Autoimmune Diseases and Pelvic Neuropathic Pain

Connection between autoimmune disease, connective tissue diseases and pelvic neuropathic pain by vascular entrapment – a review of 128 consecutive patients treated at the Possover International Medical Center over the last two years.

This retrospective analysis investigates the relationship between autoimmune diseases, connective tissue diseases and pelvic neuropathies caused by vascular entrapment, a condition often misdiagnosed as "Chronic Pelvic Pain Syndrome of unknown origin".

Prof. Prof. DK Prof.hc (China) Dr Med. Marc Possover

Pelvic Neuropathic Pain by Vascular Entrapment - Part 1

Pelvic Neuropathic Pain by Vascular Entrapment - Part 2

SUMMARY

This retrospective analysis investigates

the relationship between autoimmune diseases, connective tissue diseases and pelvic neuropathies caused by vascular entrapment, a condition often misdiagnosed as "Chronic Pelvic Pain Syndrome of unknown origin". The study analyzed 128 female patients who underwent laparoscopic nerve decompression at the Possover International Medical Center. The average age of the patients was 42 years, with 33% having a history of autoimmune diseases, predominantly hypermobility spectrum disorder (HSD) and Ehlers-Danlos syndrome (EDS), which were present in 21.87% of cases. Intraoperative findings revealed vascular entrapment in all patients, with aberrant or enlarged blood vessels being the most common anomalies. Bilateral vascular entrapment was observed in 80% of the cases. These results suggest a significant association between autoimmune diseases and pelvic neuropathies due to vascular entrapment. The findings underscore the importance of a comprehensive patient history, particularly concerning autoimmune and hematologic conditions, in the accurate diagnosis and treatment of pelvic neuropathies. Rheumatologists should consider the possibility of vascular entrapment in patients with autoimmune diseases, especially those with EDS, who report neuropathic pelvic or sciatic pain that improves when lying down. This awareness could lead to more accurate diagnoses and improved patient outcomes in cases of intractable pelvic neuropathy.

INTRODUCTION

Pelvic neuropathies and sacral radiculopathies are conditions characterized by the compression or irritation of nerves in the pelvic and sacral regions, often resulting in significant mostly intractable neuropathic pain with possible other neurological symptoms. Such pains are almost always labeled in daily practice as "Chronic Pelvic Pain Syndrome of unknown origin”. A prominent cause of these neuropathies – and probably the most frequent - is vascular entrapment, where blood vessels compress or entrap nerves, leading to a range of debilitating clinical manifestations. This condition is well-known by neurosurgeons¹ but was first described in relation to pelvic neuropathies in 2011 ². Key nerves affected include the endopelvic portion of the pudendal nerve at the level of the less sciatic foramen, the sciatic nerve just before it entry through the greater sciatic foramen – which is by far the most frequent for of pelvic neuropathy by vascular entrapment, and the sacral plexus manifest as lower back pain, pudendal pain, sciatica, and bladder or bowel dysfunction ³. Vascular entrapment can occur due to various anatomical and physiological anomalies, including:

• Aberrant Blood Vessels: Anomalies in blood vessels, such as abnormal branching or positioning, can lead to nerve compression ⁴.
• Enlarged Vessels: Conditions like varicose veins or aneurysms can enlarge blood vessels, leading to entrapment ⁵.

Identifying these underlying vascular anomalies is crucial for understanding the pathophysiology of pelvic neuropathies and sacral radiculopathies and for guiding effective treatment strategies.

Since approximately 2008, we have been performing laparoscopic exploration of the pelvic nerves for the treatment of intractable pelvic neuropathies and radiculopathies by vascular entrapment. However, it was not until 2022 that we became aware, through our daily observations of affected patients, that a significant number of those with vascular entrapment also suffer from autoimmune diseases. This observation led us to hypothesize a potential cause-and-effect relationship between these two conditions. Consequently, starting in 2022, we systematically included inquiries about autoimmune diseases in our neuropelveological patient’s history. This study is the result of our observations and inquiries conducted with all our patients who presented with vascular entrapment and in who pelvic neuropathy/radiculopathy by vascular entrapment was also confirmed operatively. This study aims to identify common risk factors and anatomical characteristics associated with vascular entrapment, thereby contributing to the body of knowledge required for the development of targeted therapeutic interventions and improved patient outcomes.

AIM OF THE STUDY

In this study, we retrospectively analyzed all patient’s data from 02/2022 who have underwent laparoscopic exploration for non-neurogenic pelvic neuropathy or sacral radiculopathy by vascular entrapment. During laparoscopic exploration, a vascular entrapment was confirmed as the etiology in all patients in this series and was treated laparoscopically by nerve release. Infra- and supralevator sacral radiculopathies were treated by a single supralevator approach through the lumbosacral space. In this study, we also report on pudendal neuralgia caused by vascular entrapment. This is not about pudendal neuralgia below the pelvic floor (Alcock’s canal syndrome), but rather about intrapelvic pudendal neuralgia, where the nerve is entrapped by the pudendal vessels as it enters through the lesser sciatic foramen ⁶.

We examined retrospectively the medical histories of all patients to identify risk factors for pelvic neuropathy/radiculopathy by vascular entrapment with particular attention on hematologic risks and autonomic disorders. All participants voluntarily approached our center for diagnosis and treatment for pelvic neuropathy/radiculopathy and signed informed consent forms for surgery and publication of case details. The study was conducted following the Declaration of Helsinki. Due to the retrospective nature of the study, the need of obtaining approval was waived by our own institution.

RESULTS

We analyzed data from 128 consecutive female patients. The following key findings emerged from the analysis:

Demographics and Patient History

• The average age of the patients was 42 years, with a range from 20 to 83 years.
• Countries of origin are shown in figure 1.

Figure 1: Distribution of Patients by Country of Origin

• A significant proportion of patients (33%) had a history of autoimmune diseases (AID), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Hashimoto's thyroiditis (n=three), Marfan syndrome (n=three), and, most notably, Hypermobility Spectrum Disorder (HSD) and Ehlers-Danlos Syndrome (EDS), with both conditions present in 28 patients (21.87%) in this series (Figure 2).

Figure 2: Proportion of Patients with autoimmune disease and pelvic neuropathy by vascular entrapment. Marfan Syndrome (MS) - Ehlers-Danlos Syndrome (EDS)- Factor V Leiden Mutation (FVLM) - Hashimoto's Thyroiditis (HT) - Thalassemia (Th) - May-Thurner Syndrome (MTS) - Nutcracker Syndrome (NS)

This proportion of autoimmune diseases is likely much higher: the more the questioning is focused on identifying such autoimmune conditions—which are almost never spontaneously mentioned by the patients I the context of pelvic pain—the more autoimmune diseases are found. The aforementioned 21.87% of HSD/EDS is quite high, especially considering that HSD has an estimated prevalence of about 3%, and the estimated incidence for all types of EDS combined is approximately 1 in 5,000 to 1 in 20,000 people in the general population. These figures come from recent surveys and research, highlighting the occurrence of joint hypermobility with associated symptoms that do not meet the criteria for more specific conditions like hypermobile Ehlers-Danlos Syndrome (hEDS). The prevalence can vary depending on age and specific population groups, with higher rates seen among younger individuals. The vascular type of EDS (vEDS), which is more severe, is rarer, with an estimated incidence of about 1 in 50,000 to 1 in 200,000 people ⁷.

• Of the 128 patients, only 14 had no history of previous surgeries. All other patients had undergone multiple prior procedures—on average, three surgeries for endometriosis to treat pelvic neuropathy. Figure 3 provides a list of these previous surgeries.

Figure 3: List of previous surgeries for tentative of treatment for refractory pelvic neuropathy

• Five patients presented with a thalassemia and four with Factor V Leiden mutation
• Six patients presented with a May-Thurner-Syndrome, two with a Nutcracker Syndrome

Clinical Presentation (figure 4)

• The most common symptoms were vulva and perineal pain 82.8% followed by sciatic pain (70.3%) and perianal pain (69.5%). It was typical for all patients that these pains significantly increased during prolonged sitting and the first 2-3 days of menstrual bleeding but noticeably decreased at night or during the day when lying down, or in any other situation where blood pressure dropped.
• Other symptoms included bladder hypersensitivity (62.5%) with urgencies and pollakiuria, bladder hypo-/atonia in three patients and bowel dysfunction (constipation and outlet constipation) in almost all patients.
• Neuropelveological diagnoses were as following: Sacral Radiculopathy (SR) Left (n=31) - Bilateral SR (n=46) –– SR Right (n=33) – Pudendal Neuralgy (PN) left (n=seven) – PN right (n=6) – Bilateral P (n=three) – Other Nerves – ON/FN (n=two)
• Neurogenic vs non-neurogenic neuro/radiculopathy: Except for one patient, all radiculopathies/neuropathies caused by vascular entrapment were “non-neurogenic”.
• Uni-versus bilateral vascular entrapment: Even when pain was reported on one side, bilateral exploration and decompression were systematically performed if intraoperative vascular entrapment was confirmed. Bilateral vascular entrapment was confirmed in 103 patients (80%), even when the pain was unilateral.

Figure 4: Most common Symptoms and Diagnoses

Intraoperative Vascular Entrapment Findings

• Intraoperative findings confirmed vascular entrapment in all patients.
• The primary vascular anomalies observed were:
  • Aberrant blood vessels such as atypical superior gluteal vessels overlying the sciatic nerve in 60% of the patients
  • Enlarged vessels due to varicose veins or aneurysms (35%).
  • Vascular anomalies associated with pelvic vein thrombosis (5%).
  • Arteriovenous fistula in two patients.

In summary, autoimmune diseases and blood clotting disorders can cause or exacerbate vascular anomalies through mechanisms such as inflammation, immune complex deposition, and endothelial dysfunction and be responsible pelvic neuropathies by vascular entrapment. This connection underscores the importance of patient’s history focusing on autoimmune conditions in patients suffering from refractory pelvic neuropathies.

DISCUSSION

This study shows a clear connection between autoimmune diseases and vascular anomalies. Autoimmune diseases can affect blood vessels in various ways, leading to vascular anomalies. This relationship is often seen in conditions such as Vasculitis, Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) but also in

• Scleroderma: This condition causes hardening and tightening of the skin and connective tissues and can affect small blood vessels, leading to abnormalities such as Raynaud's phenomenon and digital ulcers.
• Behçet's Disease: A rare autoimmune disorder causing inflammation of blood vessels, leading to vascular complications like aneurysms and thrombosis.
• Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, can cause endothelial dysfunction, which is an early sign of vascular disease.

Further situations and conditions in a woman's life can lead to the development of a pelvic vein thrombosis (PVT) and must be part of patient’s history. These include Pregnancy and Postpartum Period, Oral Contraceptives and Hormone Replacement Therapy, Pelvic Surgery, Sedentary Lifestyle or Immobility, Obesity and certain Medical Conditions like cancer, or inflammatory diseases can elevate the risk of PVT.

This study also shows a connection between pelvic neuropathy by vascular entrapment and some genetic Predisposition such as:

• Thalassemia is a group of inherited blood disorders characterized by reduced hemoglobin production, leading to pulmonary hypertension, Deep vein thrombosis (DVT) or pulmonary embolism (PE).
• Factor V Leiden Mutation leads to resistance to activated protein C.
• Antithrombin III Deficiency: Antithrombin III inhibits thrombin and other clotting factors.
• Antiphospholipid Syndrome (APS): This autoimmune disorder causes the immune system to mistakenly attack normal proteins in the blood, leading to an increased risk of blood clots.
• Hyperhomocysteinemia: Elevated levels of homocysteine in the blood can damage blood vessels.
• Myeloproliferative Neoplasms (MPNs)
• Disseminated Intravascular Coagulation (DIC) is a complex condition characterized by widespread activation of the clotting cascade, leading to both clot formation and bleeding. It can occur in various clinical settings such as sepsis, trauma, and malignancies.
• Leukemias and Lymphomas can increase the risk of thrombosis due to hyperviscosity of blood, direct invasion of blood vessels by malignant cells, or as a paraneoplastic syndrome.
• Sickle Cell Disease causes red blood cells to become misshapen and sticky, which can block blood flow and increase the risk of thrombosis.
• Heparin-Induced Thrombocytopenia (HIT) is a reaction to heparin treatment that paradoxically increases the risk of thrombosis despite low platelet counts.

IMPLICATIONS IN CLINICAL NEUROPELVEOLOGY

The integration of clinical symptoms with a detailed examination of the face, eyes, and skin for vascular anomalies is essential in the neuropelveological diagnosis. By carefully observing these physical signs and corroborating them with patient reports, healthcare providers can more accurately diagnose and manage conditions involving hyperactivity of the sympathetic nervous system and associated vascular anomalies. This holistic approach ensures a thorough understanding of the patient's condition and paves the way for more effective treatment strategies. While patient history inquiries about family history of hematologic, vascular or connective tissue disorders, physical inspection includes meticulous examination of the patient with particular attention to any discoloration, swelling, visible blood vessels, face form and other skin changes.

Shape and Proportions of the Face

Recognizing vascular diseases by examining a patient's face involves looking for specific signs and symptoms that may indicate underlying vascular issues. When inspecting the face, several factors are taken into consideration, including the overall shape and the proportions of different facial features. Here's a breakdown of the key aspects:

• Ehlers-Danlos Syndrome (EDS): Some facial characteristics for EDS include soft, doughy skin, High-arched palate, narrow or thin nose, large eyes (prominent eyes), small or recessed chin and thin lips. The high proportion of patients with HSD/EDS suggests a potential correlation between autoimmune diseases and pelvic neuropathy/radiculopathy by vascular entrapment.
• Marfan Syndrome: Facial features often associated with Marfan syndrome include long, narrow face, high-arched palate, crowded teeth, downward-slanting eyes, receding or small jaw (micrognathia) and deep-set eyes.
• “Bird Face” is less commonly referenced in the literature, but it is often associated with facial features that can be observed in certain genetic or vascular conditions. It typically includes thin, elongated face, Downward-slanting eyes and prominent nasal bridge.
• Basedow’s disease combines a Goiter, Tremors, Muscles Weakness (hand shacking), Exophthalmos, Lid Retraction and Pretibial Myxedema.
• Loeys-Dietz Syndrome combines an hypertelorism, bifid uvula, cleft palate, craniosynostosis, downward-slanting eyes, small chin and thin, and translucent skin.
• Neurofibromatosis Type 1 (NF1). This genetic disorder causes tumors to form on nerve tissue, which can affect the vascular system. Facial features can include freckling in the armpits or groin area, lisch nodules (tiny bumps on the iris of the eye), café-au-lait spots (light brown skin patches) and neurofibromas (soft bumps on or under the skin).

Facial and skin signs

Some signs such Pallor or Cyanosis, Edema, Telangiectasias, ulcers or Sore, petechiae and purpura, jaundice and erythema might signal underlying cardiac or vascular issues and vasculitis.

• Motled Skin (Livedo Reticularis): A lacy or net-like pattern on the skin can be a sign of vasculitis or other vascular diseases.
• Rashes: Specific types of rashes, like the butterfly-shaped malar rash in systemic lupus erythematosus, can indicate underlying vascular or autoimmune conditions.
• Petechiae and Purpura: Small red or purple spots that do not blanch when pressed can suggest bleeding disorders, often associated with vascular conditions.
• Jaundice: Yellowing of the skin can point to liver issues, which may have vascular implications such as hepatic vein thrombosis.

Ocular Signs

• Red and dry eyes are in favor to a Sjögren’s Syndrome is an AID with slightly increased risk for vascular diseases and non-Hodgkin Lymphoma.
• Retinal Changes: Hemorrhages, cotton wool spots, or other changes observed during an eye exam can indicate vascular issues, such as hypertension or diabetes-related vascular complications.
• Yellowish Deposits: Xanthelasma, yellowish deposits around the eyes, can be indicative of high cholesterol and related vascular risks.

Clubbing (“Ongle en Lupe”) include bulbous enlargement of the distal phalanges and nails curve downward more than usual and sponginess of the nail beds. Clubbing is often associated with vascular conditions and chronic right atrial and ventricular overload leads to systemic venous congestion potentially responsible for pelvic varicosities.

CONCLUSION

The origin of the patients, who come from various places kin the world, as well as the number of unsuccessfully prior interventions in the patients included in this study, demonstrates the medical wandering these patients endure and highlights the significant diagnostic challenges in pelvic medicine. This underscores the necessity of a Neuropelveological diagnosis for patients suffering from unexplained pelvic pain combining genitoanal pain, sciatic pain, back pain and pelvic organs dysfunctions.

The results of this study highlight the complex interplay between autoimmune diseases and vascular anomalies leading to pelvic neuropathies/radiculopathies by vascular entrapment. The findings suggest that autoimmune-related vascular inflammation and thrombosis are significant contributors to nerve entrapment in the pelvic region. Therefore, a thorough evaluation of patient history, including autoimmune conditions and hematologic conditions, is crucial in the diagnosis and management of pelvic neuropathies and radiculopathies. A significant portion of autoimmune diseases can already be suspected based on the clinical observation of the patient upon entering the consultation room, even before any anamnesis and clinical examination.

The specific inquiry about the risk of thrombosis or vascular pathology must absolutely be part of the patient’s history in neuropelveology but also in urology and gynecology. This emphasize that in neuropelveology, an accurate diagnosis is essential to establish an appropriate therapeutic approach tailored to the situation of each patient. The accuracy of this diagnosis will directly influence the quality of therapeutic outcomes.

Every pain management specialist or pelvic pathology practitioner, when confronted with a patient suffering from any autoimmune disease, particularly Ehlers-Danlos syndrome, who presents with neuropathic pain in the pelvic region, genitoanal areas, or lower limbs, and if this pain notably improves or even disappears while lying down at night, should consider the possibility of pelvic neuropathy due to vascular compression.

REFERENCES

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Try to found out if your physician is trained in neuropelveology, and certified from the ISON and have already publish on this pathology /see: https://pubmed.ncbi.nlm.nih.gov/ and enter the name of your doctor to see his publications on this issue.