revealed extensive networks to the hemopoietic and lymphopoietic cells in the bone marrow. [31–33] The functional role of such innervation is provided by Maestroni et al,  in which syngeneic bone marrow transfer (after chemical sympathectomy) increased peripheral white blood cell count. In secondary lymphoid organs such as the spleen, studies have shown noradrenergic fibers distribute to T lymphocytes and within follicular B cell zones, as well as macrophage zones at the marginal sinus. [37, 37] This innervation is also observed in the cervical, mesenteric, and popliteal lymph nodes, as well as Peyer's patches. [37–39] Having established a neural connection, how then does autonomic stimulation influence immunologic reactivity? To address this question, let us examine the role of neuropeptides; in particular, the role of substance P, somatostatin and the effects of catecholamines. Substance P can induce interleukin-1, tumor necrosis factor, and interleukin-6 production by unstimulated human blood monocytes.  Substance P has been found to play a role in local and systemic host defense response to inflammation and injury. In vitro studies have demonstrated that both B- and T-cell activity can be influenced by substance P. [40, 41] Human T lymphocyte in vitro proliferation has been shown to be augmented by substance P. Polyclonal immunoglobulin A production in Peyer's patch and mesenteric lymph nodes in vitro is enhanced by substance P, whereas immunoglobulin M production was not as affected, and immunoglobulin G production was unchanged. [42–44] Substance P has also been found to act directly on B cells to induce changes in immunoglobulin secretion.  In vitro, somatostatin has been found to have inhibitory effects opposite those described for substance P. [44–47] Of interest is the suggestion that substance P and somatostatin may mediate isotype- and organ-specific regulation of B-cell differentiation in vitro. There is further suggestion that both may act in concert to regulate the neurophysiological response to influence tissue-specific synthesis of a particular cell isotype.
Adrenoreceptors exist on T and B lymphocytes, as well as on neutrophils and macrophages. [48–50] They are therefore targets for catecholamine signaling, particularly sympathetic nerve terminal release of norepinephrine. Experimental evidence exists that antibody responses, proliferation, and lytic activity could be reduced, increased, or modified by adrenoreceptor stimulation. Of particular interest are the findings that epinephrine may act directly on lymphocytes to alter antibody response. [50–52] The effect of catecholamines is not a simple up- or down-regulation of the immune response but may be dependent on the individual cells involved. Preliminary evidence exists that spinal manipulation may have demonstrable physiological effects suggestive of a neuroendocrine-immune function. [53, 54] A possible mechanism of the effects of spinal manipulation may work through somatovisceral reflexes. [55–57] That is, somatic afferent nerve stimulation via chiropractic adjustments may somehow regulate various visceral responses that are neurologically reflex in nature. This continues to be a controversy in our profession and has important implications to the scope and practice of chiropractic. The exact mechanisms remain to be fully elucidated. However, there is now additional evidence to suggest that somatovisceral reflexes may be a mediator. For example, studies in animals examining somatovisceral reflexes involving immune function exist. In anesthetized rats, pinching the hind paws increased splenic sympathetic efferent nerve activity. Sympathetic splenic efferent nerve activity can decrease the activity of natural killer cells.  Electrical stimulation of vagal afferents has been shown to increase the release of lymphocytes from the thymus. 
The third possible reason why a patient's condition may improve is due to nonspecific effects. For example, patient and doctor expectations of treatment efficacy and the quality of their interactions, the doctor's attention and interest in the patient's complaints, as well as the reputation, cost, and impressiveness in the treatment may contribute to the effectiveness in the management approach of the patient. These nonspecific factors are often referred to as “placebo effects.” Historically, the success of chiropractic care in the treatment of patients with various disorders and concomitant subluxation have often been dismissed by skeptics who attribute the success of treatment to “placebo effects.” Only in recent years have their importance and implications in the treatment of various disorders been appreciated. Especially when alternative therapies, much maligned and dismissed by skeptics in the past, are now more popular and in growing demand by health consumers.  Turner et al  reviewed articles pertaining to the placebo effects in English-language articles and books through Medline (1980–1993) and PsychLit (1963–1993) to estimate the importance and implications of placebo effects. It is beyond the scope of this writing to address all the issues involved. However, in brief, Turner et al  have found that placebo response rates vary and are much higher than the much-quoted one third. Placebo effects have characteristics similar to active medications such as time effect curves and peak, cumulative, and carryover effects. With respect to patient responses, they found that individuals are not consistent in their placebo responses. Anxiety, expectations, and learning are important factors to explain the placebo effect. Turner et al  emphasize that the patient's symptoms, illnesses, and their changes over time are a reflection of the complex interactions between the anatomic and neurophysiological processes of the individual, as well as cognitive-behavioral and environmental factors. Such interactions give rise to the burgeoning field of psychoneuroendoimmunology. [62, 63]
Today, much of the literature and clinical practice accepts and places much emphasis on the importance of the placebo effect.  Kienle et al  critically examined and questioned the role and existence of the placebo in clinical practice. The authors examined more than 800 works on the subject of the placebo. We encourage the reader to refer to the original article for details of the study. After their analysis they concluded that the widespread data in the literature on the magnitude and frequency of the placebo effect are largely exaggerated, if not altogether false. We bring up this study in the discussion not so much to refute the effects of the placebo but rather to echo the sentiments of the authors. The point is that one should not rule out the possibility that the patient's self-healing powers are influenced by a variety of nonpharmacologic or nonsurgical approaches and not dismiss other types of therapeutic procedures. In addition, they comment that to credit the success of such procedures merely to “placebo” is inappropriate and may indicate our ignorance and lack of understanding of such treatments. They emphasize that research and attempts at understanding are more appropriate and serve our patients better. We could not agree more.
In the management of myasthenia gravis, no standard measure of disease severity and no medical treatment approach has been proven efficacious by rigorous, prospective, controlled studies. The preponderance of evidence certainly links a “connection” between the immune system and the central nervous system beyond a reasonable doubt. The exact mechanisms involved and the role of chiropractic care and its putative effects largely remain unexplored. Although a specific myasthenia gravis osseous structure does not exist per se, chiropractic approaches to case management use signs (ie, biomechanical and postural assessment), palpatory findings, specific range of motion findings, x-ray studies, and symptoms (ie, pain) to determine the spinal level to be adjusted. Patient outcomes are also determined as above. If the patient's condition does not improve, then subluxation findings are reevaluated, and the patient's treatments are varied accordingly. Whether such a treatment process or approach brings about healing as a result of specific or nonspecific effects of the treatment or the treatment is merely “riding on the wave” of remission remains to be fully elucidated.
The exact mechanisms leading toward disease and the role of spinal adjusting continue to be some of the greatest challenges for our profession. We hope that this case study encourages further investigation into the holistic approach to patient management by chiropractors vis-à-vis specific adjustments of vertebral subluxation.