Category Archives: News

Wilkinson, A.J., Ege, E., Osborne, A., Driver, L., Chai, T.

 Abstract

The management of head, neck, and facial pain due to oncologic origin in patients is difficult and often undertreated. Many patients experience pain refractory to common treatment modalities, both non-interventional and interventional.^{1, 3} The sphenopalatine ganglion (SPG) is considered to be the autonomic hub of the skull, with association with the sensory nerve fibers of the maxillary nerve. Blockade of the SPG has been previously shown to be useful in headache syndromes and is considered safe and minimally invasive.¹ Yet, there is limited literature on the use of SPG blockade for head, neck, and facial pain due to oncologic origin.^{1, 2, 3} We present the successful use of sphenopalatine ganglion blockade for the treatment of refractory head, neck, and facial pain of oncologic origin.

Introduction

In highly prevalent head and neck cancer, pain is difficult to manage, with many patients failing conventional treatment with oral analgesics and adjuvant therapies.^{1, 3} Interventional techniques can be beneficial to treat such patients. The association of the sphenopalatine ganglion (SPG) with the maxillary nerve sensory fibers makes it an area of interest in treating pain in this population. The SPG blocks can be used to treat the pain of the hard and soft palate tonsils, nasal cavities, paranasal sinuses, oral gingiva, premaxillary soft tissue maxilla, and orbital floor.¹ We present the successful use of an SPG nerve block for the treatment of head and neck cancer pain due to a cervicomedullary-junction glioma. 

 Case Report

A 62-year-old male with an oncologic history of a cervicomedullary-junction glioma status post proton therapy presented to the clinic due to a severe, persistent headache, skull base/neck pain, and left-sided facial pain. (Figure 1) Multiple treatment modalities were attempted in this patient, including multi-modal pain therapies and opioids. The patient also failed to respond to other interventional treatments including occipital nerve blocks, cervical facet joint injections, onabotulinum-A toxin chemodenervation of the craniofacial muscles, ketamine infusions, and intrathecal trials with opioids and ziconotide. After the failure of these above treatments, he was deemed a candidate for a sphenopalatine ganglion blockade for refractory pain. 

He later underwent a left-sided sphenopalatine ganglion (SPG) block via a transnasal approach utilizing a catheter designed specifically for the procedure.⁴ He was placed in a supine position with his neck slightly extended. The tip of the catheter was advanced intranasally through the left nostril, superior to the middle nasal turbinate. 1.5 ml of 2% viscous lidocaine was injected, flowing toward the nasal mucosa overlying the SPG. Afterward, the patient’s position was held for five minutes. He reported substantial pain relief which was not felt with any of his other previously discussed treatment modalities. This relief lasted for several weeks, prompting the patient to undergo repeated, monthly SPG blocks. 

Discussion

The sphenopalatine ganglion (SPG) is considered the autonomic hub within the skull. The SPG is located within the pterygopalatine fossa, and numerous sympathetic and parasympathetic fibers synapse at or course through the ganglion.¹ The SPG blockade, considered safe and minimally invasive, can be performed via transnasal, infrazygomatic or transoral approaches.^{1, 5} Based on the highest level of evidence available, the SPG blockade is indicated for the treatment of cluster headaches, trigeminal neuralgia of the maxillary division, and migraine headaches. There is sparse evidence in the literature for the use of SPG blockage in the treatment of neoplasm-related head, neck, and facial pain.^{1, 2, 3} (Figure 2)

Conclusion

The management of head, neck, and facial pain continues to be an area of needed improvement in the treatment of oncologic patients. The sphenopalatine ganglion (SPG) blockade presented in this case report should be considered as a potential addition to the treatment modalities in this patient population.

Sources:

1. Pena I, Knoepfler ML, Irwin A, Zhu X, Kohan LR. Sphenopalatine Ganglion Blocks in the Management of Head and Neck Cancer-Related Pain: A Case Series. A A Pract. 2019 Dec 15;13(12):450-453. doi: 10.1213/XAA.0000000000001106. PMID: 31609721.
2. Sanghavi PR, Shah BC, Joshi GM. Home-based Application of Sphenopalatine Ganglion Block for Head and Neck Cancer Pain Management. Indian J Palliat Care. 2017 JulSep;23(3):282-286. DOI: 10.4103/IJPC.IJPC_39_17. PMID: 28827931; PMCID: PMC5545953.
3. Mirabile A, Airoldi M, Ripamonti C, Bolner A, Murphy B, Russi E, Numico G, Licitra L, Bossi P. Pain management in head and neck cancer patients undergoing chemoradiotherapy: Clinical practical recommendations. Crit Rev Oncol Hematol. 2016 Mar;99:100-6. DOI: 10.1016/j.critrevonc.2015.11.010. Epub 2015 Dec 3. PMID: 26712589.
4. Candido KD, Massey ST, Sauer R, Darabad RR, Knezevic NN. A novel revision to the classical transnasal topical sphenopalatine ganglion block for the treatment of headache and facial pain. Pain Physician. 2013 Nov-Dec;16(6):E769-78. PMID: 24284858.
5. Forrest, A., Cantos, A., & Butani, D. (2018). How we do it: Sphenopalatine ganglion blockade for migraine treatment. American Journal of Interventional Radiology, 2, 14. https://doi.org/10.25259/ajir-34-2018

Figures:

Figure 1: Magnetic resonance image of the cervical spine in sagittal view showing a T2 hyperintense expansile mass extending from the posterior caudal medulla to the C2-3 region (arrow).

Figure 2: Transnasal approach for the sphenopalatine ganglion blockade.

Wilkinson, AJ; Osborne, AT; Kovitz, CA., Chai, T; Huh BK

 Abstract

The performance of any neuraxial procedure carries an inherent risk of neurologic damage. Bleeding is of great concern in these procedures, as occult spinal epidural hematoma formation in these procedures carries the risk of causing significant neurologic deficits. While the development of spinal epidural hematomas in neuraxial interventions is estimated to be extremely low, the anatomy, medications, and other factors need to be carefully considered along with close adherence to established guidelines for patient safety are necessary to minimize the risk in every patient. We present an 84-year-old woman on secondary anticoagulation with aspirin who underwent a low-risk neuraxial procedure that presented one week later with significant neurologic impairment and pain due to a spinal epidural hematoma requiring emergency decompressive surgery for hematoma evacuation. 

 Introduction

Epidural hematoma after neuraxial pain interventions is rare, the earliest estimate of this complication suggested an incidence of 1:200,000 after a spinal block and 1:150,000 after an epidural block for all patients.¹ While risk factors, including the presence of anticoagulants, multiple punctures needed during the procedure, and anatomical variations in vertebral processes, have been demonstrated, case reports have described the formation of spinal epidural hematoma after neuraxial procedures without these traditional risk factors.² Yet, the complicated care of patients with oncologic processes that induce potential coagulopathy raises the need for further consideration of this complication when considering performing neuraxial procedures. We present the case of an 84-year-old female with an oncologic history of multiple myeloma who presented to the hospital one week after a lumbar spine pain procedure, found to have an epidural hematoma causing severe spinal stenosis necessitating emergency lumbar laminectomy for hematoma evacuation. 

Case Report

An 84-year-old female with a past medical history of multiple myeloma, on maintenance therapy, and a history of lumbar spondylosis, was admitted for severe low back pain and difficulty walking. At that time, she was noted to be on 81 mg of aspirin daily. On admission, she underwent a lumbar “nerve ablation” procedure by a local pain doctor the week prior.

Lumbar imaging by Magnetic Resonance Imaging (MRI) for workup demonstrated a dorsal epidural hematoma at L2, resulting in several central spinal canal stenosis. In the T1 sequence, there was an intrinsic hyperintensity estimated to be 10 mm in the AP dimension and 6 cm in the cranial-caudal dimension which contributed to the several spinal canal stenosis at L2 with constriction of the caudal equina. No cord signal abnormality was detected. Post-contrast imaging demonstrated minimal peripheral enhancement of the dorsal epidural collection. (Figures 1 and 2)

The patient then underwent an emergency evacuation of the epidural hematoma via L2-L4 laminectomy by the Neurosurgery service, without any complications. Postoperatively, she reported significant improvement in her pain and regained the ability to walk at baseline with her walker. 

Discussion

Any neuraxial procedure carries with it risks, which include vasovagal syncope, post-dural puncture headaches, infections, and bleeding (hematoma formation),⁴ among others. The incidence of any general neuraxial blockade (GNB) complication is estimated to be between 1/1000 and 1/1,000,000.⁵ These risks should be considered in every patient, especially in patients carrying the additional risk factors aforementioned in this report. 

Spinal epidural hematoma (SEH) resulting from neuraxial procedures is a rare complication seen in pain management. The estimated prevalence of SEH is 1:200,000 after a spinal block and 1:150,000 after an epidural block for all patients.¹ Notably, this estimation does not specify or account for particular risk factors, like coagulopathy, anatomical variations, or technical errors in performing the procedure. Thus, one can infer that a patient without any notable risk factors or any technical errors in performing the procedure would have a smaller risk of complications. This patient stated that she underwent a lumbar “nerve ablation” procedure; therefore, it is unclear what specific procedure was done; however, SEH after nerve ablation procedures appears to have been described in the literature.³

The American Society of Regional Anesthesia’s (ASRA) guidelines for avoiding neurological damage in neuraxial procedures identify the importance of proper imaging and documentation of patient-specific anatomy, avoidance of conditions that lead to increased bleeding, principally concurrent use of anticoagulants or imminent use of anticoagulants, use of proper sterile technique, avoidance of overdosing of local anesthetic during the procedure, and that the procedures be done in a setting capable of necessary resuscitation in the event of serious complications.⁶ Furthermore, ASRA outlines recommended durations of discontinuation necessary for all classes of anticoagulants and the recommended wait period before restarting of the medication after various neuraxial procedures. These recommendations require physician interpretation of the relative risk of bleeding involved in each procedure, as holding parameters for anticoagulants vary depending on this perceived risk. For this patient, a “high-risk” procedure would require six days of discontinuation of aspirin if for primary anticoagulation, but shared assessment if for secondary anticoagulation or any procedure less than “high-risk.” This further highlights the necessity of this report demonstrating the possibility of spinal epidural hematoma formation even in a lower-risk procedure and patient. All the risks should be considered for each patient, regardless of the level of risk of the procedure, the number of times the procedure has been performed on that patient, or their pharmacologic history. 

Conclusion

Preventing neurologic and hematologic complications in patients undergoing neuraxial procedures remains a top priority within the field of interventional pain management. Even in low-risk patients undergoing low-risk procedures, there is still a chance of potentially devastating complications such as the formation of a spinal epidural hematoma resulting in neurologic injury. This case demonstrates the need for a careful review of each patient’s history, anatomy, and risk factors combined with adherence to published guidelines and close follow-up to minimize the development of bleeding complications after neuraxial procedures.

Sources:

1. Chan L, Bailin MT. Spinal epidural hematoma following a central neuraxial blockade and subcutaneous enoxaparin: a case report. J Clin Anesth. 2004 Aug;16(5):382-5. doi:10.1016/j.jclinane.2004.05.001. PMID: 15374561.

2. Nam KH, Choi CH, Yang MS, Kang DW. Spinal epidural hematoma after pain control procedure. J Korean Neurosurg Soc. 2010 Sep;48(3):281-4. doi:10.3340/jkns.2010.48.3.281. Epub 2010 Sep 30. PMID: 21082060; PMCID: PMC2966734.

3. Kim SW, Chang MC. Epidural hematoma after caudal epidural pulsed radiofrequency stimulation: A case report. Medicine (Baltimore). 2018 Nov;97(45):e13090. DOI:10.1097/MD.0000000000013090. PMID: 30407313; PMCID: PMC6250492.

4. Alkhudari AM, Malk CS, Rahman A, Penmetcha T, Torres M. Epidural hematoma after routine epidural steroid injection. Surg Neurol Int. 2016 May 6;7:55. DOI: 10.4103/21527806.181906. PMID: 27213109; PMCID: PMC4866065.
5. Agarwal A, Kishore K. Complications and controversies of regional anaesthesia: a review. Indian J Anaesth. 2009 Oct;53(5):543-53. PMID: 20640104; PMCID: PMC2900086.
6. Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK, Heit JA, Mulroy MF, Rosenquist RW, Rowlingson J, Tryba M, Yuan CS. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus

Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003 May-Jun;28(3):172-97. DOI: 10.1053/rapm.2003.50046. PMID: 12772135.

Figure Legends:

Figure 1: MRI Lumbar Spine T1 Sequence, Sagittal Section. Annotated arrowheads demonstrating epidural hematoma.

Figure 2: MRI Lumbar Spine T2 Sequence, Sagittal section (left) and Transverse section (right). Arrows showing the location of the epidural hematoma in both views

Harry J. Gould, III MD, PhD

It has been more years than I care to admit since I graduated from medical school. As most of us have realized, with time, advances are made, with experience, skills are refined and as practitioners, we adapt to change and challenge and improve in our ability to care for patients. An unfortunate corollary to the essential fine-tuning of the evolving practitioner, especially in specialty and sub-specialty practices, is that many components of our general training are infrequently called to bear in daily practice, are less well remembered, and suffer from lack of reinforcement. I have recently been more aware of this disappointing realization both in my own practice when confronted with patients suffering with problems involving infectious disease, endocrinology, hematology, pulmonology, cardiology, and gynecology and from a different perspective, in observing the practices of colleagues who consult me for recommendations to help care for their patients in pain.  Some problems require complex solutions, but surprisingly, most can be addressed simply by returning to the basic principles learned in those early courses when we received so much “irrelevant material”.

My reason for addressing this topic is that I have noticed, more recently, probably over the last 2-3 years, that well over half of the consults directed to our in-patient consultation service for pain management have inquired as to what else can we recommend to control pain and/or whether an additional opioid medication should be added to the analgesic regimen to improve pain control for a patient. Virtually all of the presenting analgesic regimens in these cases, regardless the type of pain or pain history, include gabapentin < 300 mg daily, a muscle relaxant, and not atypically, orders for multiple formulations of mu-opioid analgesics, e.g., hydrocodone PO as needed for pain between 3-6/10 in intensity, oxycodone PO as needed for pain > 7/10 and hydromorphone IV scheduled every 3-4 hours.  The total daily morphine milligram equivalents (MME) ordered is, not infrequently, less than that in the patient’s routine outpatient regimen for chronic pain. It is possible that the initial ineffective treatment regimens have been designed in an attempt to comply with published guidelines designed to minimize opioid use, but it seems more likely that the failed attempts reflect a prevailing assumption that complex problems require complex solutions.  Obvious to a specialist, but not so to the physician with medical school a distant image in the rearview mirror of life, is that simple solutions within recommended guidelines are more often likely to produce favorable outcomes because they are less likely to introduce complications that lead to confounding results.

More efficient use of the dynamic interaction between referring physician and consultant may be the best way improve patient care because the best learning opportunities seem to occur when therapeutic approaches are introduced or reviewed in the context of administering in real-time to an interesting patient or a problem situation (“When I was a resident, I had a patient that…”) and take less time out of a busy practitioner’s day than a formal course for review.  A referral for consultation provides a platform for the specialist to offer a focused review of basics from their specialty that reinforce optimum therapeutic approaches for managing a given problem and a platform for the referring team to provide feedback to the specialist as to the rationale for either accepting or declining to implement a given recommendation.

In the offered example, a good place to start might be to determine and establish an analgesic treatment base before embarking on diagnostic tests or therapeutic treatments that are likely to produce additional pain. The process of determination would be comprised of an assessment of the type of pain that is being experienced, a determination of co-morbid problems and whether the patient has had or is currently receiving medications, especially opioids, for a previous acute or a chronic problem, for which medications had been used and if current, what dose is being taken. It also would seem reasonable to take advantage of prior history and to start with a medication that has been shown to be effective for the particular patient and to anticipate that any new pain may require MME dosing equal or greater than the premorbid regimen to achieve adequate pain control and to prevent the onset of withdrawal symptoms. The pharmacologic principles that simple, monotherapy regimens are easier to administer, have higher rates of compliance and are more effective are generally good principles to follow when designing a treatment regimen.  Mu-opioid agonists due to chemical configuration and available routes of administration have different benefit potential and different side effect profiles that provide the basis of therapeutic selection.  Unfortunately, analgesic benefits of mu-agonists are achieved through a single mechanism of action, regardless the formulation precluding a hoped for reduction of daily MME by providing treatment with multiple mu-opioid agonist at low doses. Furthermore, the simultaneous initiation of treatment with multiple formulations complicates the recognition of which agent(s) might be responsible for any benefits or adverse effects observed.  Because of incomplete cross-tolerance between mu-opioid agonists, the concurrent use of multiple formulations, also effectively eliminates or greatly reduces any possibility for drug rotation, if needed. Thus, selecting a single mu-agonist formulation, determining the route of administration and the proper dosing allows for early identification of tolerance and dosing efficacy. Finally, the use and selection of potentially beneficial adjuvant agents based on pain type and benefits that may be realized from their otherwise adverse, side effect profile, e.g., drowsiness in patients with difficulties sleeping, are important components of the analgesic regimen that are likely to produce benefit without undesired adverse effects if they are prescribed in adequate doses. 

In the midst of the exponential growth in technology and continued advances in the era of information explosion that often lead to overwhelming increases in system complexity, it may be comforting to remember that the old, simple, basic principles that we learned as fledgling healthcare providers are still useful and may be our best means for caring for our modern day patients in a rapidly expanding and changing world of pain medicine.

Lawrence Robbins, MD and Hanah Alley, MD

(originally published in Medicine Connections, 2021 vol.1, issue 2: a journal of the World Headache Society)

Abstract

Introduction: This was a small open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine (RCM) patients. It is probable that the immune system is involved in migraine.¹ Helminth worms have populated the GI tract of primates for millions of years. They downregulate the immune response. When the helminths (and other parasites) are removed, the result may be an increase in autoimmune illness. The immune system and inflammation are involved in migraine pathophysiology.

Study design:  Eleven RCM patients were enrolled. After the run-in period, patients ingested the helminth eggs every 2 weeks for 5 months.  These eggs were from the pig whipworm, T. suris. The primary endpoint involved the number of moderate or severe headache days per month. The first (run-in) month was compared to the last 2 months of active therapy. Secondary endpoints included disability, depression, anxiety, and quality of life.

Results:  5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 of the 5 patients who met the primary endpoint.

4 of 11 patients who completed the study did not meet the primary endpoint. 1 other patient did not supply data, and another discontinued treatment due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not improve.

Conclusion:  This study indicates that there may possibly be a role for helminth therapy in treating refractory chronic migraineurs. 5 of 11 patients did well. This treatment is rooted in evolution. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may possibly help in the treatment of conditions that involve the immune system, such as migraine.

Keywords:  Migraine, Refractory Migraine, Headache, Helminth,  Evolution, Chronic Migraine, long haul Covid worm eggs,

Introduction

The concept of migraine as an autoimmune entity has been discussed for many years.¹ Migraine is a common disabling neurological disorder. Despite available therapies, a subset of patients remains unresponsive to preventive treatment. Individuals with Refractory Chronic Migraine (RCM) have failed a number of the available preventatives, and suffer from frequent moderate or severe headaches^2,5. Individuals with Chronic Migraine (CM) are those with a headache occurring on 15 or more days/month for more than 3 months.  For at least 8 days/month their headaches are migrainous.^4,6  The pathophysiology of migraine is interwoven with the immune system, which is the reason for the current study^7,8.

Helminth worms have co-existed in primates for millions of years. Helminths, along with other parasites, downregulate the human immune response. In many human populations, the helminths have largely been eradicated. This resulted in an increase in autoimmune illness. 9,10,11,12,16,17,18.

There is a robust literature, dating back more than 20 years, introducing helminth eggs into the GI tract of those with various autoimmune illnesses. 

Helminth therapy has been extensively evaluated for its safety and efficacy in the context of autoimmune diseases^9,10,11,15. These include Inflammatory Bowel Disease (IBD)^9,10,12, Type 1 Diabetes Mellitus (T1DM) ^16,17 and Systemic Lupus Erythematosus (SLE)^12,13,18. Helminths elicit an immune response by promoting production of anti-inflammatory mediators^14,15,19,.  The result is to downregulate the host immune response to various antigens⁹ .

Helminths have lived in the GI tract of primates for millions of years.  Over time, a homeostasis was achieved between the parasites and the host immune system.  The host primate’s immune system has been downregulated in response to the helminths. It is easy and relatively safe to reintroduce helminth eggs into the GI tract.  This study was undertaken in order to assess the effect of introducing helminth eggs into the GI system of patients with refractory chronic migraine.

Materials/Methods:   

Study patients:  Eleven patients (10 women, 1 man) with the diagnosis of refractory chronic migraine were enrolled in the study. Refractory chronic migraine was defined according to the European federation consensus.² They were patients well known to the treating physician.  Ages ranged from 25 to 67. Patients’ names and information were de-identified.

Study Design: This was an open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine patients. The study included a one-month run-in prior to the actual treatment phase.  Patients then were to receive the helminth eggs every 2 weeks for 5 months.  There were 11 total doses of the eggs.  Patients kept daily track of the headache severity. They used a simple paper calendar.  A visual analog scale, 1 to 10, was utilized. A headache day was considered moderate to severe if the severity was rated 5 or greater. Mild days were listed but did not count for the purpose of this study. IRB approval was obtained. The IRB was through Advarra: PRO ID# 00051859, CR 00316902.  Possible risks were explained, and written consent was obtained.

The patients were allowed to remain on stable preventive medication/approaches. They were asked not to add new preventive medication or approaches. To our knowledge, none of the patient received new preventive medication during the study.

Safety of the Eggs: The eggs are from the whipworm, Trichuris suis. Safety of these eggs has been evaluated for 20+ years. There have been various studies, primarily regarding autoimmune illnesses.  Patients have also been able to order the eggs from the Tanawisa Company. Over 36,000 patients have ingested the eggs. There is a helminth therapy Facebook group.  The eggs have not produced adverse effects, except for occasional mild diarrhea¹⁴. There was one instance of eggs maturing into actual worms (which are benign). The company stated that it was unclear whether the eggs actually contributed to that one case.  We had multiple conversations with the Tanawisa Company regarding safety. The eggs are contained in a solution with 98% viable eggs. These attach to the mucosa surrounding the caecum. The eggs release molecules that induce regulatory T-cells by the human host. In theory, with a severely compromised GI mucosa, the eggs could attach and hatch, although this has not happened in the studies involving GI illness. We did not allow patients with GI mucosal illnesses to participate. The eggs “modulate” the immune system, but have not resulted in infections or immune deficiency issues. The eggs were donated by Tanawisa, the company that produces them. The company has extensive safety and efficacy information on Tanawisa.com.  The results of the studies, and extensive information on safety and risks, were given to all patients as part of the informed consent.  A number of these studies are listed in the reference section below. There has been no evidence that the egg exposure actually compromises the immune system, or leads to infection or immune based problems.

Patient visits and lab tests:  Patients were seen in person prior to the run-in month, after 1 month, after the 3^rd month, and after the 6^th month. Patients were given the egg solutions to ingest every 2 weeks, and the solutions were stored in their refrigerators. In addition, phone visits were done after the 2^nd, 4^th, and 5^th months. A physical exam was performed on the first visit, at the 3^rd visit, and after the final visit. An ECG was performed prior to the study. Blood tests (cbc, cmp, TSH, T4, sedimentation rate, ANA, and Hemoglobin A1c) were drawn 2 times: prior to month 1, and after month 3. All visits and blood tests were at no cost to the patient.  

Screening tests: These were done prior to the study, and after the last visit. The screens included the Beck Depression Inventory, the Beck Anxiety Inventory, Migraine Disability Assessment Test (MIDAS), and the Health Related Quality of Life Measure (number of unhealthy days per month).

Beck Depression Inventory:  1 to 10=none, 11 to 16=mild mood disturbance, 17 to 20= borderline clinical depression, 21-30=moderate depression, 31 to 40= severe depression, 40 or more=extreme depression.

Beck Anxiety Inventory:  0 to 7=none or minimal, 8 to 15=mild, 16 to 25= moderate, 26 to 63=severe.

MIDAS:  0 to 5=little or no disability, 6 to 10= mild, 11 to 20=moderate, 21 or more=severe.

HRQOL:  # of unhealthy days per month: maximum number= 30 days per month

Refractory Chronic Migraine Severity Scale: This scale was developed by Lawrence Robbins, and separates patients into mild, moderate, and refractory chronic migraine. Ten criteria are used in the scale. (5)

Inclusion Criteria: Patients known to the Robbins Headache Clinic, 18 to 70 years old.  Each patient had a well-established diagnosis of chronic migraine, according to ICHD-3 criteria (4). Every patient had the diagnosis of refractory chronic migraine (RCM)(2). The patients were graded as to the severity of the RCM (5).

Exclusion Criteria:  1. Patients with IBS-D or other gastrointestinal conditions that would result in diarrhea. Patients with a compromised GI mucosa due to a GI illness were excluded, 2. Severe psychiatric or medical illness which, in the judgment of the PI, might endanger the patient, 3. Use of probiotics during the course of the trial, 4. Inability to adequately track the headaches and side effects, Any other condition that would interfere with the ability of the patient to successfully complete the study, and 6. Pregnancy: See pregnancy section below.

Medication Use: Patients were allowed to continue on their usual medications. If possible, patients were encouraged not to change the dosage of their preventive medications. They were also asked not to start new preventive medications. If necessary, medications changes were allowed. If patients needed to take an antibiotic that opposed the action of the egg solution, they would be discontinued from the study.

No patients changed preventives during the trial. The doses of their pre-existing preventives were kept steady throughout the trial.

Pregnancy:  There is not enough evidence to state that the eggs are safe for use during pregnancy. If pregnancy was being considered, the patient was excluded from entering the study. For those women where pregnancy was not being considered, but was possible, adequate birth control methods were to be employed. To our knowledge no patient became pregnant during the trial.

Safety Monitoring and Adverse Events/Adverse Effects:  Dr. Robbins or the study coordinator conducted monthly discussions with each patient about adverse events and adverse effects.  Patients were encouraged to report any new effects, particularly GI adverse effects.

Primary endpoint: The number of moderate or severe headache days during months 5 and 6 (average of the 2 months), as compared to the number of moderate or severe headache days during the run-in period (first 30days).   Success is a decrease in monthly moderate or severe headache days by 3 or more days per month. Moderate or severe was a 5 or greater on the 1 to 10 severity scale.   

Secondary endpoints: 1. Disability assessment before and after the study (MIDAS), 2. Evaluation of depression before and after the study (Beck Depression Inventory),  3. Comparison of anxiety after the study versus during the run-in phase (Beck Anxiety Inventory) and 4. Evaluation of a quality of life assessment before and after the study (Health-Related Quality of Life Scale, as measured by the number of unhealthy days per month).

Results

Patient #1: 42 y.o. F with moderate refractory chronic migraine (RCM).

Pre-study month (run-in) # of moderate or severe headache days: 30

Month #1 (active study): 30 moderate to severe days

Month #2: 24 days

Month #3: 24 days

Month #4: 22 days

Month #5: 22 days

Midas (disability): pre-study=51, post-study=30

Beck Depression: pre-study=0, post-study=1

Beck Anxiety: pre-study=6, post-study=3

QOL: pre-study # of unhealthy days per month=30, post-study (the last month)=26

Summary: The # of moderate or severe headache days did decrease from 30 to 22 (average of the last 2 months). Disability remained high but improved. Depression was low (pre and post) and anxiety, which was mild pre-study, did lessen.

Patient #2: 39 y.o. F with mild RCM.

Pre-study month (run-in): 20 moderate or severe headache days(and 6 mild days)

1^st  (active) month: moderate to severe days: 13

2nd month: 15

3^rd month: 12

4^th month: 8

5^th month: 6

Midas: pre-study= 18, post-study=9

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=5, post-study=3

QOL: pre-study= 0, unhealthy days, post-study= 0

Summary: The # of moderate or severe headache days decreased from 20 pre-study to 7 (average of the last 2 months). Midas disability improved. Depression was low and anxiety, which was low, did improve.

Patient #3  36 y.o. F with moderate RCM.

Pre-study month (run-in): 9 moderate to severe headache days(and 11 mild days)

1^st month (active): 7 moderate to severe days

2^nd month: 3

3^rd month: 2

4^th month: 2

5^th month: 2

Midas: pre-study=15, post-study=8

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=3, post-study=0

QOL: pre-study=7 unhealthy days, post-study= 0

Summary: The # of moderate to severe headache days decreased from 9 pre-study to 2 (average of the last 2 months).  Midas disability improved. There was no depression, and anxiety, which was low, did improve. The # of unhealthy days dropped significantly.

Patient #4   68 y.o. F with moderate RCM.

Pre-study month (run-in): 15 moderate to severe headache days(and 7 mild days)

1^st month (active): 11 moderate to severe days

2^nd month: 5

3^rd month: 5

4^th month: 5

5^th month: 2

Midas: pre-study=42, post-study=30

Beck depression: pre-study=7, post-study=8

Beck anxiety: pre-study=12, post-study=8

QOL: pre-study=4 unhealthy days, post-study=4

Summary: The # of moderate to severe headache days decreased from 15 pre-study to 3.5 (average of the last 2 months).  Midas disability improved. Depression did not change, and anxiety improved.  The # of unhealthy days remained the same.

Patient #5 65 y.o F with severe RCM.

Pre-study (run-in): 8 moderate to severe headache days(and 12 mild days)

1^st month (active): 9 moderate to severe days

2^nd month: 4

3^rd month: 5

4^th month: 5

5^th month: not recorded

Midas: pre-study= 131, post=100

Beck depression: pre-study=4, post=6

Beck anxiety: pre-study=23, post=5

QOL: pre-study=30 unhealthy days, post=30

Summary: The # of moderate to severe headache days decreased from 8 pre-study to 5 (4^th month). Midas disability improved. Depression was slightly worse from pre-study to month 4. Anxiety improved significantly. The # of unhealthy days remained the same.

Patient #6  55 y.o. with moderate RCM.

Pre-study (run-in): 30 moderate to severe headache days

1^st month (active): 28 moderate to severe days

2^nd month: 30

3^rd month: 30

4^th month: 26

5^th month: 29

Midas: pre-study=25, post=12

Beck depression: pre-study=3, post=3

Beck anxiety: pre-study=10, post=10

QOL: pre-study=10 unhealthy days, post=6

Summary: the # of moderate to severe headache days decreased from 30 pre-study to 27.5 (average of 4^th and 5^th month). Midas disability improved.  Depression was low, and did not change. Anxiety remained unchanged. The # of unhealthy days improved.

Patient #7  24 y.o. M with severe RCM

Pre-study (run-in): 30 moderate to severe days

1^st month (active) and months 2 thru 5: 30 moderate to severe days each month

Midas: pre-study=210  (post-study not done)

Beck depression: pre-study= 27  (post-study not done)

Beck anxiety pre-study= 22   (post-study not done)

QOL: pre-study=27 unhealthy days  (post-study not done)

Summary: the # of moderate to severe headache days did not change (30 days per month). This patient did not complete post-study surveys. Pre-study his Midas revealed high disability. Depression and anxiety were significant.

Patient #8: 64 y.o. F with severe RCM.

Pre-study (run-in): 19 moderate to severe headache days(and 6 mild days)

1^st month (active study): 22 moderate to severe days

2^nd month: 20 moderate to severe days

3^rd month: 17

4^th month: 22

5^th month: 20

Midas disability: pre-study=23, post=26  (post-study not done)

Beck depression: pre-study=26  (post not done)

Beck anxiety: pre-study=21  (post not done)

QO: pre-study=30 unhealthy days  (post not done)

Summary: The # of moderate to severe headache days increased slightly by the 5^th month. Disability, depression, and anxiety levels were high (post-study surveys were not done). Pre-study every day of the month was an unhealthy day.

Patient #9:  34 y.o. F with severe RCM

Pre-study (run-in): 21 moderate to severe headache days(and 9 mild days)

1^st month (active study): 21 moderate to severe days

2^nd month: 19

3^rd month: 22

4^th month: 23

5^th month: 23

Midas disability: pre-study=42, post-study=30

Beck depression: pre-study= 0, post=0

Beck anxiety: pre-study=3, post=2

QOL: pre-study=24 unhealthy days, post=23

Summary: the # of moderate to severe headache days were slightly increased by the 5^th month. Disability improved somewhat. There was no depression, and mild anxiety was unchanged.  The # of unhealthy days was essentially unchanged.

Patient #10:  62 y.o F  Severe RCM.

Pre-study:  moderate or severe headache days: 30

This patient did ingest the eggs but no headache data was captured.

Patient #11: 39 y.o. F  Moderate RCM.

Pre-study: moderate to severe headache days: 30. This patient ingested only one dose of the eggs. She subsequently had GI upset and mild diarrhea. She discontinued the therapy. Over the ensuing 4 months, the GI upset and diarrhea improved but did not resolve. GI work-up was pending. The headaches remained unchanged.

Lab tests/ECG:  blood tests were drawn prior to the study, and after the 3^rd month. There were no abnormal tests that resulted from the treatment. ECGs did not reveal significant abnormalities.

Summary of Results

5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 patients and remained the same in 3 patients.

4 of 11 patients did not meet the primary endpoint. 1 patient did not supply data, and another discontinued due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not have a successful trial.

Discussion

Eleven patients with refractory chronic migraine were enrolled. Five patients met the primary endpoint.  The 5 patients experienced a decrease in moderate to severe headache days per month of 14 days, 10 days, 8 days, 7 days, and 3 days. Four of the remaining patients finished the study but did not incur any benefit.  One patient did not provide data, and another discontinued the eggs due to diarrhea.  That was the only adverse effect observed in the trial.

The 5 patients who experienced a decrease in the number of moderate to severe headaches also observed a significant lessening of disability. All of these 5 patients had low baseline depression scores.

This was a small open label study that included patients with refractory chronic migraine. They ingested helminth eggs for 5 months. The purpose of the eggs was to downregulate the immune response. Helminths may modulate the immune system via release of excretory/secretory proteins. The cell mediated inflammation may be modulated by the helminth eggs. While the helminth eggs modulate immune activity, there has been no evidence for harm. Tdhe concept of migraine as an autoimmune illness, or at least involving the immune system, has been debated and discussed for decades.¹ This study is rooted in evolution. For millions of years the GI tract of primates (and other animals) has been colonized by various worms or other parasites.  It has only been recently, in the past hundred years, that helminths and other parasites have been eradicated from human GI tracts.  This has been accomplished through improved sanitation as well as the introduction of clean water and food.

The role of helminth therapy has been discussed in the introduction section (above).  The studies have involved introducing helminth eggs into patients suffering from various autoimmune illnesses.  

There have been 12 helminth therapy studies conducted for various autoimmune diseases^9,10,11,15.  The use of helminthes for various autoimmune disorders has met with reasonable success, with minimal adverse effects. The study on Inflammatory Bowel Disease (IBD)^9,10,12 revealed that this may be a viable therapy, and that the eggs appear to be safe.  A study on Type 1 Diabetes Mellitus (T1DM) ^16,17 also indicated that the eggs are safe for human consumption. This was also confirmed in a study involving the eggs and Systemic Lupus Erythematosus (SLE)^12,13,18.  

Conclusion: This small study indicates that there may be a role for helminth therapy in the treatment of refractory chronic migraineurs. This approach is rooted in evolution. We ignore evolution at our peril. For millions of years helminths and other parasites have populated the GI tract of animals. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may aid in the treatment of migraine headache.  A randomized, placebo-controlled trial would be welcome.

Acknowledgments

Diana Delatre was the study coordinator. The Tanawisa Company donated the eggs for the study. Other than donating the eggs, the company did not play a role in the study.  

Conflicts of interest: none

NOTE: This therapy could be helpful for long haul Covid symptoms, if studies revealed sufficient efficacy…

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