Critical illness & sedation | Panorama of Emergency Medicine

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Mohammed Al-Amri, Kamal Majed, Deena Kodakatill, Guru T. Arun, Mohamed M. Baumy, Adel N. Al-Hariri, Aftab Azad (Author)

Elderly patient with late diagnosed metastatic bone lytic lesions

Low back pain is a frequent reason for emergency department visits, pain management and screening for red flags should be considered for every patient, especially in elderly even with reassuring physical exam. In this case report, we discuss a case of an elderly patient who visited the emergency department many times with low back pain. His physical exam was reassuring. A low suspicion threshold, and a prompt history taking were the keys for diagnosis of bone-destroying lesions with multiple fractures and metastases. The patient had history of liver cirrhosis post hepatitis B, Alpha foetoprotein was high and he was diagnosed with metastatic hepatocarcinoma with extensive bone metastasis. Persistent pain, especially in older adults with progressive back pain, should be thoroughly investigated for serious conditions like bone metastases. Remember the "red flags" for lower back pain and note that physical exams may appear normal even with advanced bone issues.

Introduction

Acute back pain is one of the main reasons for emergency department (ED) presentations, and constitutes 4.4% of emergency department applications worldwide [1]. Advanced age places the patient at higher risk and requires further investigation [4]. Malignancies and related metastatic bone lesions form a small part of people who present to the emergency department with low back pain [4]. However, it should not be forgotten in elderly people with low back pain [3]. Emergency physicians should utilize red flag screening methods to detect those with serious diseases and, thus, patients who need to be investigated [2,3]. History of malignancy and cancer risk factors are considered among the serious red flags, since bone tissue appears as a frequent region in terms of metastasis. The presence of bone metastases is an indicator of poor prognosis in cancer patients. Prostate and breast cancers frequently metastasize to the skeletal system. Bone metastases occur much more often than primary bone cancers, especially in adults. The overall incidence of bone metastasis is unknown. The presence of bone metastases may cause severe pain as well as pathological fractures, limitation of mobility, bone marrow aplasia, compression of the spinal cord, and hypercalcemia [5].
In this case report, we present a patient with extensive bony lytic lesions who were mobile despite having many pathological fractures and metastatic lesions that caused almost complete disappearance of one-half of the pelvis. The institution's approval was obtained from Medical Research Center (CIRC-RDB-43-12-2022), and written informed consent was obtained from the patient. The paper was presented at the World Academic Congress of Emergency Medicine in Antalya, Türkiye, from October 28 to 31, 2023.

Case Presentation

A sixty-seven-year-old male presented to the emergency department with a complaint of lower back pain for 4 months. There was no history of trauma. The pain was on and off, radiating to his right hip and gluteal region, worsening for the last two weeks, and associated with walking difficulty for the last ten days. Within this period, the patient was seen multiple times in primary health care services and at the ED. Detailed neurological examination was reported as normal. Non-steroidal anti-inflammatory drugs were prescribed at various times at the health center and ED, but the patient's complaints gradually increased, although there was no reduction in his pain during these four months. He had a past medical history of hypertension, chronic gastritis, and liver cirrhosis post hepatitis B, with no regular follow-up for the last three years. During the last ED visit, the patient’s vitals were stable. On physical assessment, motor and sensory examination results were normal. There was tenderness in the right gluteal region and the lower back. At the same time, it was seen that the anal sphincter tone was normal. There was no saddle anesthesia or signs of dropping foot. The X-ray of the pelvis and thoracic spine showed a compression fracture of thoracic (T) 9 vertebra, absence of right pedicle of lumbar (L) 4 vertebra, destruction of bilateral pubic rami and ischial tuberosity, a large pelvic bone lytic lesion accompanied by a secondary pathological fracture, as well as a large soft tissue component eroding the adjacent part of the sacrum (Figure 1).

Thoracolumbar spine and pelvis computed tomography (CT) performed and showed multiple lytic lesions in the thoracic and lumbar spine involving both vertebral bodies and posterior elements of the spine. Bilateral pelvic bones multifocal lytic lesions with pathological fractures are seen (Figure 2).

Magnetic resonance imaging (MRI) of the spine showed multiple expansile osteolytic lesions along the axial skeleton, including the thoracic and lumbar vertebrae, ribs, and pelvic bones. A large expansile lesion involving the posterior neural element of the (T3) vertebra with intraspinal epidural soft tissue component compressing the posterior aspect of the upper thoracic cord was noted. Another expansile lesion, as seen in the (T6) and (T7) vertebra with a large soft tissue component totally occluding the neural canal, was noted (Figure 3).

The patient was admitted to the neurosurgery department for pain management and further workup. Alpha fetal protein (AFP) level was 12,244 IU/ml (AFP normal level 0-6 IU/ml). Pan CT showed extensive bony lesions with soft tissue components through the cervical spine, cirrhotic liver with portal hypertension, and extensive portosystemic collateral formation, metastases involving the liver and the lung parenchyma. The most likely diagnosis was hepatocellular carcinoma with metastases. The case was discussed in the oncology team meeting, and a decision for palliative radiotherapy was made considering the patient’s status and the cancer stage. The patient was discharged after one week, and a rapid appointment with the radiotherapy clinic was arranged.

Discussion

In this case report, we presented a patient who came to the emergency department with back pain and had metastatic bone lesions with failure to diagnose early, even after multiple visits to the hospital. It was quite surprising that the patient had osteolytic lesions, causing severe destruction, and yet, was mobile. We have not encountered a patient presentation with such advanced lesions and are still mobile in the literature. We tried to emphasize that advanced age is a red flag for low back pain. In addition, it should be kept in mind that the neurologic examination may be normal despite advanced vertebral lesions. Back pain is one of the common reasons for emergency presentation; it is a condition that seriously affects people's daily activities and comfort [1]. Our patient visited health care facilities frequently despite taking his analgesics properly. During the last days preceding the last visit, he had walking difficulties affecting his daily routine. Low back pain is often defined as nonspecific or mechanical low back pain and constitutes 90% of the cases. Usually, the condition is self-limited and resolves within 4 to 6 weeks [3]. Rarely, patients may have serious pathologies, and critical diagnoses are often missed at the first presentation because of cognitive errors, lack of knowledge, and overlooked signs and symptoms [3]. Considering the frequency of patients presenting with back pain, it is necessary to comprehensively evaluate patients with lumbar complaints to keep patients with overlooked serious pathology to a minimum. The alarming signs should be figured out, and a detailed systemic investigation and examination should be carried out. Failure to notice these symptoms promptly can lead to a poor patient outcome. Getting a comprehensive history is particularly important in this stage. Our patient had history of liver cirrhosis post hepatitis B with no follow up for three years. This detail in history should alert the treating physician to consider further investigation considering the well-known risk of hepatocarcinoma in cirrhotic patients [6]. A complete physical examination following this will guide clinicians in recognizing the danger signs [7]. For this purpose, red flag scanning methods have been developed. While taking the history, age, history of surgery, trauma, immunosuppression, intravenous drug use, and sexual dysfunction should be questioned. In addition, the patient should be asked about any history of fever, anticoagulant use, urinary retention, epidural injection, decrease in anal sphincter tone, lower extremity motor weakness, and saddle anesthesia [8]. Serious pathologies can be revealed from the patient's history or by identifying abnormal musculoskeletal systems and abnormal neurological examination findings. In general, progression, change in character, or persistence of symptoms are alarming and may indicate serious pathology [8]. The presence of acute back pain in patients under the age of 18 or over the age of 50 should be a cause of concern. In young patients, congenital defects, spondylolysis, or vertebral fractures may be the cause of low back pain [9]. In patients over 50 years of age, new-onset back pain may be associated with intra-abdominal processes such as tumor, infection, abdominal aortic aneurysm, pancreatitis, or kidney stone. Osteoporosis accelerates with age progression. The decrease in the strength of bone tissue with osteoporosis may cause fractures in the bone tissue without trauma or with minor traumas. These fractures can be in the whole bone tissue as well as in the vertebrae. Therefore, vertebral fractures should be investigated in elderly patients presenting with acute onset low back pain. In addition, malignancy and metastatic bone lesions can be seen in both adolescents and the elderly, the presence of night pain and weight loss together with back pain requires investigation for malignancy [10]. Bone metastases are much more common than primary bone cancers, especially in adults [5]. Once cancer has spread to the bones, it is rarely curable, but treatments are used to slow the progression of the disease. Bone metastases may be osteolytic, osteoblastic, or mixed [5].
Our patient had extensive osteolytic lesions, interestingly, his physical exam was reassuring and did not identify any neurological compromise. However, he had walking difficulties but was still ambulating with walking aid despite the extensive pelvic lesions with pathological fracture. This could be explained by the fact that body movement is multifactorial and does not depend only on bone integrity. Interactions between bones, muscles and joints play a major role in maintaining movements including the capacity of walking [11]. Osteolytic metastases are characterized by osteoclast-mediated destruction of normal bones. The main malignancies in which osteolytic metastases are seen are multiple myeloma, renal cell carcinoma, melanoma, non-small cell lung cancer, non-Hodgkin lymphoma, thyroid cancer, and Langerhans cell histiocytosis [12]. Osteoblastic metastases are characterized by new bone deposition. The main malignancies are prostate cancer, carcinoid, small cell lung cancer, Hodgkin lymphoma, or medulloblastoma [13]. Mixed metastases are malignancies in which both osteolytic and osteoblastic lesions are seen. The main causes are breast cancer, gastrointestinal cancer, and squamous cancers [14]. Bone metastasis in hepatocarcinoma are predominately osteolytic like in our case report, however osteoblastic or mixed lesions are possible [15]. Uncomplicated acute lower back pain and/or radiculopathy of less than six weeks is considered a self-limiting and benign low back pain and does not require any imaging studies. However, further investigation should be carried out to determine if malignancy or infection is suspected clinically by red flags or pathological markers. In the presence of severe, progressive neurological deficits, diagnostic imaging, and laboratory tests are recommended to guide treatment. Although the systemic examination is completely normal, initial investigation efforts should begin with X-ray, metastases and malignant tumors come to mind, especially if bone lesions are seen in advanced ages. For this reason, the age of patients with suspected bone tumors or metastasis at the time of presentation is of great importance [16]. For elderly patients with persistent back pain and advanced bone lesions, a comprehensive treatment plan is essential. Medications such as bone-building drugs (e.g., bisphosphonates), pain medications, steroids, hormone therapy, and chemotherapy play a crucial role in managing symptoms and reducing pain [6]. Radiation therapy, including intravenous radiation for multiple bone metastases and external beam radiation for localized pain relief, is also recommended [14]. Surgical interventions, such as curettage and bone grafting for benign lesions, marginal resection or wide resection for aggressive lesions, and minimally invasive spine stabilization for spinal involvement, are important treatment options [8]. Palliative care techniques, like percutaneous cryoablation and embolization, help manage pain and improve quality of life [14]. Early diagnosis through imaging techniques like X-rays, CT scans, and MRIs, along with a multidisciplinary approach and patient education, is vital for effective management and improved prognosis [16].

Conclusion

This case highlights the need for thorough evaluation in elderly patients with persistent back pain, especially when standard treatments fail. Despite extensive bone lesions and fractures, the patient's mobility was preserved, stressing the importance of considering malignancy, even with a reassuring physical exam. Physical exams can appear normal despite advanced lesions, hence a low threshold of suspicion for serious conditions like bone metastases should be maintained especially in elderly patients. Comprehensive diagnostic workups, starting with X-rays and progressing to CT scans, MRIs, and lab tests, are crucial for early detection and management, enhancing symptom control and overall prognosis.

Declarations
Author contributions
All authors contributed equally and validated the final version of record.

Conflicts Of Interest
The Author(s) declare(s) that there is no conflict of interest.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration
No registration applicable

Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval
The institution’s approval was obtained from Medical Research Center (CIRC-RDB-43-12-2022), and written informed consent was obtained from the patient.

References

1. Coombs DM, Machado GC, Richards B, Wilson R, Chan J, Storey H, et al. Healthcare costs due to low back pain in the emergency department and inpatient setting in Sydney, Australia. Lancet Reg Health West Pac. 2021 Jan 29;7:100089. https://doi.org/10.1016/j.lanwpc.2020.100089

2. Traeger A, Buchbinder R, Harris I, Maher C. Diagnosis and management of low-back pain in primary care. CMAJ. 2017 Nov 13;189(45):E1386–E1395. https://doi.org/10.1503/cmaj.170527

3. DePalma MG. Red flags of low back pain. JAAPA. 2020 Aug;33(8):8–11. https://doi.org/10.1097/01.jaa.0000684112.91641.4c

4. Saes-Silva E, Vieira YP, Saes MO, Meucci RD, Aikawa P, Cousin E, et al. Epidemiology of chronic back pain among adults and elderly from Southern Brazil: a cross-sectional study. Braz J Phys Ther. 2021 May-Jun;25(3):344–351. https://doi.org/10.1016/j.bjpt.2020.12.005

5. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone Metastases: An Overview. Oncol Rev. 2017 May 9;11(1):321. https://doi.org/10.4081/oncol.2017.321

6. Shiffman ML. Approach to the patient with chronic hepatitis B and decompensated cirrhosis. Liver Int. 2020;40(Suppl. 1):22–26. https://doi.org/10.1111/liv.14359

7. Oliveira CB, Maher CG, Pinto RZ, Traeger AC, Lin CC, Chenot JF, et al. Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview. Eur Spine J. 2018 Nov;27(11):2791–2803. https://doi.org/10.1007/s00586-018-5673-2

8. Verhagen AP, Downie A, Popal N, Maher C, Koes BW. Red flags presented in current low back pain guidelines: a review. Eur Spine J. 2016 Sep;25(9):2788–802. https://doi.org/10.1007/s00586-016-4684-0

9. Casazza BA. Diagnosis and treatment of acute low back pain. Am Fam Physician. 2012 Feb 15;85(4):343–50.

10. O'Sullivan P, Smith A, Beales D, Straker L. Understanding Adolescent Low Back Pain from a Multidimensional Perspective: Implications for Management. J Orthop Sports Phys Ther. 2017 Oct;47(10):741–751. https://doi.org/10.2519/jospt.2017.7376

11. Lu TW, Chang CF. Biomechanics of human movement and its clinical applications. Kaohsiung J Med Sci. 2012 Feb 1;28(2S):S13–25. https://doi.org/10.1016/j.kjms.2011.08.004

12. Della-Giustina D. Evaluation and treatment of acute back pain in the emergency department. Emerg Med Clin North Am. 2015 May;33(2):311–26. https://doi.org/10.1016/j.emc.2014.12.005

13. Taube T, Elomaa I, Blomqvist C, Beneton MNC, Kanis JA. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone. 1994 Mar 1;15(2):161–6. https://doi.org/10.1016/8756-3282(94)90703-X

14. Coleman RE. Metastatic bone disease: clinical features, pathophysiology, and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165–76. https://doi.org/10.1053/ctrv.2000.0210

15. Yuan X, Zhuang M, Zhu X, Cheng D, Liu J, Sun D, et al. Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma. Front Oncol. 2022 Jun 29;12:943866. https://doi.org/10.3389/fonc.2022.943866

16. Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: Clinical studies in the treatment and prevention of bone metastases. Semin Oncol. 2001 Apr 1;28:11–6. https://doi.org/10.1016/S0093-7754(01)90260-X
Pourya Pouryahya, Benjamin Chrisp, Meyer Alastair (Author)

Unilateral optic disc swelling: an atypical presentation for a large frontal meningioma

Intracranial masses pose frequent diagnostic dilemmas for community facing physicians especially in patients presenting with neurological or ophthalmological signs. We describe a case of a large meningioma in a 47-year-old man presenting with left sided optic disc swelling and right visual field disturbance alongside atypical headaches, and mild behavioural disturbance. Neuroimaging demonstrated a large mass with signs of raised intracranial pressure (ICP) and parenchymal herniation. He underwent surgical debulking and biopsy, confirming the suspected diagnosis. Post-operative course was complicated by day one hemiparesis due to venous strokes, with full subsequent motor recovery. Whilst raised ICP is classically thought to cause bilateral optic disc swelling, unilaterality does not exclude this. Careful assessment and use of red flag indicators are therefore needed in determining need for neuroimaging. Declining utility of fundoscopy in non-specialists creates an additional barrier to diagnosis in these presentations and warrants increased research or training to bridge this gap.

Introduction

Primary brain tumours (BT) are common cancers in those under 65 but are uncommon when pooled across cancers in all ages. Despite this, they demonstrate disproportionately higher morbidity and mortality rates, even among non-malignant cases. Meningiomas represent the commonest non-malignant primary BT, with data from the United States demonstrating that they account for 53% of cases 1. Symptoms associated with intracranial masses include headaches, new focal neurology, visual acuity (VA) changes, persistent vomiting, new onset seizures or behavioural changes (including reduced energy, apathy, executive dysfunction and disinhibition) (2– 4). Symptoms such as these are commonplace, but as BT remain a rare cause each symptom, correctly diagnosing a brain tumour from such symptoms can be troublesome 3. For instance, at least 50% of headaches are attributed to primary causes: tensiontype, migraine and trigeminal neuralgia 5. Intracranial masses represent an important differential in these presentations.

The challenge to community facing physicians is stratifying which patients require more investigation. Studies advocate for the utilisation of ‘red flag’ indicators in headache presentations. These include changes in severity from orthostatic/Valsalva manoeuvres, acute change in existing headaches, new headache in those >50 years, progressive change in headache over days/weeks, focal neurology or prior malignancy history 4. Fundoscopic assessment for raised optic discs should form a part of this diagnostic workup but, through multiple factors regarding training and healthcare professionals’ perceptions of this component, it’s utility by non-specialists, has been declining 6.

Case report
In September 2024, a 47-year-old man with a history of hypercholesterolaemia and hypertension was referred to the emergency department (ED) by his optician, having noted new left sided optic disc swelling compared to two months prior. This review was due to patient concerns of new progressive right eye visual disturbance despite a recent new glasses prescription. He denied loss of vision, diplopia or photophobia. The patient also reported intermittent, severe headaches with bilateral cervical to frontal radiation. He denied diurnal, orthostatic or Valsalva exacerbations and reported only a single, isolated episode of vomiting. He had achieved moderate control of these headaches with the use of simple analgesia, physiotherapy exercises and heat packs. He denied weight loss, fevers, change in energy levels or seizure activity during this time. The patient’s family raised concerns of cognitive changes including mild intermittent delays in responses to questions.

Ophthalmological assessment demonstrated no diplopia, no visual field loss, normal conjugate gaze, normal pupillary light reflexes, no change in colour vision and no periorbital, cranial or cervical skin changes or tenderness. He was orientated to time, place and person with preserved attention and memory with his wife corroborating the history. With his new glasses prescription, right eye VA was 6/30 and left eye VA was 6/6. Following pupillary dilation using topical tropicamide drops, left sided optic disc swelling was visualised on fundoscopy with a normal appearing right optic disc.

Further examination demonstrated preserved power (MRC grade 5/5) in all limbs, preserved reflexes, no loss to light touch sensation and no signs of cerebellar dysfunction.

The ophthalmology team suggested computerised tomography (CT) imaging of the brain was indicated and, if negative for acute pathology, the patient could be reviewed as an outpatient. The neurology team also suggested a CT brain and, if this were negative, no further neurology input would be needed at this time. A CT angiogram demonstrated a large (52mm TR x 50mm AP x 49mm CC) right, homogenously hyperdense paraclinoid frontal lobe mass (Figure 1). Involvement of multiple intracranial arterial vessels was noted including narrowing and medial displacement of the right supraclinoid internal carotid artery (ICA), posteromedial displacement of the right M1 middle cerebral artery (MCA), non-enhancement of right M2 MCA (with surrounding collateral vessel enhancement) and displacement of the anterior cerebral arteries (ACA). This scan also demonstrated compression of the right optic nerve, global sulcal effacement, right lateral ventricle effacement, anterior and posterior clinoid process erosions and 14mm left midline shift. Given the appearance and location, a sphenoid wing meningioma was suspected.

Given these findings, this patient was discussed with the neurosurgical on call team. He was commenced on oral dexamethasone and transferred urgently to the tertiary neurosurgical centre for urgent review. Magnetic Resonance Imaging (MRI) (Figure 2) of his brain and orbits detailed further significant vascular involvement, including invasion of the right cavernous sinus, encasement of the right supraclinoid ICA, proximal right M1 MCA and foetal posterior cerebral artery (PCA). The A1 ACA segment was absent or occluded and the right M1 MCA was severely stenosed. The mass directly abutted the lateral surface of the right optic nerve but without evidence of involvement or chronic nerve atrophy (Figure 3).

Formal ophthalmology assessment noted improvement in his VA to 6/6 bilaterally with grade 1-2 optic disc swelling in the left eye without evidence of vascular changes and normal appearance of the right optic disc. Operative management involved craniotomy with dissection of the tumour, retrograde to the direction of the MCA. Gradual tumour bulk removal allowed for visualisation of the optic nerve, ICA, ACA, MCA, posterior communicating artery (PCOM) and anterior communicating artery. Despite the operation’s success in removing the majority of the tumour bulk, the mass was closely adherent to the MCA (and associated perforators), avernous sinus and right posterior communicating artery. These sections were unable to be completely excised. Biopsies were taken, demonstrating tissue consistent with World Health Organisation (WHO) grade 1 meningioma without invasion into brain parenchyma.

Post-operative recovery was complicated with day one dense left hemiparesis. A CT stroke code identified an acute right MCA territory infarct with a subsequent MRI identifying acute infarcts of the right basal ganglia and caudate head. As perforator arteries were thought to be culprit, the patient was managed conservatively, where, over the following week, he made a full neurological recovery. This rapid symptomatic improvement suggested that the observed infarcts were likely related to venous strokes. On discharge, the patient had regained power, was mobilising independently and remained fully cognisant. He was planned for reviews from neurosurgical, endocrinology, ophthalmology and physiotherapy perspectives.

Discussion

This case demonstrates a rare and important presentation for community facing clinicians when assessing individuals for raised ICP, both regarding the discordance in findings between eyes and the atypical secondary symptoms.
Presentation with unilateral optic disc swelling was the main diagnostic dilemma, especially given the contralateral changes in reported vision. Classically, an intracranial mass large enough to precipitate raised ICP and therefore optic disc swelling is thought to do so bilaterally7. Unilateral optic disc swelling usually suggests local pathologies (AION, ON and, by extension, multiple sclerosis) or with concomitant contralateral optic nerve atrophy (Foster-Kennedy syndrome (FKS)) 8.

FKS may have offered an explanation in the mismatch between optic disc appearance and VA changes. Though, without direct evidence of optic nerve involvement or atrophy, this case would not match this conditions usual phenotype 8. Pathophysiological studies demonstrated that development of raised optic discs is not directly due to raised ICP, rather consequential disruptions in axoplasmic flow within the optic nerve sheath causing cellular oedema and extracellular fluids accumulation. These studies also demonstrated that supratentorial masses would initially lead to a unilateral or asymmetrical raised optic disc but, importantly, affecting the optic nerve ipsilateral to the mass – contrary to this case 7.

Case reports detailing individuals presenting with unilateral optic disc swelling are sparse with the majority of these attributed to idiopathic intracranial hypertension (IIH) 9. Knowledge of this atypical presentation is therefore crucial to avoid premature exclusion of raised ICP.

The additional symptoms in this patient’s presentation were also not stereotypical for an intracranial mass. His headache lacked the orthostatic variation and persistent vomiting consistent with raised ICP. Secondly, the behavioural changes reported by his family were not fully consistent with those usually found in frontal brain tumours (apathy, disinhibition, executive dysfunction or anergy) 2.

Bedside fundoscopy remains an important component of these assessments 7. Despite this, clinical utilisation by non-specialists has been declining. Contributory factors to this include lack of equipment or knowledge to perform the examination, perceived disapproval from seniors and low perceived clinical utility 6.Bedside ocular ultrasound (BOUS) has been shown to be a useful non-invasive clinical adjunct to assess for the presence of optic disc swelling, demonstrating sensitivities between 90-100% and may offer an alternative approach to this part of the assessment 10.

Conclusion

Intracranial masses remain an important differential for those presenting with visual changes, headaches and changes in behaviour. With the ever-increasing utilisation of CT imaging in the ED, investigating such pathologies is becoming more straightforward. This case demonstrates the importance of a comprehensive assessment in those with symptoms consistent with raised ICP, with specific focus on lesser assessed and atypical features. This, combined with screening for red flag symptoms, are key to stratifying these patients, allowing for early identification of potentially life threatening diagnoses.

The linchpin in this case was the ophthalmoscopy findings, as without this, he may have presented later in his disease course. Given the noted decline in fundoscopy in non-specialists, without work into increasing its utility or incorporating alternative tools, patients such as this, may be missed.

Declarations

Author contributions

All authors contributed equally and validated the final version of record.

Conflicts Of Interest

The Author(s) declare(s) that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration

No registration applicable

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval

Written informed consent was given by the patient about which this case was written. Details of the history have been anonymised and any imaging for this report have been deidentified. Ethics approval for this case report has been granted by the local hospital ethics committee. ERM: 114100.

References

1. Miller KD, Ostrom QT, Kruchko C, Patil N, Tihan T, Cioffi G, et al. Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 2021 Sep 24;71(5):381–406. https://doi.org/10.3322/caac.21693

2. Cabrera S, Edelstein K, Mason WP, Tartaglia MC. Assessing behavioral syndromes in patients with brain tumors using the frontal systems behavior scale (FrSBe). Neurooncol Pract. 2016 Jun 1;3(2):113–9. https://doi.org/10.1093/nop/npv055

3. Comelli I, Lippi G, Campana V, Servadei F, Cervellin G. Clinical presentation and epidemiology of brain tumors firstly diagnosed in adults in the Emergency Department: a 10-year, single center retrospective study. Ann Transl Med. 2017 Jul;5(13):269. https://doi.org/10.21037/atm.2017.06.12

4. Palmieri A, Valentinis L, Zanchin G. Update on headache and brain tumors. Cephalalgia. 2021 Apr 28;41(4):431–7. https://doi.org/10.1177/0333102420974351

5. Viera AJ, Antono B. Acute Headache in Adults: A Diagnostic Approach. Am Fam Physician. 2022 Sep;106(3):260–8.

6. Dunn HP, Kang CJ, Marks S, Dunn SM, Healey PR, White AJ. Optimising fundoscopy practices across the medical spectrum: A focus group study. PLoS One. 2023;18(1):e0280937. https://doi.org/10.1371/journal.pone.0280937

7. Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Prog Retin Eye Res. 2016 Jan;50:108–44. https://doi.org/10.1016/j.preteyeres.2015.10.001

8. Hata M, Miyamoto K. Causes and Prognosis of Unilateral and Bilateral Optic Disc Swelling. Neuroophthalmology. 2017 Apr 10;41(4):187–191. https://doi.org/10.1080/01658107.2017.1299766

9. Huna–Baron R, Landau K, Rosenberg M, Warren FA, Kupersmith MJ. Unilateral swollen disc due to increased intracranial pressure. Neurology. 2001 Jun 12;56(11):1588–90. https://doi.org/10.1212/wnl.56.11.1588

10. Carter SB, Pistilli M, Livingston KG, Gold DR, Volpe NJ, Shindler KS, et al. The role of orbital ultrasonography in distinguishing papilledema from pseudopapilledema. Eye (Lond). 2014 Dec 5;28(12):1425–30. https://doi.org/10.1038/eye.2014.210
Mahmoud El-Hussein, Cima Hamieh, Patrick Nasrallah, Yara Mouawad, Eric Revue (Author)

Peritoneal carcinomatosis presenting as a mimic for DVT

Unilateral leg swelling poses a diagnostic challenge with a myriad of potential differential diagnosis, including deep vein thrombosis (DVT), Baker's cyst, and cellulitis. As some of these causes can be benign and easily treatable, other causes may be more severe and even life threatening. This article highlights the critical need for healthcare professionals to expand their differential diagnosis when common causes have been excluded, recognizing that some rare etiologies may signify severe underlying conditions. We present the case of a 55-year-old female with a two-month history of right leg swelling, initially attributed to erysipelas due to negative DVT findings. Upon closer examination, an abdomino-pelvic CT scan revealed diffuse peritoneal carcinomatosis, obstructing the right external iliac vein and elucidating the unilateral lower limb edema. This case focuses the importance of considering atypical causes, especially in patients with a history of cancer, and the potential life-threatening nature of rare etiologies. The article emphasizes the significance of a multidisciplinary approach, comprehensive laboratory assessments, and advanced imaging techniques in achieving accurate and timely diagnoses, ultimately guiding effective patient management.

Introduction

Unilateral leg swelling can be attributed to various factors, with deep vein thrombosis (DVT), Baker's cyst, and cellulitis being the most prevalent causes. It is particularly crucial for healthcare professionals to promptly diagnose DVT, due to its potential life-threatening complication of pulmonary embolism (1).

When ruling out these more common etiologies, it is important to recognize that numerous less common causes of unilateral leg swelling exist, spanning a spectrum from benign to potentially serious conditions. Therefore, clinicians should be mindful of rare etiologies, such as arterial insufficiency, lymphatic or venous obstruction, or systemic diseases like vasculitis (2). Conditions like popliteal artery entrapment syndrome, lymphangioleiomyomatosis, or Behçet's disease may present with unilateral leg swelling, posing diagnostic challenges due to their infrequent occurrence (3). Furthermore, certain rare genetic disorders, such as hereditary angioedema or Milroy's disease, can manifest as unilateral leg swelling (4). These conditions, though infrequent, underscore the importance of considering a broad differential diagnosis.

In fact, any lesion or disease process that mechanically obstruct major abdominal veins, can potentially present as unilateral or bilateral leg swelling, mimicking DVT, ranging from cysts, malignancies, even abscesses (5). This article presents a never yet reported case of upstream venous obstruction, due to diffuse peritoneal carcinomatosis obstructing at the level of the right external vein, in a patient with 2-month history of unilateral leg swelling, with negative workup for DVT and no improvement with antibiotics.

Case presentation

This is the case of a 55-year-old female patient, known to have breast carcinoma in 2010 status post remission after chemotherapy and radiotherapy, and endometrial cancer in 2019 status post hysterectomy and bilateral oophorectomy, presented to the emergency room for unilateral right leg pain and swelling of two months duration.

The history goes back to multiple visits to her primary care physician for the same complaint; ultrasound was conducted at that time and eliminated a DVT of the lower extremity, or the presence of a cyst. The patient was then prescribed antibiotics, assuming erysipelas was the etiology of the clinical presentation. After a 7 days course of treatment, the patient noticed no amelioration, therefore she presented to the emergency department.

Upon presentation, the patient was tachycardic, afebrile and in pain. Physical exam was unremarkable, except for non-pitting right lower limb edema extending to the mid-thigh, with minimal erythema and positive pedal pulses (Figure 1).

Review of personal history was non-significant except for the previously mentioned oncologic disorder, and recent ablation of a cutaneous lesion on right leg that was found benign on histology; review of family history and review of systems were insignificant.

Laboratory workup were ordered and showed an elevated D-Dimer (3120 ng/ml with a reference value of <500 ng/ml) and CRP (22 mg/L), with a negative white blood cells count, normal creatinine and normal liver enzymes. In light of a negative DVT workup, and elevated D-Dimer, malignancy was suspected, and therefore an abdominal-pelvic CT with injection was ordered. Surprisingly, the report showed diffuse peritoneal carcinomatosis, with an intra-peritoneal speculated lesion, lateral to the bladder on the right, compressing the right external iliac vein that could explain the unilateral lower limb swelling. After seeking surgical, gynecologic and oncologic consults, the plan was to admit the patient and put her on prophylactic anticoagulation, waiting for further investigations and management, including chest CT scan, MRI of the pelvis, biopsies.

Verbal consent was taken from the patient to publish these data anonymously.

Discussion

This case highlights the imperative need for healthcare professionals to maintain a broad and comprehensive approach when confronted with unilateral leg swelling, particularly when common etiologies like deep vein thrombosis (DVT), Baker's cyst, and cellulitis have been ruled out. Although rare etiologies can be benign and non-life threatening, others can be more serious, and can be the superficial, visible tip of an iceberg, hiding underneath the surface a very serious condition, that needs prompt investigations and management. For instance, the case of unilateral lower limb edema, depicted in this report, unveiled a hidden malignancy and introduces a rare etiology of venous obstruction, although mechanical obstruction due to compression by a mass is relatively a common cause of edema and swelling (6), having peritoneal carcinomatosis as the cause of the presentation is not documented in the literature yet. In fact, obstruction related to peritoneal carcinomatosis have been reported mainly as small bowel occlusion (highlighting the distinctiveness of this case report (7-8).

Furthermore, this patient had strong risk factors and signs for DVT: unilateral leg swelling, 2 months duration, elevated D-Dimer, history of breast and endometrial cancer, no improvement on antibiotics, and was tachycardic upon presentation (which could be a sign of consequences of DVT such as pulmonary embolism), which could easily lead to a bias in diagnosis; but the negative Doppler Ultrasound mead the physicians in the emergency department into further investigation. Given her past medical history, other diagnosis could be thought of such as idiopathic lymphedema, heart failure, kidney failure, pulmonary hypertension … all of which were eliminated by the physical exam, laboratory workup and imaging done in the ER.

The delayed diagnosis in this case demonstrates the potential life-threatening nature of rare etiologies and the importance of promptly identifying and addressing them, even though Peritoneal Carcinomatosis (PC) is a late-stage manifestation of several gastrointestinal and gynecological malignancies, and is usually a sign of metastatic disease and has a poor prognosis (9).

Finally, it is important to note that, in low-resource settings, the practical challenges of investigating lower limb edema can be significant. Relying on expensive imaging techniques like CT scans may not be realistic due to the high costs involved and limited access to such technology. This can make it difficult for healthcare providers to accurately diagnose the underlying cause of a similar presentation and develop an appropriate treatment plan. In these settings, healthcare providers may need to rely on less expensive and more readily available diagnostic tools, such as physical exams and basic laboratory tests, which can lead to misdiagnosis.

The multidisciplinary approach taken, involving surgical, gynecologic, and oncologic consultations, exemplifies the complexity of managing such cases. The decision to initiate anticoagulation while awaiting additional investigations reflects a cautious approach given the potential complications associated with venous obstruction, including a chest CT to rule out any potential pulmonary embolisms. Further investigations are in order, including MRI, biopsies with histological and pathological studies to assess the extent of the disease and potentially the source of PC.

Conclusion

This case underscores the significance of broadening the differential diagnosis for unilateral leg swelling beyond common causes. Clinicians should remain vigilant for rare etiologies, recognizing their potential to be life threatening or indicative of more extensive and serious underlying conditions. A multidisciplinary approach, comprehensive laboratory assessments, and advanced imaging techniques are essential in ensuring timely and accurate diagnoses, thereby facilitating appropriate and effective patient management.

References

1. Brice G, Mansour S, Ostergaard P, Connell F, Jeffery S, Mortimer P. Milroy disease. In: Adam M, Ardinger H, Pagon R, Wallace S, Bean L, Stephens K, et al., editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1239/

2. Davis DD, Shaw PM. Popliteal artery entrapment syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441965/

3. Demarest K, Lavu H, Collins E, Batra V. Comprehensive Diagnosis and Management of Malignant Bowel Obstruction: A Review. J Pain Palliat Care Pharmacother. 2023 Jan 2;37(1):91–105. https://doi.org/10.1080/15360288.2022.2106012

4. Elgendy IY, Lo MC. Unilateral lower extremity swelling as a rare presentation of non-Hodgkin’s lymphoma. BMJ Case Rep. 2014 Jan 13;2014:bcr2013202424. https://doi.org/10.1136/bcr-2013-202424

5. Gasparis AP, Kim PS, Dean SM, Khilnani NM, Labropoulos N. Diagnostic approach to lower limb edema. Phlebology. 2020 Oct 1;35(9):650–5. https://doi.org/10.1177/0268355520938283

6. Ijaz M, Sakam S, Ashraf U, Marquez JG. Unusual Presentation of Recurrent Pyogenic Bilateral Psoas Abscess Causing Bilateral Pulmonary Embolism by Iliac Vein Compression. Am J Case Rep. 2015;16:606–610. https://doi.org/10.12659/ajcr.894206

7. Santangelo ML, Grifasi C, Criscitiello C, Giuliano M, Calogero A, Dodaro C, et al. Bowel obstruction and peritoneal carcinomatosis in the elderly. A systematic review. Aging Clin Exp Res. 2017 Feb 1;29(1):73–8. https://doi.org/10.1007/s40520-016-0656-9

8. Stone J, Hangge P, Albadawi H, Wallace A, Shamoun F, Knuttien MG, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017 Dec 21;7(Suppl_3):S276–84. https://doi.org/10.21037/cdt.2017.09.01

9. Szadkowska MA, Pałucki J, Cieszanowski A. Diagnosis and treatment of peritoneal carcinomatosis – a comprehensive overview. Pol J Radiol. 2023;88:89–97. https://doi.org/10.5114/pjr.2023.125027
Pourya Pouryahya, Mikhar Haripersad, Alastair Meyer (Author)

The Killer Wound; Early Diagnosis and Management of Necrotizing Fasciitis Utilizing Point-of-Care Ultrasound: A Case Repor

Background: Necrotizing fasciitis (NF) is a rapidly progressive and life-threatening infection of the fascia and subcutaneous tissues. Early diagnosis and prompt surgical intervention are critical to reducing morbidity and mortality. This case report highlights the importance of point-of-care ultrasound (PoCUS) in the rapid diagnosis of NF.

Case Presentation: A 34-year-old male carpenter presented to the Emergency Department of Casey Hospital, with a 48-hour history of increasing swelling and pain in his right arm and chest. Two weeks prior, he sustained an open wound to his right wrist from a rusty nail. Initial management by his family doctor focused on musculoskeletal injury without antibiotics. On ED presentation, the patient exhibited signs of systemic infection and gross swelling of the right upper limb and chest. PoCUS demonstrated characteristic findings of NF, including cobble stoning and subcutaneous air with dirty shadowing, leading to an expedited surgical consultation and immediate intervention.

Management and Outcome: The patient underwent multiple debridements, antibiotic therapy, and hyperbaric oxygen therapy. Post-surgical rehabilitation showed substantial gains in function and mobility.

Discussion: This case underscores the crucial role of PoCUS in the early diagnosis and management of NF. PoCUS allows for rapid bedside imaging, enabling timely surgical consultation and intervention, thereby improving patient outcomes. The multidisciplinary approach, involving emergency physicians, surgeons, and intensivists, is essential for optimal management of NF.

Conclusion: Early recognition and treatment, facilitated by PoCUS, are key to reducing the high morbidity and mortality.

Key Messages

* Early surgical intervention and antibiotic therapy are crucial in reducing morbidity and mortality in Necrotizing Fasciitis.

* Multidisciplinary coordination is required for patient stabilization and rapid transfer from the Emergency Department to the operating theatre, as surgical debridement is the definitive treatment.

* Utilization of Point-of-Care Ultrasound (PoCUS) is essential for the early diagnosis and management of Necrotizing Fasciitis and associated complications, significantly impacting patient outcomes.

Presentation

In November 2022, a 34-year-old male carpenter presented to the Emergency Department (ED) of Casey Hospital, Monash Health, a 229-bed facility providing comprehensive health services, including ICU, to Melbourne’s outer-east communities. The patient reported increased swelling and pain in his right arm and chest over the past 48 hours. Two weeks prior, he sustained an open wound to the dorsum of his right wrist from a rusty nail at work. He did not seek medical treatment and only cleaned the wound with a Betadine wash. Three days before presenting to the ED, he visited his family doctor due to feeling unwell with right arm swelling and right-sided chest pain. He was managed as a musculoskeletal (MSK) injury with analgesia, including non-steroidal anti-inflammatory drugs (NSAID), and rest. The day before his ED presentation, he revisited his family doctor with worsening pain and lethargy. An X-ray and MSK ultrasound were planned, and the NSAID was discontinued. No antibiotics were considered at that time.

Initial ED Assessment and Management

Upon ED presentation, he was tachycardic at 139/min, borderline tachypneic at 28 breaths per minute, apyrexial at 36.7°C, with an initial blood pressure of 115/78 mmHg. Examination revealed gross swelling of the right upper limb and chest, a 2 cm sloughy, partially healed open wound on the posterior aspect of the right forearm with surrounding erythema, and no purulent discharge (Figure 1). No palpable subcutaneous emphysema was noted. A C6 dermatomal sensation deficit was observed, likely secondary to inflammation and swelling. Capillary refill time (CRT) was greater than 5 seconds with a palpable radial pulse. The patient reported increasing pain, intermittent fevers, anorexia, and anuria for the past two days¹. His social history revealed he was a non-smoker, social drinker, and did not use illicit drugs.

ED Investigations and Initial Management

He was triaged as category 2 (ATS; to be seen within 10 minutes) and self-mobilized to a resuscitation cubicle after identification of his critical condition. Observations and monitoring were applied, and two large-bore 18G IV cannulas were inserted into his left arm. An ECG (Figure 2) showed sinus tachycardia. Pathology tests, including a venous blood gas, inflammatory markers, UECs, LFTs, coagulation screen, and troponin, were taken².

His VBG indicated respiratory acidosis (pH 7.09, pCO2 65) and profound hyperlactatemia of 10.5. It also noted a haemoglobin of 166, potentially being indicative of dehydration/sepsis. His electrolytes were noted to be mildly deranged (Na 133, K 5.1, Cl 97).

With a provisional diagnosis of sepsis, resuscitation with crystalloid intravenous fluids (NaCl) was initiated. Point-of-Care Ultrasound (PoCUS) demonstrated cobblestoning and subcutaneous air with dirty shadowing of the entire upper limb and right-side chest wall³(Figure 3), suspicious for Necrotizing Fasciitis, as well as a non-compressible proximal part of the axillary vein suspicious for concurrent thrombus (Figure 4), likely secondary to swelling and immobility. Extended PoCUS showed a hyperdynamic heart without effusion, LV dysfunction, or significant right heart strain.

Triple antibiotics, including clindamycin, piperacillin/tazobactam, and vancomycin, were commenced according to therapeutic guidelines⁴, followed by surgical and plastics consultation for urgent debridement⁵ in the operating theatre (OT) and post-op ICU admission. During transport to OT, he became hypotensive with septic shock and was managed with peripheral metaraminol with a good temporary response.

Operative and Post-ED Management

Upon arrival to the theatre, he was intubated, and invasive access for monitoring and management, including arterial and central venous lines, was established. Initial debridement found a large collection of pus under the pectoral, with pustular tracts noted between the pectoral major and minor towards the axilla. The fascia was healthy. Further exploration later that night revealed pus collections in the acromioclavicular and sternoclavicular joints, requiring washouts. Tissue samples were sent for microscopy and culture. Triple antibiotic therapy continued, and he was transferred to the ICU at Casey Hospital.

With a confirmed diagnosis of Necrotizing Fasciitis intraoperatively, he was transferred to the Alfred Hospital, a metropolitan tertiary centre, for hyperbaric oxygen therapy and ongoing care. At the Alfred Hospital, he underwent two further debridements. His antibiotics were changed to cefepime, benzylpenicillin, and clindamycin, aligned with intraoperative tissue sample antibiogram sensitivities. Nasogastric feeds commenced, and he weaned off vasopressor support. Bilateral pleural effusions secondary to sepsis were found, and intercostal catheters were placed after bronchoscopy.

He was transferred back to Monash Health (Dandenong Hospital) for ongoing management under plastics surgery care. Due to ongoing fevers and concerns for an empyema, his antibiotic therapy was escalated to include ciprofloxacin, linezolid, metronidazole, and micafungin⁴.

Surgical Timeline

D0: Initial debridement of the right upper limb/chest wall with biopsies concerning for Necrotizing Fasciitis.

D2: Secondary debridement of the right arm/axilla/chest wall.

D4: Third debridement with change of VAC dressing right upper limb and chest wall.

D7: Fourth debridement and VAC change right arm, axilla, and chest.

D14: VAC change and re-washout (assisted by Cardiothoracic Surgical team).

D16: VAC change right chest wall.

D21: Right axilla debridement and VAC change.

Discussion

Diagnosis of Necrotizing Fasciitis

Necrotizing Fasciitis is a rapidly progressive, life-threatening infection of the fascia and subcutaneous tissues that requires immediate medical and surgical intervention. Early diagnosis is crucial to prevent significant morbidity and mortality. Clinical diagnosis can be challenging due to its variable presentation and overlap with other less severe soft tissue infections. Typical symptoms include severe pain, swelling, erythema, and systemic signs of sepsis such as fever, tachycardia, and hypotension. However, these symptoms can be nonspecific and may lead to initial misdiagnosis, as seen in this case, where the patient was initially treated for a musculoskeletal injury⁶. Diagnostic imaging plays a pivotal role in the early detection and management of Necrotizing Fasciitis. Radiographic imaging such as X-rays may show soft tissue gas, while computed tomography (CT) and magnetic resonance imaging (MRI) can provide more detailed information regarding the extent of infection. However, these modalities can be time-consuming, and may delay critical treatment.

Utility of Point-of-Care Ultrasound (PoCUS) in Diagnosis

Point-of-Care Ultrasound (PoCUS) has emerged as a valuable tool in the rapid diagnosis of Necrotizing Fasciitis, especially in the emergency department setting. PoCUS allows for bedside imaging, which can significantly reduce the time to diagnosis and subsequent treatment. In this case, PoCUS was instrumental in identifying the hallmark features of Necrotizing Fasciitis, including cobblestoning, subcutaneous air with dirty shadowing, and non-compressible veins suggesting thrombus formation⁷. These findings prompted immediate surgical consultation and expedited surgical intervention. The utility of PoCUS extends beyond diagnosis to include ongoing management and monitoring of disease progression. It provides real-time information about the extent of infection and can be used to guide fluid resuscitation, identify complications, such as abscess formation, and monitor the effectiveness of therapeutic interventions. Additionally, PoCUS can be used to evaluate cardiac function and detect hemodynamic instability, as was done in this case⁶.

Antibiotic Stewardship

The Australian Therapeutic Guidelines (ETG) is a leading source of independent, evidence based, practical treatment advice to assist practitioners with decision making at the point-of care. The content is regularly updated, based on the latest international literature, interpreted by Australia’s most respected experts, with input from an extensive network of general practitioners, pharmacists and other users. Thus, becoming the standard of practice in Australasia and most other countries like the United Kingdom and the United States of America. As per ETG, three antibiotics are required for empirical therapy for necrotizing skin Infections; Either meropenem or piperacillin/tazobactam, plus vancomycin, plus either clindamycin or lincomycin can be commenced⁴. This regime provides appropriate gram-positive and gram-negative aerobic cover, as well as coverage for anaerobes and MRSA.

Decision for Limb Sparing Surgery

In many instances there is a preference to preserve limbs whilst performing surgical intervention if possible. This coincides with the desire to avoid amputation in order to best return the patient to as close to return of function as possible⁸. Even though there is a deficit in published studies to support this claim, it was the preferred choice of the patient and the surgical team.

Role of Multi-Disciplinary Intervention

The initial suspicion and subsequent diagnosis of Necrotizing Fasciitis was completed by the Emergency Department team. Prompt inclusion of the intensive care, surgical/plastics team was required for definitive and post operative supportive treatment⁹. Post operative care included allied health involvement (physiotherapy, hand therapy, occupational therapy and social work). A multi-disciplinary approach provided the best outcome for this patient, giving him the greatest chance for return to function.

Conclusion

This case highlights the critical importance of early diagnosis and multidisciplinary management in patients with Necrotizing Fasciitis. Point-of-Care Ultrasound (PoCUS) proved to be a rapid, effective diagnostic tool that facilitated prompt surgical intervention and appropriate medical management, ultimately improving patient outcomes¹⁰. Early recognition and aggressive treatment, including the use of PoCUS for rapid bedside assessment, are key to reducing the high morbidity and mortality associated with Necrotizing Fasciitis.

Patient Outcome

Following surgical interventions, antibiotic therapy, and rehabilitation, the patient has made significant gains in function and mobility. Almost two years post-initial presentation, he has not fully returned to baseline but continues to make progress (Figure 5).

References

1.      Stevens DL, Bryant AE, Goldstein EJ. Necrotizing soft tissue infections. Infect Dis Clin North Am. 2021;35(1):135–155. https://doi.org/10.1016/j.idc.2020.10.004

2.      Fernando SM, Tran A, Cheng W, Rochwerg B, Kyeremanteng K, Seely AJE, et al. Necrotizing Soft Tissue Infection: Diagnostic Accuracy of Physical Examination, Imaging, and LRINEC Score: A Systematic Review and Meta-Analysis. Ann Surg. 2019;269(1):58–65 https://doi.org/10.1097/SLA.0000000000002774

3.      Marks A, Patel D, Sundaram T, Johnson J, Gottlieb M. Ultrasound for the diagnosis of necrotizing fasciitis: a systematic review of the literature. Am J Emerg Med. 2023;65:31–35. https://doi.org/10.1016/j.ajem.2022.12.037

4.      Therapeutic Guidelines [Internet]. 2024 [cited 2024 Dec 9]. Therapeutic Guidelines | Independent, reliable, relevant and respected. Available from: https://www.tg.org.au/

5.      Wong CH, Yam AK, Tan AB, Song C. Approach to debridement in necrotizing fasciitis. Am J Surg. 2008;196(3):e19–e24. https://doi.org/10.1016/j.amjsurg.2007.08.076

6.      Goh T, Goh LG, Ang CH, Wong CH. Early diagnosis of necrotizing fasciitis. Br J Surg. 2014;101(1):e119–e125. https://doi.org/10.1002/bjs.9371

7.      Kohen B, Halperin M, Felix G, Dixon T, Montenegro M, Patel F. Sonographic crepitus, a point-of-care ultrasound finding. POCUS J. 2022;7(1):129–130 https://doi.org/10.24908/pocus.v7i1.15406

8.      Misiakos EP, Bagias G, Patapis P, Sotiropoulos D, Kanavidis P, Machairas A. Current concepts in the management of necrotizing fasciitis. Front Surg. 2014;1:36. https://doi.org/10.3389/fsurg.2014.00036

9.      Marchesi A, Marcelli S, Parodi PC, Perrotta RE, Riccio M, Vaienti L. Necrotizing fasciitis in aesthetic surgery: a review of the literature. Aesthetic Plast Surg. 2017;41(2):352–358. https://doi.org/10.1007/s00266-016-0754-2

10. Raj S, Williams EM, Davis MJ, Abu-Ghname A, Luu BC, Buchanan EP. Cost-effectiveness of multidisciplinary care in plastic surgery: a systematic review. Ann Plast Surg. 2021;87(2):206–210. https://doi.org/10.1097/SAP.0000000000002931
Omar El Tarras, Hilal Abdessamad, Jonathan Mina, Hussein Farhat, Wassim Serhal, Rola Husni, Rima Moghnieh, Jacques E. Mokhbat (Author)

Spinal Rosai-Dorfman Disease with Isolated Severe Neuropathic Pain: A Case Report

Introduction: Rosia-Dorfman disease is a rare histiocytic disorder that presents as generalized lymphadenopathy. Rarely, patients experience atypical extra-nodal manifestations which can mimic other diseases.
Case Presentation: We report a challenging diagnosis of Rosai-Dorfman disease in a 52-year-old female presenting with isolated symptomatic neuropathic pain. After excluding common diseases, a challenging diagnosis was made based on imaging, CSF studies and clinical progression that showed thoracic spine involvement and emperipolesis confirming RDD diagnosis and with a great clinical response to corticosteroids.

Discussion: Clinical, laboratory and radiologic manifestations of the disease can vary a lot depending on the areas involved and patient progression. This can lead to challenges in establishing the diagnosis and deciding on treatment. Then unusual, first reported manifestations in our patient made the diagnosis exceptionally challenging, highlighting the importance of this report.

Conclusion: This disease can have an atypical presentation that should be detected early to avoid any delay in diagnosis or treatment. Unusual cases must be reported to aid in such a difficult diagnosis in future similar cases.

Introduction

Rosai-Dorfman disease (RDD) is a rare non-neoplastic histiocytic disorder, also known as sinus histiocytosis with massive lymphadenopathy. Histopathologically, RDD emperipolesis is seen as the phagocytosis of erythrocytes and lymphocytes without their destruction.¹ Usually, this disease presents as painless lymphadenopathy affecting cervical nodes. However, extra-nodal involvement is seen in more than 40% of the cases. ² Such presentations are challenging to diagnose because they have a plethora of symptoms and mimic many multisystemic illnesses and malignancies such as lymphomas, tuberculosis and other granulomatous diseases.³ In addition, multi-site involvement is a common manifestation, affecting up to 73% of cases in some studies.⁴ Involvement of the central nervous system (CNS) is rare with only 210 reported cases.⁵ Due to this lack of literature, and in the absence of a consensus diagnostic and treatment approach, management of such patients is difficult.⁴ Here, we present a patient with a progressive lymphadenopathy with thoracic spinal cord involvement, which is, to our knowledge, among the first reported cases of RDD with such a presentation.

Case Report

We describe a case of Mrs. X, a 52-year-old female who presented to us on the 30^th of January, of 2023 for lower back pain radiating to the thighs bilaterally. Two months ago, she received a lumbar spine corticosteroid injection for radiculopathy. Four weeks later she started having headaches and low-grade fevers of 38.5C. She presented to another institution where a head scan revealed chronic sinusitis, and she was then discharged on antibiotics. The symptoms continued, and on 13^th of January 2023 she was admitted in another institution, and a repeat head scan was also normal and a urinalysis, troponin, Brucella serology, Borrelia serology, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, Aspartate transaminase, and Alkaline Transaminase were insignificant. She was discharged on symptomatic treatment. Two weeks later she started having progressively worsening abdominal pain with back tenderness radiating to the thighs, where she was readmitted, and a plain brain and spine Magnetic Resonance Imaging (MRI) showed mild degenerative spondylosis. An electromyogram (EMG) which was normal, and she was diagnosed with fibromyalgia. The symptoms persisted until the patient presented to our institution on January 30^th, 2023.

She is a non-smoker, occasional alcohol drinker without drug use history. She does not have previous medical or surgical history. She has no known allergies. There is no recent travel and no animal exposure. She lives in central Lebanon. Family history is significant for psoriasis, sarcoidosis, and breast cancer.

Upon admission, physical exam was only significant for lower back, lower abdominal, and anterior and posterior thigh tenderness. Neurological exam was normal.

Laboratory workup was unrevealing, provided in table 1. X-ray of the lumbosacral spine showed mild disc narrowing L5-S1. Enhanced brain and spine MRI showed a linear leptomeningeal enhancement of the mid-thoracic vertebra with intramedullary cord edema and patchy intramedullary and diffuse circumferential intradural extramedullary enhancement at the conus medullaris at L5-S1. This was suggestive of infection or inflammation. Lymphoma was ruled out by enhanced whole body Computed Tomography (CT). Blood flow cytometry excluded leukemia. Positron Emission Topography (PET) CT scan was negative for any nodal involvement or uptake.

Upon further history, she mentioned that she had contact with refugees residing in Lebanon. This exposure, with the Lumbar Puncture (LP) and imaging results, raised the possibility of tuberculosis (TB) and she was started empirically on isoniazid, rifampin, pyranzimide, ethambutol with dexamethasone. The symptoms completely resolved after the first dose of dexamethasone.

Cerebrospinal fluid (CSF) examination (table 2) showed monocytic cells and basophilic monocytoid cells with a high nucleus-to-cytoplasm ratio, occasional plasma cells, and images of emperipolesis, a proliferation of histiocytic cells with phagocytosed lymphoid cells that are not fragmented, with a collection of lymphocytic cells around them (figure 1). CSF cytology showed reactive neutrophils and macrophages without malignant cells. CSF cultures showed no growth and negative brucella antibodies. Acid-fast stain, and PCR for Tuberculosis were also negative. Peripheral blood smear showed no morphological abnormalities and a complete rheumatological workup was normal.

TB treatment was stopped as the emperipolesis and histiocytosis were suggestive of Rosai-Dorfman Disease. The slides then underwent S-100 staining, which was strongly positive, further confirming the diagnosis.

The patient was kept on dexamethasone, and her condition improved. She was discharged on prednisone 80 mg once daily. After 2 weeks, another LP showed decreasing protein concentration and leukocyte count (table 2). Follow up MRI showed findings consistent with ongoing epiduritis and resolving myelitis.

The patient remained on prednisone, with no recurrence. Follow-up MRI showed improving T2 signal involving the central aspect of the spinal cord, decrease in intradural enhancement and loss of enhancement in the conus medullaris. On August 23, 2023, she was successfully tapered off steroids with no recurrence of symptoms. She is still symptom free today and has not had recurrence of symptoms. Follow-up has stopped and she was instructed to return to the clinic in case she has any new findings.

Discussion

This case illustrates an unusual presentation of RDD manifesting as cervical lymphadenopathy. The diagnosis could not be easily established due to the rarity of this disease and the unusual manifestations. Since first described in 1969, around 210 cases of RDD were reported, out of which 174 cases had CNS involvement.⁶ The pathogenesis of RDD is not well understood, believed to be a reactive non-neoplastic histiocytic disorder that lacks clonality. Several mutations are linked to RDD including ARAF, MAP2K1, NRAS, KRAS, and CSF1R as well as multiple gene alterations in intracellular trafficking, transcription, cell cycle regulation, Deoxyribonucleic acid (DNA) mismatch, and ubiquitin-proteasome pathway.⁷ However, some presentations are linked to infectious etiologies such as EBV, CMV, HIV, and Herpes virus-6.² The prevalence of RDD is about 1:200 000, most common in young adult males of African descent.⁸

RDD is classified as sporadic, cutaneous, and familial. The sporadic form classically presents as painless bilateral cervical lymphadenopathy mostly in the head and neck. It can also present as an extra-nodal disease in 40% of cases.⁸ The median age is 50 years and it seems to have a slight female predominance of 1.5:1.⁴ The gender and age distribution go with our patient demographics but she did not seem to have a family history of such a presentation.

Skin involvement is seen in 10% of extra-nodal RDD cases, but isolated cutaneous manifestations are rare. Usually, this presents as skin-painless nodules, papules, or plaques affecting the head, neck, and upper trunk areas. These lesions can vary in size, shape, and color. The main diagnostic method is a histopathological picture of large histiocytes with abundant cytoplasm and emperipolesis showing phagocytosis of intact lymphocytic cells.⁹ Intrathoracic involvement is not common, only seen in 2% of patients with RDD. The symptoms can mimic other diseases presenting as cough or even respiratory failure, it can appear as lung nodules, intrathoracic lymphadenopathy, pleural effusions, or interstitial lung disease. Cardiac involvement is extremely rare, described in less than 0.2% of patients.⁸ Renal involvement is usually associated with poor prognosis. Symptoms can vary from flank pan and hematuria to severe renal failure which makes the diagnosis much more complicated.¹ Testicular involvement in men, bone, gastric and hematological manifestations of RDD have been described in the literature.¹⁰ However, our case had isolated CNS affection which made the diagnosis rather challenging. She had none of these described systemic findings. The lack of such systemic symptoms in our patient made the diagnosis more challenging.

Involvement of the CNS is described in about 5 % of cases.⁶ Moreover, Only 25% of the lesions reported are spinal, where it is mostly a manifestation of systemic disease.⁶ In contrast to systemic RDD, isolated CNS manifestations lack constitutional symptoms and are usually unilateral. Symptoms may vary from headaches to seizures, motor and sensory abnormalities, and focal deficits.⁶ Our patient's symptoms included lower back pain, non-specific abdominal pain, and thigh pain, which was unusual as per the literature. In a similar case reported by Huang et al., the patient experienced sciatica-like symptoms caused by RDD of the sacral bone, which is a very rare presentation seen with our patient.

Ophthalmic manifestations are described in 10% of CNS cases, where sinus and ophthalmic involvement is seen due to the close anatomical area. This can lead to vision impairment, with nasal obstruction, epistaxis and facial deformity.¹ Our patient did not have any ophthalmic symptoms.

Goyal et al. reported 60 cases of RDD followed-up from 1994 to 2017. They found that only 8% had nodal disease and above 90% had extra-nodal manifestations. 52% had skin and subcutaneous masses, 21% had bone or muscle involvement and 4 cases (6.2%) had CNS frontal lesions. Interestingly, the median time from initial presentation to diagnosis was around 7 months, which highlights how challenging the diagnosis of RDD is. ⁴ This was one of the largest studies of RDD reported. While a lot of the mentioned presentations were not seen with our patient, the article highlights the long median periods to establish the diagnosis in the presence of some suggestive findings. In our case, and with the lack of the already rare disease manifestations, the diagnosis remained challenging to establish.

In another case series, 3 middle-aged patients with multiple subcutaneous and intra-abdominal masses were found to have RDD after excisional biopsy.¹¹ According to the authors, extra-nodal disease can mimic malignancy and other viral illnesses, and that in most cases immunohistochemistry (IHC) is the main tool for diagnosis, especially that it excludes other diseases.¹¹ In our case, IHC and pathologic examination of the CSF is what helped most in establishing the diagnosis, which goes with what this case series concludes.

According to Mar et al, computed tomography (CT), MRI, and Positron Emission Tomography (PET) are important tools to suspect RDD.¹² However, the diagnosis can overlap with other conditions like lymphoma, infection, and granulomatous disease. There are a variety of appearances on radiology for different RDD involvements.¹² For instance, cardiothoracic involvement can manifest as lymphadenopathy, tracheobronchial or lung nodules, pleural effusions, or cardiac masses.¹² Abdominal involvement can affect any organ system, often presenting as masses or lymphadenopathy. Pelvic involvement can involve pelvic lymph nodes, and reproductive systems, and musculoskeletal involvement can manifest as subcutaneous masses or lytic bone lesions. Nevertheless, definitive diagnosis requires a multidisciplinary approach. ¹²

Rosai Dorfman Disease involving the CNS has a wide array of radiological findings. While intracranial lesions mostly consist of extra-axial masses mimicking a meningioma or diffuse pachymeningitis, spinal or epidural lesions are most common in the cervical and thoracic areas which are usually enhancing on MRI T2.⁸ A case report in 2019 describes significant edema on T1 and T2 and thickened meninges.¹³ Another one describes a large enhancing soft-tissue mass at L5-S1, with histopathological findings of Rosai-Dorfman disease and complete resolution on steroids.¹⁴ Furthermore, a case series of 11 patients with isolated CNS RDD reported the possible involvement of the spinal canal, skull dura and different cerebral lobes.¹⁵ Isolated thoracic spine findings were, to our knowledge, never described before, which presented a radiological picture that is not very familiar, which posed further difficulty in reaching a diagnosis with our patient.

CSF and histopathological studies usually offer the definitive diagnosis. They show elevated proteins, low glucose, leukocytosis with lymphocytic predominance and emperipolesis as seen in our case. The histiocytes involved are usually positive for S100⁺, CD68⁺, and CD1a⁻(CD: Cluster of Differentiation).⁸ In our case they were positive for S100. On cytology, we hypercellularity with predominance of lymphocytes and histiocytes with emperipolesis is what is usually seen.¹⁶These findings were seen on CSF examination and IHC with our patient, and they were what confirmed our diagnosis.

Although there are no clear guidelines for the treatment of Rosai Dorfman disease, a consensus management was established by Abla et. Al. Although observation might be suitable for patients with uncomplicated lymphadenopathy, cutaneous RDD, or post-operatively for unifocal disease, treatment with prednisone (40-70 mg per day) or dexamethasone (8-20 mg per day) is recommended.⁸ Surgical resection can also be an option for unifocal extra-nodal disease, or symptomatic cranial, spinal, sinus or airway disease. Neurosurgical evaluation in our patient deemed the lesions unresectable for no discrete masses could be found and due to the diffuse spread of enhancement involving different parts of the spinal cord and vertebrae. Sometimes, cladribine or methotrexate can be considered for in refractive diseases, however the exact duration of the therapy is unknown. Our patient was not offered any treatment other than steroids. Clofarabine is currently under study for CNS involvement but the myelosuppressive effects and the high cost of this medication are of concern.⁸ In our case, the patient had an excellent response to prednisone and entered long-term remission, without any relapses even after steroids were tapered and stopped. She enjoys a healthy life with no residual symptoms.

Other treatments are also available, such as cladribine, methotrexate, vincristine and mercaptopurine.⁸ However, such treatments have undesirable side effects such as immunosuppression, and the data regarding their effect on RDD is less conclusive. Up until this time, they are considered in cases refractory to corticosteroids or when corticosteroids are contraindicated.⁸ Some case reports also consider sirolimus, but its use in this context is very limited, described more in the pediatric population. Besides, sirolimus availability and price can be limitations to its usage.⁸

With regards to our patient, the initial non-specific symptoms of lower back pain and systemic symptoms of fever and headaches led to multiple inconclusive investigations. Initial differential diagnosis included infectious and rheumatologic causes, including degenerative disc diseases and discitis and ankylosing spondylitis. Upon imaging, MRI findings suggested inflammatory or infectious origins of the pain, excluding solid malignancies and discitis but keeping inflammatory and infectious etiology. Moreover, conditions such as sarcoidosis or granulomatous disease could be excluded by MRI. among the differentials. CSF analysis with emperipolesis is what shifted the diagnosis to RDD, confirmed by S-100 staining, which is very sensitive but not specific for RDD. ¹² Emperipolesis and S100 staining together is what establishes the diagnosis. This case is a very good example of the diagnostic journey it takes to detect RDD, which involves a multi-disciplinary approach of neurology, rheumatology, infectious diseases, radiology and pathology.

Conclusion

RDD is a benign disease of histiocytes manifesting as a resistant refractory generalized lymphadenopathy sometimes with systemic manifestations that can be quite variant. Due to the wide array of reported sites of involvement, the clinical presentation as well as laboratory and radiologic findings can be diverse, posing a diagnostic challenge. While there are many cases describing RDD with CNS involvement, none has mentioned thoracic meningeal inflammation. To date, only CSF histopathological studies and microscopic evaluation aid in a definitive diagnosis. This is why reporting all new presentations of this disease is important, as they can aid in establishing an identifiable plethora of findings that help in establishing a timely diagnosis and a more cost-effective approach to this already rare disease.

References

1.      McAlister WH, Herman T, Dehner LP. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Pediatr Radiol. 1990 Jul 1;20(6):425–32. https://doi.org/10.1007/BF02075199

2.      Sendrasoa FA, Ranaivo IM, Raharolahy O, Andrianarison M, Razanakoto NH, Ramarozatovo LS, et al. Rosai-Dorfman disease involving multiple organs: An unusual case with poor prognosis. Case Rep Med. 2016 Oct 31;2016:3920516. https://doi.org/10.1155/2016/3920516

3.      Mohammadi O, Zylberglait Lisigurski M, Mehra D, Pishdad R, Gulec S. Rosai-Dorfman Disease and Unusual Local Invasive Presentation. Cureus. 2020 Mar 19;12(3):e7328. https://doi.org/10.7759/cureus.7328

4.      Goyal G, Ravindran A, Young JR, Shah MV, Bennani NN, Patnaik MM, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020 Jan 31;105(2):348–57. https://doi.org/10.3324/haematol.2019.219626

5.      Adeleye AO, Amir G, Fraifeld S, Shoshan Y, Umansky F, Spektor S. Diagnosis and management of Rosai–Dorfman disease involving the central nervous system. Neurol Res. 2010 Jul 1;32(6):572–8. https://doi.org/10.1179/016164109X12608733393836

6.      Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, Velazquez-Vega J, Borja MJ, Rosenberg S, et al. Rosai-Dorfman Disease of the Central Nervous System: Report of 6 Cases and Review of the Literature. Medicine. 2014;93(3). https://doi.org/10.1097/MD.0000000000000030

7.      Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020 Nov 1;73(11):697. https://doi.org/10.1136/jclinpath-2020-206733

8.      Abla O, Jacobsen E, Picarsic J, Krenova Z, Jaffe R, Emile JF, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018 Jun 28;131(26):2877–90. https://doi.org/10.1182/blood-2018-03-839753

9.      Gawdzik A, Ziarkiewicz-Wróblewska B, Chlebicka I, Jankowska-Konsur A, Szepietowski JC, Maj J. Cutaneous Rosai-Dorfman Disease: A Treatment Challenge. Dermatol Ther (Heidelb). 2021 Aug 1;11(4):1443–8. https://doi.org/10.1007/s13555-021-00557-1

10. Fernandopulle SM, Hwang JSG, Kuick CH, Lui J, Tan PH, Siow WY, et al. Rosai-Dorfman disease of the testis: an unusual entity that mimics testicular malignancy. J Clin Pathol. 2006 Mar 1;59(3):325–327. https://doi.org/10.1136/jcp.2005.028423

11. Magableh HM, Jaber HD, Magableh AM, Alrabiah MA, Dahhan AF, Azzam AZ, et al. Rosai-Dorfman Disease: Case Series and Literature Review. Cureus. 2023 Feb 19;15(2):e35193. https://doi.org/10.7759/cureus.35193

12. Mar WA, Yu JH, Knuttinen MG, Horowitz JM, David O, Wilbur A, et al. Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck. Am J Roentgenol. 2017 Apr 1;208(4):721–32. https://doi.org/10.2214/AJR.15.15504

13. Wen JH, Wang C, Jin YY, Xu D, Jiang B, He XJ, et al. Radiological and clinical findings of isolated meningeal Rosai–Dorfman disease of the central nervous system. Medicine. 2019;98(19):e15365. https://doi.org/10.1097/MD.0000000000015365

14. Bahauddin R, Al-Taie A, Al-Khafaji F, Barah A. Rosai-Dorfman Disease of the Spine: A Case Report of a Rare Disease and Review of the Literature. Cureus. 2022 Jun 25;14(6):e26317. https://doi.org/10.7759/cureus.26317

15. Andriko JAW, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman Disease Isolated to the Central Nervous System: A Report of 11 Cases. Mod Pathol. 2001 Mar 1;14(3):172–8. https://doi.org/10.1038/modpathol.3880278

16. Rajyalakshmi R, Akhtar M, Swathi Y, Chakravarthi R, Reddy JB, Maddirala BP. Cytological Diagnosis of Rosai–Dorfman Disease: A Study of Twelve Cases with Emphasis on Diagnostic Challenges. J Cytol. 2020;37(1). https://doi.org/10.4103/JOC.JOC_4_19
Hilal Abdessamad, Charbel Saad, Tarek Abou Saad, Shaza Mortada, Sarkis Ejbeh, Richard Zalloum, Rola Husni, Jacques E. Mokhbat (Author)

Post-COVID-19 Kawasaki-Like Vasculitis and Endocarditis: A Case Report

Background: Coronavirus Disease of 2019 (COVID-19) can cause mild to severe infection, but with a combination of inflammatory complications that target virtually anywhere in the body. Cardiac complications remain of utmost importance as they have the highest association with mortality.

Case presentation: A 32-year-old male presents with a fever of unknown origin for a period of 3 months post SARS-CoV-2 infection. He was found to have endocarditis and underwent an aortic valve replacement that was complicated by an aortic aneurysm, needing another surgery. The fever and aneurysm remitted after a new COVID-19 infection and the patient underwent a Bentall procedure with reimplantation of the coronary arteries.

Discussion: Cardiac complications of COVID-19 can range from small to large arteritis, valvopathy and aortic aneurysms, which can have significant morbidity and mortality, leading to the need of surgery and prolonged treatment. The scarcity of such cases makes reporting imperative so that clearer guidelines of management can be established.

Conclusion: Cardiovascular complications of COVID-19 remain the scariest and the least reported, which necessitates the presence of more evidence of their management, which can be lifesaving.

Introduction

COVID-19 usually presents as upper respiratory infections and pneumonias triggering an inflammatory cascade that can be prolonged, in what is known as long COVID. This can manifest as autoimmune diseases, neurologic illness, cardiovascular disorders and others.[1, 2] The surplus of complications this viral infection can cause is unique, but its vascular complications are the most mortal, causing acute endothelial dysfunction driven by inflammation, leading to tissue ischemia.[3] Nevertheless, very few data with weak evidence exist on managing such conditions.

These complications can range from small to medium vasculitis all the way to aortitis, aortic valvopathy and aortic aneurysms causing acute myocardial ischemia and severe congestive heart failure (CHF).[4] They can be self-limiting over a few weeks, or life-threatening, requiring emergent intervention that can range from anticoagulation and control of the inflammatory storm, to intra-vascular or surgical intervention.[5]

In this case report, we present a 32-yer-old male who had a Kawasaki-like vasculitis after his COVID-19 infection, that was complicated with aortitis, aortic valve inflammation and thoracic aortic aneurysm that required three surgeries and a long treatment duration. To our knowledge, such a case has never been described, which proves the importance of reporting.

Case Presentation

First admission:

On 24/03/22, Mr. FK, a 32-year-old patient presented to our clinic for fever without focus. 3 months ago, he had COVID-19 infection, after which the fever never resolved, with fatigue, weight loss, and lower extremity weakness. He is previously healthy with no significant medical, surgical or travel history. He has a no significant family history of chronic disease.

He was admitted for workup at another institution 1 month prior where he took 2 courses of Augmentin and Levofloxacin without improvement. The workup included negative blood cultures, and negative tests forHIV, syphilis, hepatitis B and C, brucella and tuberculosis, with negative anti-nuclear antibodies (ANA). FK has received the Pfizer mRNA COVID vaccine twice, 2 weeks apart a few months back with no complications.

Upon initial physical examination, he was febrile (38°C) and tachycardic (110 BPM). Cardiac auscultation showed a holosystolic murmur in the aortic area. Lower extremities showed mild atrophy.

The patient trans-thoracic echocardiography (TTE) showed a vegetation of the aortic valve with severe regurgitation (Figure 1), hence he was admitted for infectious endocarditis. Blood cultures were taken, and he was started on penicillin and gentamycin. Blood cultures and brucella, salmonella and coxiella serologies were negative. A complete autoimmune workup was also negative except for beta-2 glycoprotein.

On 27/3/22, he complained of dyspnea and a chest x-ray showed mild congestion, managed by furosemide and oxygen. Shortly after, he had sudden dyspnea with hypotension, desaturation and rapidly progressing cardiogenic shock. Repeat TTE showed acute decompensated right heart failure and pulmonary congestion. He underwent emergency bioprosthetic aortic valve replacement.

Intraoperatively, multiple coronary artery aneurysms were seen. The aortic valve was almost non-existent, extensively eroded without vegetations. It was replaced by a bovine valve. Coronary artery bypass grafting (CABG) could not be performed due to high mortality risk.

Valve cultures were negative, and pathology showed neutrophilic infiltration. The diagnosis of non-infectious endocarditis and Kawasaki-like vasculitis was made based on the gross vascular findings and pathologic evaluation, and he was discharged on Prednisone1 mg/kg/day taper and followed up in an out-patient setting.

Second admission:

Three months later, the patient presented to the ED for severe chest pain. Four days prior, he was having flu-like symptoms for which COVID-19 PCR tested positive.

He was found to have an anterior ST elevation myocardial infarction. A TTE showed septo-apical dyskinesia with severe dilatation of the aortic root. He received a loading dose of heparin and coronary angiography was performed (Figure 1). It showed a LAD stenosis and total occlusion of the diagonal artery. CT-Angio scan of the chest (Figure 2) showed an ascending aortic aneurysm of 7.3 cm diameter. TTE showed a severe dilatation of the sinus of Valsalva.

Cardiothoracic surgery were consulted, and an aortic root replacement was recommended. He was started on methylprednisolone pulse therapy followed by dexamethasone 6 mg daily. He also received 6mg/kg IV tocilizumab (600 mg) and IV immunoglobulins (IVIG) 3g/kg once to halt the inflammatory reaction. For fever in immunosuppression, he was covered with remdesivir, meropenem and vancomycin.

On 28/7/22, the patient underwent aortic aneurism repair. CABG was not performed because of high risk of rupture. Cultures of the ascending aorta were negative again, and pathology showed neutrophilic infiltration.

The patient was discharged on prednisone, mycophenolate mofetil and a prophylactic dose of trimethoprim/sulfamethoxazole.

Third admission:

The patient re-presented on 16/11/22 for chest discomfort with high grade fever, cough, and hemoptysis. He was found to be hypotensive to 80/60 mmHg and with elevated inflammatory markers. Due to his immunosuppressed status, hypotension and fever, he received meropenem, vancomycin and voriconazole to cover for a possible sepsis. Besides, due to his known history of on-going vasculitis affecting the coronary vessels and aortic root, he was started on tocilizumab and IVIG. His diagnosis was a demand myocardial ischemia with cardiogenic shock, the reasons behind this to be investigated, with highest suspicion of recurrence of the vasculitis.

On 19/11/22, his condition deteriorated again and TTE that showed severe mitral regurgitation and EF of 30%, with an aortic root aneurysm and prosthetic valve dehiscence with regurgitation. He underwent an emergent Bentall procedure and reimplantation of coronary arteries, replacing the bioprosthetic valve (Figure 3) with a metallic one. He recovered well and was placed on Prednisone taper again with daily baricitinib and clinical follow-up. Afterwards he was doing well and returned to supervised physical activity.

On September 15^th, 2023, the patient passed away of sudden onset ventricular fibrillation while at home.

Discussion

The case provides a rare depiction of a serious complication of COVID-19 infection, systemic vasculitis. At the time of the diagnosis, no clear management guidelines existed, therefore we extrapolated from what was known previously. COVID-19 infection overdrives the immune system, triggering a wide array of inflammation such as vasculitis.[6] It can trigger B and T lymphocytes, leading to cytokine release and vascular injury.[7]

Kawasaki vasculitis affects medium-sized arteries in children and is linked to viral infections. Since the emergence of COVID-19, Multisystem Inflammatory Syndrome in Children (MISC) emerged, which had a similar presentation.[8] MISC can present with cardiac manifestations, muco-cutaneous involvement and refractory fever.[9]

Many systemic reviews and case series then started studying vasculitis post COVID-19 infection, but in almost all, Kawasaki-like disease was only described in children. These findings, caused by COVID-19 usually present as a remitting fever with rashes, lymphadenopathy and mucosal lesions, diagnosed by biopsy. The prognosis in children is usually good with steroids and/or IVIG [10] Such a condition was never described in adults before. A systemic review published in France in 2020 state that it can be seen in African-French descent and is associated with self-limiting multi-system inflammation.[11] In January 2022, Elouardi et al described a very similar presentation in a 28 year-old female who succumbed due to severe myocardial damage due to inflammation and coronary artery disease and aneurysms due to a Kawasaki-like vasculitis after infection with COVID-19.[12]

The involvement of large arteries has been rarely described. By February 2022, only 4 case reports were published about it.[13] Aortitis can also be caused in the early viremic phase, where the viruses attack the endothelium, causing vasa vasorum intramural thrombosis.[14] This can progress to myocarditis or to CHF, such as in our patient.[4] No treatment guidelines for this condition exist. Data is mostly provided through case reports. A course of steroid taper has been suggested, in combination with other immunomodulatory agents, JAK inhibitors and IVIG.[6]

It is worth mentioning that there are reported cases of prolonged fever after COVID-19 vaccination itself, which presents as a chronic dysautonomia and fatigue. [16]. There are also cases of multi-system inflammation following the vaccine, which are a very rare entity. [17] However, such an augmented inflammatory response is mostly reported post-COVID infection rather than vaccination, and in the case of our patient, the symptoms started after an infection. In addition, the exacerbation of his symptoms in the second admission were directly after a re-infection. He did not have any complications after he took his vaccines.

Our patient presentation remains a unique one. He had a plethora of complications that were never described together. His presentation is a MISC-like reaction in an adult male, refractory to treatment. He had relapsed arteritis and valvopathy with every new infection. Reporting this case can shed light on the complications and treatment options for post-viral vasculitis considering scarce data with the subject.

Conclusion

COVID-19 has a variety of complications which can affect almost any organ in the body. Cardiovascular complications remain the rarest, yet the deadliest. Our patient had coronary vasculitis, aortitis and inflammatory aortic valve infiltration which were recurrent with every new COVID-19 infection he had, leading to 3 distinct open-heart surgeries. This is why reporting every case with such complications is crucial, to raise the possibility of clustering them into larger studies, that would provide more robust evidence-based data on managing such conditions.

References

1.      Thirkell P, Griffiths M, Waller MD. Management of Coronavirus Disease 2019 (COVID-19) Pneumonia. In: Janes SM, editor. Encyclopedia of Respiratory Medicine (Second Edition) [Internet]. Oxford: Academic Press; 2022. p. 342–9. https://doi.org/10.1016/B978-0-08-102723-3.00187-6.

2.      Liu C, Wu C, Zheng X, Zeng F, Liu J, Wang P, et al. Clinical features and multidisciplinary treatment outcome of COVID-19 pneumonia: A report of three cases. J Formos Med Assoc. 2020 Nov 1;119(11):1702–9. https://doi.org/10.1016/j.jfma.2020.04.008.

3.      Rabaan AA, Al-Ahmed SH, Muhammad J, Khan A, Sule AA, Tirupathi R, et al. Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm. Vaccines (Basel). 2021;9(5):436. https://doi.org/10.3390/vaccines9050436.

4.      Rajan R, Jayakumar RB, Al-Jarallah M, Dashti R, Kobablava ZD, Brady PA. Escardio. ESC; 2021 [cited 2023 Jul 27]. COVID-19 and the heart. Available from: https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart

5.      Shimada T, Itagaki H, Shirota Y, Endo T. Spontaneous Improvement of Aortitis Associated with Severe COVID-19 Infection—A Case Report. Medicina [Internet]. 2023;59(5). https://doi.org/10.3390/medicina59050816.

6.      Zebardast A, Hasanzadeh A, Ebrahimian Shiadeh SA, Tourani M, Yahyapour Y. COVID-19: A trigger of autoimmune diseases. Cell Biol Int. 2023 May 1;47(5):848–58. https://doi.org/10.1002/cbin.11997.

7.      Christodoulou M, Iatridi F, Chalkidis G, Lioulios G, Nikolaidou C, Badis K, et al. ANCA-Associated Vasculitis May Result as a Complication to Both SARS-CoV-2 Infection and Vaccination. Life. 2022;12(7):1072. https://doi.org/10.3390/life12071072.

8.      Woo HO. Recent research trends in Kawasaki disease-related infection. Clin Exp Pediatr. 2022 Jul 22;65(11):538–9. https://doi.org/10.3345/cep.2022.00696.

9.      Folga BA, Karpenko CJ, Grygiel-Górniak B. SARS-CoV-2 infection in the context of Kawasaki disease and multisystem inflammatory syndrome in children. Med Microbiol Immunol. 2023 Feb 1;212(1):3–12. https://doi.org/10.1007/s00430-022-00756-3.

10. Wong K, Farooq Alam Shah MU, Khurshid M, Ullah I, Tahir MJ, Yousaf Z. COVID-19 associated vasculitis: A systematic review of case reports and case series. Ann Med Surg (Lond). 2022;74:103249. https://doi.org/10.1016/j.amsu.2022.103249.

11. Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020 Jun 3;369:m2094. https://doi.org/10.1136/bmj.m2094.

12. Elouardi Y, Rebahi H, Zarrouki Y, Ziadi A, Younous S, Samkaoui MA. COVID-19 associated Kawasaki-like multisystem inflammatory syndrome in an adult. Rev Esp Anestesiol Reanim (Engl Ed). 2022 Jan 1;69(1):43–7. https://doi.org/10.1016/j.redare.2020.11.009.

13. Abu Hassan F, Abu Alhalawa M, Majdoubeh Y, Nepal A, Sufan SS. COVID-19 Aortitis: A Review of Published Cases. Cureus. 2022 Feb 15;14(2):e22226. https://doi.org/10.7759/cureus.22226.

14. Manenti A, Farinetti A, Manco G, Mattioli A. Vasculitis and aortitis: COVID-19 challenging complications. J Vasc Surg. 2021 Jan 1;73(1):347–8. https://doi.org/10.1016/j.jvs.2020.08.029.

15. Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K, Heidecke H, Schulze-Forster K, et al. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines. 2023;11(11):1642. https://doi.org/10.3390/vaccines11111642.

16. Lee SJ, Park DW, Sohn JW, Yoon HJ, Kim SH. COVID-19 Vaccine–Induced Multisystem Inflammatory Syndrome With Polyserositis Detected by FDG PET/CT. Clin Nucl Med. 2022;47(5). https://doi.org/10.1097/RLU.0000000000004094.
Mahmoud El-Hussein, Cima Hamieh, Eric Revue (Author)

Hippocampus infarct following a posterior cerebral artery occlusion

A 64-year-old gentleman, presented for subacute onset of short-term memory problem, preceded by headache, right arm numbness and visual disturbances. On neurological exam, he had anterograde amnesia, decreased pinprick sensation on his right arm and right homonymous hemianopsia.

Brain Magnetic Resonance imaging (MRI) and Magnetic Resonance Angiography (MRA) showed subacute ischemic lesions in the left occipital lobe, hippocampus and thalamus, caused by a distal occlusion of the left Posterior Cerebral Artery (PCA). A distal occlusion of the PCA led to multiple infarcts in different anatomical structures, causing a constellation of variant neurological signs.

Our case demonstrates an anterior hippocampus predominantly irrigated by the PCA.

Background

The Hippocampus is mainly supplied by the PCA and to a lesser degree from the anterior choroidal artery.^[2] Visual analysis with Diffusion-Weighted MRI (DWI) have identified 4 patterns of lesions affecting the hippocampus: complete, lateral, dorsal and circumscribed lesions in the lateral hippocampus.^[3] The PCA strokes are associated with headaches, visual symptoms, sensory-motor symptoms and neuropsychological symptoms^[5] headaches being the initial and most frequently seen manifestation of infarcts in the posterior rather than the anterior circulation.^[6] Other associated symptoms of posterior strokes include dizziness, confusion, nausea and vomiting.^[5] When the involved region is limited to the hippocampal area, amnesia and memory processing are mainly affected.^[3] This amnesia is usually temporarily, not lasting more than 24 hours, and it is called Transient Global Amnesia (TGA).^[7]

The prevalence of an isolated acute stroke of the hippocampus is 0.03% in a case series of 6800 patients.^[8] Ischemic lesions are well identified on DWI due to strong contrast between affected and unaffected tissues, which offers more details in stroke syndromes.^[4] The isolated involvement of the hippocampal structures enlighten its important role for memory processing.^[9]Transient Global Amnesia TGA is characterized by a transient anterograde or retrograde amnesia without decrease level of consciousness or any other cognitive disturbances.^[7] The patient usually shows a stereotyped behavior like repetitive questioning, due to short term memory impairment.^[10] Transient Global Amnesia TGA rarely present post an ischemic stroke, and it is reported with lesions on the unilateral or bilateral hippocampus.^[10,11]

In the case discussed below, we present a patient with multiple comorbidities, presenting to the emergency with solely confusion and retrograde amnesia, that later on turned to be caused by stroke in the posterior cerebral artery; a very rare case presentation that needs to be addressed so emergency physicians and other care givers don’t miss out this diagnosis.

Case Presentation

A 64-year-old male patient presented to the Emergency Department (ED) for altered general status mainly manifested by confusion, distress, and a high blood pressure. The patient is known to have hypertension, diabetes, dyslipidemia, with reported compliance to medical treatment, along with coronary artery disease, status post stent insertion in 2011.

In the Emergency Room, patient had severe headache, and a tingling sensation in his right arm involving the fingers; he denied any chest pain, dyspnea, orthopnea, fever or chills; he also denied any blurry vision or dipoplia, loss of consciousness, vertigo or dizziness. However, the patient’ family reported difficulty in arousing the patient from sleep during the morning of that same day with a retrograde amnesia of 30 minutes duration.

Vital signs were as follow: heart rate: 78 BPM, blood pressure: of 190/100 mmHg, temperature: 36.7^oC and oxygen saturation: 98% on room air. On review of system patient had no recent complaints or any signs of infection.

On physical exam, the patient was oriented to people and place but not to time, and he was not able to recall the events of the day prior to his presentation. Systolic ejection murmur radiating to the right carotids was heard on heart auscultation.

Neurologic exam showed intact Cranial Nerves (CN) III to XII, normal motricity in all limbs, positive pupillary light reflex, +2 DTR deep tendon reflexes and an equivocal Babinski on the right. There was decreased pinprick sensation on his right arm. On eye exam, the patient had a right homonymous hemianopsia.

The rest of the bed side exam was normal.

Stroke protocol was initiated, and brain MRI and MRA showed multiple areas of cortical ischemic lesions in the left occipital lobe, left hippocampus and left thalamus, which corresponds to subacute ischemic lesions in the territory of the left PCA (Figure 1).

The patient was immediately started on dual antiplatelet and anticoagulation and admitted to regular floor. During his stay, his home medications were continued and he was being followed by neurologic exam daily until discharge. Marked improvement was noticed at 1 month follow up in outpatient clinic with return to baseline in cognition.

Discussion

A 64-year-old gentleman, with uncontrolled hypertension and diabetes mellitus, presented for subacute onset of short-term memory problem, preceded by right arm numbness and visual disturbances. On neurological exam, he had anterograde amnesia reported by family that lasted less than 1 hour, decreased pinprick sensation on his right arm and right homonymous hemianopsia.

Two thirds of the hippocampus are vascularized by the P2 segment of the PCA and the rostral third is generally irrigated by segments of the anterior choroidal arteries ^[3]. A stroke to the PCA will therefore affect cognitive and memory function; the majority will show verbal long term memory deficit ^[12], and the duration of amnesia is usually at least 10 hours to few months ^[13]. However, the patient in this case discussion, had short term memory impairment, no verbal deficit, and the duration was very short. Also, in the literature, the TGA related to hippocampal infarcts was also associated with infarcts in other vasculature territories such as middle cerebral artery and internal carotid artery ^[14], and hence no direct causation between TGA and PCA strokes solely can be made. TGA as a symptom, can be caused by several triggers such as sexual intercourse, anxiety, head trauma, emotional distress…but no vascular triggers identified in the literature, symptoms last for an average of 6 hours ^[15].
In this case, brain MRI and MRA, showed subacute ischemic lesions in the left occipital lobe, hippocampus and thalamus (Figure1), caused by a distal occlusion of the left PCA (Figure 2). A distal occlusion of the PCA led to multiple infarcts in different anatomical structures, causing a constellation of variant neurological signs. It is highly important to recognize, diagnose, and rapidly intervene in similar cases, as data reported long term hippocampal atrophy and long term cognitive and memory impairment when injuries to hippocampus blood supply are left untreated ^[16].

Our case demonstrates an anterior hippocampus predominantly irrigated by the PCA and it highlights that a damage to the hippocampus can impair memory processes, and due to its vascularization by the PCA, the hippocampus is involved in large territorial strokes from adjacent structures and when affected, clinical symptoms and signs such as amnesia should draw urgent attention.

Conclusion

Symptoms like visual field defects, confusion, weakness and general status alteration are always associated with stroke to PCA. Due to false negative and radiological delay on early CT scans, brain MRI/MRA done in emergency is essential to ensure a rapid diagnosis and identification of the ischemic area. When there is an isolated hippocampal stroke, TGA is the most apparent symptom of presentation. Usually, the amnesia is transient and resolve within 24 hours after medical therapy.

Declarations

Authorship statement

All authors contributed equally and validated the final version of record.

Conflicts Of Interest

The Author(s) declare(s) that there is no conflict of interest.

Funding statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration

No registration applicable.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval

A written and verbal consent was taken from the patient.

References

1.      Stephens RB, Stilwell DL. Arteries and Veins of the Human Brain. Thomas; 1969. (Thomas books).

2.      Szabo K, Förster A, Jäger T, Kern R, Griebe M, Hennerici MG, et al. Hippocampal Lesion Patterns in Acute Posterior Cerebral Artery Stroke. Stroke. 2009 Jun 1;40(6):2042–5. https://doi.org/10.1161/STROKEAHA.108.536144.

3.      Gass A, Ay H, Szabo K, Koroshetz WJ. Diffusion-weighted MRI for the “small stuff”: the details of acute cerebral ischaemia. Lancet Neurol. 2004;3(1):39–45. https://doi.org/10.1016/s1474-4422(03)006215.

4.      Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature. Cerebrovasc Dis. 2000;10(3):170–182. https://doi.org/10.1159/000016053.

5.      Koudstaal PJ, van Gijn J, Kappelle LJ. Headache in transient or permanent cerebral ischemia. Dutch TIA Study Group. Stroke. 1991 Jun 1;22(6):754–9. https://doi.org/10.1161/01.STR.22.6.754.

6.      Arena JE, Rabinstein AA. Transient global amnesia. Mayo Clin Proc. 2015;90(2):264–272. https://doi.org/10.1016/j.mayocp.2014.12.001.

7.      Kumral E, Deveci EE, Erdoğan C, Enüstün C. Isolated hippocampal infarcts: Vascular and neuropsychological findings. J Neurol Sci. 2015;356(12):83–89. https://doi.org/10.1016/j.jns.2015.06.01.

8.      Naldi F, Baiardi S, Guarino M, Spinardi L, Cirignotta F, Stracciari A. Posterior hippocampal stroke presenting with transient global amnesia. Neurocase. 2017 Jan 2;23(1):22–5. https://doi.org/10.1080/13554794.2016.1270329.

9.      Bhai S, Biffi A, Bakhadirov K, Prasad S. Complete Anterograde Amnesia From Simultaneous Bilateral Hippocampal Infarction. The Neurohospitalist. 2014 Jul 1;4(3):165–6. https://doi.org/10.1177/1941874414524795.

10. Cipolotti L, Bird CM. Amnesia and the hippocampus. Current Opinion in Neurology. 2006;19(6):593–8. https://doi.org/10.1097/01.wco.0000247608.42320.f9.

11. Sparaco M, Ciolli L, Zini A. Posterior circulation ischaemic stroke—a review part I: anatomy, aetiology and clinical presentations. Neurol Sci. 2019 Oct 1;40(10):1995–2006. https://doi.org/10.1007/s10072-019-03977-2.

12. Arboix A, Arbe G, García-Eroles L, Oliveres M, Parra O, Massons J. Infarctions in the vascular territory of the posterior cerebral artery: clinical features in 232 patients. BMC Res Notes. 2011 Sep 7;4(1):329. https://doi.org/10.1186/1756-0500-4-329.

13. Munk AH, Starup EB, Lambon Ralph MA, Leff AP, Starrfelt R, Robotham RJ. Colour perception deficits after posterior stroke: Not so rare after all? Cortex. 2023 Feb 1;159:118–30. https://doi.org/10.1016/j.cortex.2022.12.001.

14. Hoyer C, Szabo K. Pitfalls in the Diagnosis of Posterior Circulation Stroke in the Emergency Setting. Front Neurol. 2021;12:682827. https://doi.org/10.3389/fneur.2021.682827.

15. Salerno A, Strambo D, Nannoni S, Dunet V, Michel P. Patterns of ischemic posterior circulation strokes: A clinical, anatomical, and radiological review. Int J Stroke. 2022 Aug 1;17(7):714–22. https://doi.org/10.1177/17474930211046758.

16. Caplan LR. UpToDate. 2023. Patient education: Ischemic stroke treatment (Beyond the Basics). Available from: https://www.uptodate.com/contents/ischemic-stroke-treatment-beyond-the-basics#H7298680

17. Coutts SB, Ankolekar S, Appireddy R, Arenillas JF, Assis Z, Bailey P, et al. Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial. Lancet. 2024 Jun 15;403(10444):2597–605. https://doi.org/10.1016/S0140-6736(24)00921-8.

18. Nguyen TQ, Tran MH, Phung HN, Nguyen KV, Tran HTM, Walter S, et al. Endovascular treatment for acute ischemic stroke beyond the 24-h time window: Selection by target mismatch profile. Int J Stroke. 2024 Mar 1;19(3):305–13. https://doi.org/10.1177/17474930231208817.
Camillia Jeddi, Marwane Bel Haj, Mohamed Kilani, Hafedh Thabet (Author)

Subarachnoid hemorrhage associated with ecstasy abuse in a young adult: a case report

3,4-Methylenedioxymethamphetamine (MDMA), is a synthetic amphetamine derivative. Its usage can be complicated by intracerebral or subarachnoid hemorrhage. Drug-related intracranial hemorrhage (ICH) is a relatively uncommon occurrence, often associated with an underlying vascular anomaly,

We report the case of a 28-year-old male with a history of Ecstasy abuse prior to the onset of a sever holocranial headache. Cerebral computed tomography angiography revealed a right sided sub-arachnoid hemorrhage and blood within all four ventricles, as well as a right sided pontine hematoma and an arteriovenous malformation.

As the drug epidemic continues to worsen, it is important to take a full drug history in patients presenting with a severe headache, and to not overlook ICH as a potential complication of recreational drug abuse.

Key Messages

- MDMA abuse complicated with an intracerebral accident is a well-recognized entity, but intracerebral hemorrhage remains relatively uncommon.

- We report the first case of ecstasy abuse complicated with intracerebral hemorrhage, to our knowledge, occurring in a in a young adult in Tunisia.

- Patients presenting with severe headache and a history of drug abuse might be at risk of developing intracerebral hemorrhage.

Introduction
3,4-Methylenedioxymethamphetamine (MDMA), is a synthetic amphetamine derivative.(1) It was first developed in 1912 and was popularized in the 1980s as a recreational street drug due to its strong empathogen as well as its stimulant and minor psychedelic properties.(1) It is usually taken orally in its tablet form (“Ecstasy”) or crystal form (“Molly” or “Mandy”).
MDMA abuse is associated with multiple potentially life threatening complications.(1) Intracranial hemorrhage (ICH), including intracerebral and subarachnoid hemorrhage, is a well-known yet relatively uncommon complication. Subsequent brain imaging often reveals an underlying vascular anomaly.(2–7)
After a literature review using MeSH and keywords (MDMA, arteriovenous malformation, intracerebral hemorrhage) in PubMed. We report the first case of ecstasy abuse complicated with intracerebral hemorrhage, to our knowledge, occurring in a in a young adult in Tunisia.

Case presentation
28-year-old male with a past history of infrequent MDMA abuse spanning years presented to the emergency department for an acute onset of a severe headache. At first medical contact he was afebrile and his vital signs were normal. On further history and physical exam, four and half hours prior to his presentation, he had ingested a half of tablet of “Ecstasy”. Following this ingestion, he presented with a headache, vomiting, dizziness and dysarthria. There had been no history of hypertension or headache and the patient reported no recent head trauma or loss of consciousness. The patient denied any history of other substance abuse. During his stay at the ED his symptoms progressed and he became sleepy but conscious and orientated. Verbal and motor response, as well as eye opening, were all normal. Pupils were symmetrical and not dilated. Neurologic examination found a nuchal rigidity but Kernig and Brudzinski’s signs were both negative. There was no focal deficit and no signs of head trauma. Laboratory tests showed a white blood cell count of 16800 cells per microliter (normal range (NR) : 4.5 to 11.0 × 109/L), hyperlactatemia of 4.5 mmol/L (NR : 0.5-2.2) and hyperglycemia at glucose 11 mmol/L (NR : 4 - 7 mmol/L ). The other tests including hemostasis and electrolytes were within NR. Urine sample analysis revealed the presence of MDMA. Tests for other psychoactive substances such as cocaine, heroin and benzodiazepine as well as blood alcohol were all negative. A computed tomography (CT)- head scan was obtained and showed a right-sided sulcal sub-arachnoid hemorrhage and blood within all four ventricles, as well as a right-sided pontine hematoma (figure 1 A and B). Within the latter, contrast-enhanced CT showed an arteriovenous malformation (figure 2).

The patient was admitted to a neurosurgery unit. The AVM was classified as 4 according to the Spetzler Martin scoring system, thus a conservative treatment was adopted and endovascular embolization of the AVM was scheduled but refused by the patient. He remained stable with resolution of his headaches and no neurological deterioration. He was discharged home on day 7 of admission with a spontaneous regression of the hematoma, thus a ventricular shunt was not performed, on follow up, the patient remained asymptomatic and no complications were reported.

Discussion
MDMA is a synthetic amphetamine derivative.(1) It is taken orally to induce pleasurable feelings such as loss of inhibition, euphoria and empathy and is commonly associated with raves, concerts and dance parties .(1) It has a myriad of adverse effects, such as tachycardia, arterial hypertension, nausea, bruxism, headache, blurred vision, insomnia, anxiety and agitation , as well as more serious complications such as rhabdomyolysis, hyperpyrexia, cardiac arrythmia, hepatic necrosis and disseminated intravascular coagulation.(1) Among its complications, ICH is a well-recognized entity, (2–7) but remains relatively uncommon. To the best of the authors’ knowledge, this represents the first reported case of ICH following ecstasy abuse in Tunisia. Previously reported cases of drug induced ICH have most often revealed an underlying vascular anomaly, mainly cerebral arteriovenous malformations and aneurysms. (2,3,5). However, it is possible that the latter may form either acutely in response to the drug itself, or progressively from repeated abuse(2,5). Furthermore, some case reports of ICH following MDMA abuse have shown no unusual findings in the angiogram,(6) suggesting that a preexisting vascular anomaly is neither necessary nor sufficient to induce it. A summary of cases reported in literature are is provided in table 1. To this date, MDMA’s exact role in precipitating an intracranial hemorrhage is still unclear. Two main mechanisms of action have been postulated in literature: Cerebral vasculitis and transient elevated blood pressure. (2,5)

The proposition of cerebral vasculitis as a possible mechanism stems from MDMA's resemblance to amphetamine,(5) supported by substantial evidence linking the latter to at least some level of cerebral angiitis. Citron et al.(8) reported 14 cases of necrotizing angiitis in drug abusers, twelve of which had previously used methamphetamine intravenously, and one of which admitted to using it exclusively. Moreover, cerebral angiitis has been experimentally produced in rhesus monkeys following a two week intravenous administration of amphetamine, with the angiographic findings showing an arterial “beading” immediately after its administration.(9)
In the case of MDMA itself, some case reports of MDMA induced ICH reported arterial “beading”.(7) However, to the finest of the authors’ knowledge, there is no direct evidence linking it with cerebral vasculitis.
Transient surge in blood pressure has also been proposed as a causal mechanism.(2) Hypertension is a well-documented adverse effect of MDMA and is related to its sympathomimetic effect.(1) It has been the traditional explanation for drug-induced ICH in the context of a preexisting cerebrovascular anomaly, especially AVMs.(5) This is clearly likely to be the case in our patient.
Another potential mechanism has been suggested through an experimental study on mice,(10) which showed that exposure to methamphetamine elicited an initial five-minute increase of cerebral blood flow, followed by a prolonged decrease over 30 minutes. This study also showed a sustained vasoconstriction of the pial arterioles following the exposure. However, more studies are needed in order to elucidate how much of a role this mechanism plays.

We recognize some limitations in our report. The CT angiography has a lower sensitivity in the detection rate of cerebrovascular anomalies than the gold standard, catheter angiography. With the latter not being performed, it is possible that some vascular anomalies, such as small aneurysms, and especially vasculitis, have evaded detection.

Concerning management, according to Expert Consensus on the Management of Brain Arteriovenous Malformations in 2019, brain arteriovenous malformations (bAVMs) can be treated by one or a combination of the following treatment modalities, namely embolization, radiosurgery, or microsurgical resection. The committee made recommendations based on age, eloquence of adjacent cortex, feeders’ example superficial versus deep. These items were gathered to create the Spetzler Martin scoring system, which is an easy and successful scoring tool. In fact, Grade 4 and 5 arteriovenous malformations (AVMs), conservative management may be the best option, which is the case in our patient. (11)

Conclusion
We describe a case of ICH complicating MDMA abuse in a young adult. Cerebral accidents are a well-recognized entity in these patients, but ICH remains relatively uncommon. Patients with MDMA abuse are at risk for intracerebral accidents including intracerebral hemorrhage. A full medical history including illicit drug abuse must be taken in patients presenting with the onset of a severe headache.

Declarations
Authorship statement
All authors contributed equally and validated the final version of record.

Conflicts Of Interest
The Author(s) declare(s) that there is no conflict of interest.

Funding statement
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration
No registration applicable.

Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval
Ethical approval for this study was not required.

References

1.      Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001 Oct 2;165(7):917–28.

2.      Gledhill JA, Moore DF, Bell D, Henry JA. Subarachnoid haemorrhage associated with MDMA abuse. J Neurol Neurosurg Psychiatry. 1993 Sep 1;56(9):1036–7. https://doi.org/10.1136/jnnp.56.9.1036.

3.      Auer J, Berent R, Weber T, Lassnig E, Eber B. Subarachnoid haemorrhage with “Ecstasy” abuse in a young adult. Neurol Sci. 2002 Oct 1;23(4):199–201. https://doi.org/10.1007/s100720200062.

4.      Harries DP, De Silva R. ‘Ecstasy’ and Intracerebral Haemorrhage. Scott Med J. 1992 Oct 1;37(5):150–2. https://doi.org/10.1177/003693309203700508.

5.      Mcevoy AW, Kitchen ND, Thomas DGT. Intracerebral haemorrhage and drug abuse in young adults. Br J Neurosurg. 2000 Jan 1;14(5):449–54. https://doi.org/10.1080/02688690050175247.

6.      Kahn DE, Ferraro N, Benveniste RJ. 3 cases of primary intracranial hemorrhage associated with “Molly”, a purified form of 3,4-methylenedioxymethamphetamine (MDMA). J Neurol Sci. 2012 Dec 15;323(1):257–60. https://doi.org/10.1016/j.jns.2012.08.031.

7.      Lee GYF, Gong GWK, Vrodos N, Brophy BP. ‘Ecstasy’-induced subarachnoid haemorrhage: an under-reported neurological complication? J Clin Neurosci. 2003 Nov 1;10(6):705–7. https://doi.org/10.1016/S0967-5868(03)00151-6.

8.      Citron BP, Halpern M, McCarron M, Lundberg GD, McCormick R, Pincus IJ, et al. Necrotizing Angiitis Associated with Drug Abuse. N Engl J Med. 1970 Nov 5;283(19):1003–11. https://doi.org/10.1056/NEJM197011052831901.

9.      Rumbaugh CL, Bergeron RT, Scanlan RL, Teal JS, Segall HD, Fang HCH, et al. Cerebral Vascular Changes Secondary to Amphetamine Abuse in the Experimental Animal. Radiology. 1971 Nov 1;101(2):345–51. https://doi.org/10.1148/101.2.345.

10. Polesskaya O, Silva J, Sanfilippo C, Desrosiers T, Sun A, Shen J, et al. Methamphetamine causes sustained depression in cerebral blood flow. Brain Res. 2011 Feb 10;1373:91–100. https://doi.org/10.1016/j.brainres.2010.12.017.

11. Samaniego EA, Dabus G, Meyers PM, Kan PT, Frösen J, Lanzino G, et al. Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations. Stroke. 2024 May 1;55(5):1449–63. https://doi.org/10.1161/STROKEAHA.124.046725.
Romain Jouffroy, Basile Gilbert, Papa Gueye, Léa Thomas, Emmanuel Bloch Laine, Patrick Ecollan, Josiane Boularan, Vincent Bounes, Benoit Vivien (Author)

Association between septic shock prehospital hemodynamic parameters improvement and 28-day mortality: Septic shock prehospital hemodynamic parameters improvement and 28-day mortality

Objective: The early hemodynamic optimization of septic shock patients is a cornerstone of care to hope for a better outcome, e.g., mortality decrease. However, in the prehospital setting, hemodynamic evaluation is restricted to micro and macrocirculatory clinical parameters.

This study aims to assess the relationship between micro and macrocirculatory hemodynamic parameters improvement and 30-days mortality among septic shock patients being taken care of for by a mobile intensive care unit (mICU) in the prehospital setting.

Methods: We performed a retrospective multicenter study, from January 2015 to November 2019 including septic shock patients requiring pre-hospital mICU intervention.

Results: Three hundred thirty-seven patients were analyzed. The mean age was 69 ± 15-years-old and 226 of which 67% were male patients. One hundred thirty-six patients (40%) had previous hypertension. Pulmonary infection was the main cause of septic shock (46%) and 30-days mortality reached 30%.

After propensity score analysis, for the macrocirculation: when systolic blood pressure increased by at least 30mmHg the odd ratio (OR) for 30-days mortality was 0.77 [0.65-0.84], when diastolic blood pressure increased by at least 5mmHg, the OR for 30-days mortality was 0.95 [0.88-0.99], when mean blood pressure increased by at least 30%, the OR for 30-days mortality was 0.88 [0.77-0.92] and when the heart rate decreased by at least 30 bpm, the OR for 30-days mortality was 0.62 [0.55-0.76]. For microcirculation, when the mottling score decreased by at least 2 points, the OR for 30-days mortality was 0.83 [0.75-0.91].

Conclusion: In this study, we report that prehospital improvement in micro and macrocirculatory parameters are associated with 30-days mortality rate decrease.

Introduction

Each year, 30 million people worldwide [1–3] suffer from sepsis, leading to around 11 million deaths [3] approximately one third of in-hospital deaths [4]. Sepsis mortality rate varies from 10 to 20% for sepsis and even up to 50% - 60% for septic shock, the most severe form of sepsis [5–7].
Among the factors that have made it possible to improve patient survival, we find early diagnosis, early referral to an appropriate facility, and the implementation of adequate therapies [8]. A comprehensive management strategy combining the above factors, "bundle of care", has proven its effectiveness in improving the outcome of septic shock [8–15]. The management of sepsis requires a dynamic approach constantly adapted to the severity of the patient [16,17]. For the more serious forms, the more rapid and aggressive management is the most effective [18]. Previous studies have identified that 70% of sepsis are present before arrival at the hospital, justifying the need to implement early diagnostic and therapeutic strategies from prehospital care [19].
From a pathophysiological point of view, a sufficient tissue perfusion pressure, assessed by mean arterial pressure (MAP), is necessary for antibiotic therapy to diffuse in infected tissues [18,20]. Obtaining a correct MAP requires hemodynamic optimization, including vascular filling in the first hours, even norepinephrine administration if necessary [8]. Hypertension is associated with mortality and morbidity rise [21]. In addition, hypertension is the main medical diagnosis in patients with septic shock [22]. A recommended target MAP of 65 mmHg is probably not suitable for all patients with chronic hypertension [8,23–25].
The aim of this retrospective observational study was to assess the relationship between hemodynamic parameters improvement during the pre-hospital phase of septic shock and 30-days mortality rate after hospital admission.

Patients and methods
The specificity of the French out-of-hospital emergency and care system is based on the French prehospital emergency system; the SAMU (Service d’Aide Medicale Urgente). The SAMU organization allows prehospital care equivalent to an intensive care unit by an emergency physician and a nurse. In the context of septic shock, fluid volume expansion, norepinephrine administration and antibiotic therapy can be addressed in the prehospital setting according to the recommendations [26].
We performed a retrospective, multicenter study, from January 2015 to November 2019, including patients with septic shock, treated in prehospital setting by a mICU team from Toulouse hospital, Necker hospital, Lariboisière, Pitié Salpêtrière hospital, Hôtel Dieu and Paris Fire Brigade.
The patients received care according to the recommendations of the protocols and habits of the pre-hospital and hospital teams.
The patients included in the study were those treated by a mICU team for prehospital septic shock, according to the definition of the “sepsis 3” conference in 2016 [17]. Underage patients, deprived of their liberty, under guardianship or curatorship as well as pregnant women were not included in the study.
The data analyzed included demographic data (age, weight, height), medical history, current treatments, suspected origin of sepsis, and schedules related to the pre-hospital care phase (time of call from the SAMU, time of arrival on site of the mICU team and time of arrival at the hospital), the data of the clinical examination collected at the initial stage of the prehospital setting (1st contact with the patient) and at the end of the pre-hospital phase (last values before hospital admission) - heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), pulsed oxygen saturation (SpO2), respiratory rate (RR), Glasgow coma scale (GCS), body core temperature, capillary blood sugar, capillary refill time, skin mottling score [27] - and lactatemia at the start of pre-hospital. Skin mottling score is a clinical score ranging from 0 to 5 associated with sepsis-outcome.
The data describing the treatments administered were also collected (vascular filling (products, volume), use of vasopressors (products, dosage), mechanical ventilation parameters if applicable, antibiotic therapy (qualitative and quantitative).
IGS II, SAPS II and SOFA scores were calculated from hospital data on day 1 [28,29]. These scores are used to predict sepsis outcome among patients admitted in ICU.
The study was approved by the ethics committee of the French Society of Anesthesia and Resuscitation on December 12, 2017 (reference number: IRB 00010254-2017-026).

Statistical analysis
The primary outcome was the 30-days mortality after hospital admission. The absolute variations (initial value in the prehospital setting – final value before hospital admission) of SBP, DBP, MAP and HR were calculated in order to evaluate the treatment effect on the macrocirculation. An increase of 30 mmHg of SBP, 5 mmHg of DBP and 30% MAP as well as a decrease of 30 beats per minute during pre-hospital care, were chosen at the beginning because of their clinical relevance representing the positive effect on hemodynamic treatment of septic shock. For microcirculation, an absolute variation in the mottling score of at least 2 points was considered to be significantly representative of a positive treatment effect of pre-hospital hemodynamic management of septic shock. The components of the hemodynamic treatment, vascular filling and/or administration of norepinephrine, were not analyzed individually but as a whole, given the absence of protocolization (possibility of using one and/or other therapies left to the discretion of the team in charge of the patient).

Univariate and multivariate analysis were performed to assess the relationship between each covariate and 30-days mortality.
The results are expressed as an absolute value with relative percentage for the qualitative variables, as a mean with standard deviation for the quantitative variables of normal distribution and as a median with interquartile range (1st quartile - 3rd quartile) for the quantitative variables of non-Gaussian distribution.

Univariate analysis comparisons were made using Student's t-test for quantitative variables of normal distribution, Wilcoxon's test for continuous variables of non-Gaussian distribution, and Chi-square test for categorical variables.
In order to reduce the potential effect of confounding covariates on the relationship between 30-days mortality and changes in SBP, DBP, MAP, HR and mottling score, a propensity score analysis was performed. The propensity score was estimated using a logistic regression based on confounding covariates on 30-days mortality: pre-hospital duration, vascular filling volume, norepinephrine infusion, initial values of SBP, DBP, MAP, HR, and skin mottling score. The “nearest neighbor matching” method was used to match patients from the logit of the propensity score [30]. A threshold of 10% of the absolute differences of the means was used to estimate the balance of covariates after matching [31]. After matching, the association between 30-days mortality and micro and macrocirculation parameters was evaluated by logistic regression.
The tests performed are two-sided with a p-value <0.05 defining the significance of the difference. Statistical analyzes were performed using R software version 3,4,2 (http://www.R-project,org; the R Foundation for Statistical Computing, Vienna, Austria).

Results
In this study, 337 patients with septic shock, according to the definition of the consensus conference “sepsis 3” of 2016, were retrospectively analyzed [17].
Global characteristics of the population are summarized in Table 1.

Suspected origin of septic shock during pre-hospital care was mainly pulmonary (n=153, 46%), digestive (n=78, 23%) and urinary (n=52, 15%).

Univariate analysis

The results of the univariate analysis are summarized in Table 2.

Multivariate analysis
After matching by propensity score, the association between 30-days mortality and micro and macrocirculation parameters were evaluated by logistic regression. The balance of covariates after matching is represented by Figures 1, 2, 3, 4 and 5 for SBP, DBP, MAP, HR and skin mottling score respectively.
* Micro-circulation
For microcirculation, when the skin mottling score decreased by at least 2 points, then the OR of death at D30 was 0.83 [0.75-0.91].
* Macro-circulation
Thus, for macrocirculation, between the start and the end of pre-hospital care:
- when the SBP increased by at least 30mmHg then the OR of death on D30 was 0.77 [0.65-0.84],
- when the DBP increased by at least 5mmHg then the OR of death on D30 was 0.95 [0.88-0.99],
- when the MAP increased by at least 30% then the OR of death on D30 was 0.88 [0.77-0.92],
- when the HR decreased by at least 30 beats per minute then the OR of death at D30 was 0.62 [0.55-0.76].

Discussion
In this study, we observed that the improvement in the micro and macrocirculatory hemodynamic parameters of patients with septic shock treated in pre-hospital setting by a mICU team is associated with a 30-days mortality decrease.
Indeed, data from previous studies had reported that circulatory, clinical or biological failures are associated with worsening of the patient [32–36].
From a pathophysiological point of view, the inflammation caused by sepsis is associated with vasodilation and vascular permeability as reflected by micro and macrocirculatory parameters [37].
In prehospital setting, only clinical parameters are available to assess the micro and macrocirculatory. For macro-circulation, MAP being considered to reflect tissue perfusion, the importance of maintaining or restoring it to reduce the occurrence or worsening of organ failures appears essential. Since invasive monitoring is rarely possible in pre-hospital, a non-invasive MAP measurement is the only one that can be used in pre-hospital. For microcirculation, the advisability of considering clinical parameters as a therapeutic target has already been reported for skin mottling score and capillary refill time [38].
For optimal management, the "sepsis 3" conference of 2016 [17], recommends a fluid volume expansion initiated in the first hours, followed by the administration of norepinephrine even if the MAP remains below 65 mmHg [8,17]. However, recent studies show the benefits of using norepinephrine earlier in order to reduce the time to target MAP and improve survival [39–41].
A MAP target of 65 mmHg for all patients without taking into account their personal history does not appear physiologically logical. Indeed, among patients suffering from, pathophysiological changes aim to allow adaptation to the higher blood pressure regimen [42–44]. Previous studies have reported the benefit of a higher blood pressure target in hypertensive population without altering heart function [45–47], microcirculation [48] and kidney function [23]. Thus, Lee et al. reported that a MAP target between 75 and 85 mmHg is associated with increased survival in hypertensive patients with septic shock [49]. In addition, it has been reported that the shorter the duration of the period of low blood pressure, e.g., hypoperfusion, the better is the survival [50].

However, this study has limitations. First, this is a retrospective study. Second, the study was conducted in an adult population exclusively; therefore, the results cannot be extrapolated directly to a pediatric population. Third, the external validity is low due to the specificity of the French pre-hospital emergency medical system. Fourth, the study population is represented by septic shock, therefore the results cannot be extrapolated to non-septic shock patients, i.e., sepsis. Nevertheless, the micro and macrocirculatory hemodynamic parameters reported in this study are simple and accessible since the prehospital setting to assess the severity and the treatment effect of septic shock cared for by a mICU team. Further studies are needed to confirm whether these parameters could be used to increase prehospital management and triage of septic shock.

Conclusion
In this study, we report an association between survival and micro and macrocirculatory hemodynamic parameters improvement among septic shock patients cared for by a mICU team in the prehospital setting. An early intervention, from the prehospital setting, personalized mean arterial pressure management appears desirable among hypertensive patients.

Author contributions
All authors contributed equally and validated the final version of record.

Conflicts Of Interest
The Author(s) declare(s) that there is no conflict of interest.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration
No registration applicable

Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval
The study was approved by the ethics committee of the French Society of Anesthesia and Resuscitation on December 12, 2017 (reference number: IRB 00010254-2017-026).

References

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Chady El Tawil, Anwar Alabdulraheem, Keira Kilmartin, Jade Seguin (Author)

Lemierre Syndrome in a Pediatric Patient with Nephrotic Syndrome: a Case Report

Lemierre syndrome is a rare thrombotic complication of head and neck infections. Nephrotic syndrome is sometimes treated by immunosuppressive medications that can present with severe infections without a fever. The association of the two diseases is extremely rare.

We report the first case, to our knowledge, of Lemierre syndrome in an eleven-year-old patient with nephrotic syndrome on Tacrolimus.

A patient with nephrotic syndrome is at higher risk for all kinds of thrombotic events. Also, being on immunosuppressive therapy can lead to late presentation and the absence of fever. A low level of suspicion in those patients can lead to timely diagnosis and early treatment.

Key Messages:
Ø What is already known on this topic – Nephrotic syndrome is a thrombophilic condition and Lemierre syndrome is a rare complication of head and neck infections.
Ø What this study adds – We report the first case of Lemierre syndrome, to our knowledge, occurring in a child with nephrotic syndrome on immunosuppressive therapy.
Ø How this study might affect research, practice, or policy – Patients of immunotherapy and with nephrotic syndrome might be at a higher risk of developing Lemierre syndrome.

Introduction

Lemierre syndrome (LS) is a rare complication of head and neck infections in the pediatric population. Classically the syndrome consists of suppurative thrombophlebitis of the internal jugular veins secondary to infection of the oropharynx with Fusobacterium necrophorum bacteremia (1). The bacterial pharyngitis is usually seen with peritonsillar abscess which can rupture and spread to the carotid sheath that contains the internal carotid artery and internal jugular vein. This leads to seeding of the internal jugular vein with bacteria and the formation of thrombophlebitis which can then spread systemically. Typical presentation includes recent oropharyngeal symptoms which may resolve followed by progression to high fever, headache, neck pain, and respiratory symptoms (2). Infection may occur in previously healthy children and in individuals with chronic conditions such as systemic lupus erythematosus and antiphospholipid syndrome (3).

Nephrotic syndrome (NS) is defined as proteinuria of > 3 g/day and hypoalbuminemia (<30 g/L). The protein loss leads to loss in Immunoglobulins which predisposes patients to infections. NS is also associated with hypercoagulability and patients are at increased risk of venous thrombosis. The incidence of venous and arterial thromboembolism is low in children occurring in only 2-3% of cases (4). Only one pediatric case report of thrombosis of the internal jugular vein in a child with NS without any evidence of infection, has been published (5).

After a literature review using MeSH and keywords (Lemierre syndrome, NS, thrombophlebitis) in PubMed, we report the first case of LS, to our knowledge, occurring in a child with NS on immunosuppressive therapy.

Case presentation

11-year-old boy, known for NS treated with Tacrolimus, presented for headache and neck pain of 2 weeks duration with decreased oral intake and urine output. He had previously sought medical attention twice but was diagnosed with muscular neck sprain and discharged home. His symptoms progressed and he was brought to the emergency department. At triage, the patient was in severe pain, appeared uncomfortable and was found to have a stiff neck. He was afebrile and his vital signs were normal.

On further history and physical exam, the boy looked tired and was complaining of occipital headache and sore throat. The patient had a muffled voice and right sided peritonsillar swelling. Laboratory tests showed a white blood cell count of 14100 cells/microliter with 82.9% neutrophils, high C-Reactive Protein of 122 mg/L (12.2 mg/dL) and 0.3 g/L of protein in the urine, the other tests including electrolytes were normal. Computed tomography angiogram was obtained and showed a large retropharyngeal abscess with acute thrombosis of the proximal third of the right intrajugular vein (Fig. 1).

The patient was started on piperacillin tazobactam and sent to the operation room for emergent drainage. After the drainage, the patient was started on anticoagulation, but his stay was complicated by reformation of the abscess that required repeat incision and drainage. He was discharge home on day 8 of admission with close follow up with ENT.

Discussion

We describe the first known case of LS in a patient with NS. Despite reduction in mortality from LS with antimicrobial therapy (6), there are reports of increasing rates of F necrophorum infections (1) and clinicians need to be aware of this aggressive infection as early diagnosis and therapy is critical. There are several published case studies over the past years that report cases of LS in previously healthy individuals and associated thrombosis in different sites, including lungs, bones, and brain. Also, LS was described in patients with different medical conditions including systemic lupus erythematosus, different types of arthritis among others (7, 8). The emergency physician should have a low threshold for LS in any patient with such conditions presenting with neck pain, sore throat, fever, or high inflammatory markers to the emergency department.

LS has been reported in all ages, but approximately 70% of the documented cases were in adolescents and young adults between 16-25 years old. Typically, patients present with infection in the oropharynx, fever, neck stiffness, cervical lymphadenopathy which invades the lateral pharyngeal space leading to serious complications.

Fusobacterium necrophorum is the most common cause of LS. It is an anaerobic, nonmotile, pleomorphic, gram-negative bacillus that exists in normal oral flora. It becomes pathogenic when there is a break in the oral mucosa with infections such as pharyngitis.
The pathophysiology of the thrombotic events in LS remains unclear. Some studies attribute it to underlying inherited thrombophilia whereas in other cases, it is believed to be caused by a cascade of enzymes activities triggered by the bacteria. The thrombotic process caused by fusobacterium is multifactorial. Like any thrombosis event, it is mainly the result of Virchow’s triad: systemic hypercoagulability, venous stasis by vessel occlusion caused by inflammation, and endothelial damage by the direct endovascular invasion of the bacteria.

F necrophorum consists of multiple virulence factors, including lipopolysaccharide endotoxin, leucocidin, hemolysin, lipase, hemagglutinin, and a cytoplasmic toxin, all contribute to the thrombotic process. These enzymes may produce endothelial damage and diffuse intravascular coagulation by promoting platelet aggregation in an anaerobic environment, which also permits F necrophorum to grow (9).

In our case, the patient is known for NS, he was at higher risk of developing complications of LS. As it is commonly known, NS is defined by increased urinary protein losses, edema, hypoalbuminemia, hyperlipidemia, and can be complicated by infectious and thromboembolic manifestations. The pathogenesis of platelet hyperaggregability and its association with NS has been widely reported throughout the years. It is reported that hypoalbuminemia leads to increased thromboxane A2 production in platelets, which trigger platelet aggregation. Also, increased levels of low-density lipoprotein may induce platelet aggregation (4). Patients with NS characteristically lose plasma proteins in the urine (factors IX, X, and XII, prothrombin, antithrombin, and α2-antiplasmin), which inhibit the systemic hemostasis. On the other hand, high molecular weight proteins are exceedingly synthesized and primarily promote thrombosis. These proteins include factor V, factor VIII, von Willebrand factor, fibrinogen, and α2-macroglobulin accumulate. Factor VII has an essential role in starting the coagulation cascade. It is shown that increased factor VIII led to an increase in the risk factor for thromboembolism in nephrotic patients (10).

So, with all these factors, a patient with NS is at higher risk for all kinds of thrombotic events, especially that our patient was also on immunosuppressive therapy which can explain his late presentation and the absence of fever.

Conclusion

We describe a case of LS in a child with NS. LS is a rare disease that has a high morbidity and mortality if not diagnosed and treated early. Patients with NS are at higher risk for thrombotic event including thromboembolism of the internal jugular vein. A low level of suspicion in those patients can lead to timely diagnosis and early treatment.

Declarations
Author contributions
All authors contributed equally and validated the final version of record.

Conflicts Of Interest
The Author(s) declare(s) that there is no conflict of interest.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration
No registration applicable

Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval
Ethical approval for this study was not required.

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