Can Wernicke's Encephalopathy Be Precipitated by Administering

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Case Reports in Clinical Medicine, 2019, 8, 239-273 https://www.scirp.org/journal/crcm ISSN Online: 2325-7083 ISSN Print: 2325-7075

Table of Contents

Volume 8 Number 9 September 2019

A Case with XXXX Syndrome Who Was Incidentally Diagnosed during Examination for Suspected Post-Human Papillomavirus Vaccination Syndrome A. Hineno, T. Kosho, H. Kato, Y. Sekijima, S. Ikeda……….…...... …...... …239 Can Wernicke’s Encephalopathy Be Precipitated by Administering Glucose before Thiamine in Severely Malnourished or Alcoholic Patients? J. Altman, M. F. Ryan……...... …245 Spontaneous Bilateral Carotid Artery Dissection Revealing Multifocal Fibromuscular Dysplasia W. Bnouhanna, W. Fakir, M. Rahmani, M. Benabdeljlil, S. Aïdi………...... …...... …250 Fabella Syndrome: A Typical Case of Misdiagnosis and Discussion M. H. K. Alsharif, J. M. Almasaad, N. M. Bakhit, K. M. Taha, M. I. Eltahir, M. A. Alfaki, A. Y. Elamin, M. A. Noureddin...... …258

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For manuscripts that have been accepted for publication, please contact: E-mail: [email protected] Case Reports in Clinical Medicine, 2019, 8, 239-244 https://www.scirp.org/journal/crcm ISSN Online: 2325-7083 ISSN Print: 2325-7075

A Case with XXXX Syndrome Who Was Incidentally Diagnosed during Examination for Suspected Post-Human Papillomavirus Vaccination Syndrome

Akiyo Hineno1,2, Tomoki Kosho3, Hiroyuki Kato4, Yoshiki Sekijima2, Shu-ichi Ikeda1*

1Intractable Disease Care Center, Shinshu University Hospital, Matsumoto, Japan 2Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan 3Department of Medical Genetics, Shinshu University Hospital, Matsumoto, Japan 4Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan

How to cite this paper: Hineno, A., Ko- Abstract sho, T., Kato, H., Sekijima, Y. and Ikeda, S. (2019) A Case with XXXX Syndrome Who A 19-year-old Japanese woman was referred to us with the complaints of Was Incidentally Diagnosed during Exami- arthralgia and meralgia following human papillomavirus (HPV) vaccination. nation for Suspected Post-Human Papillo- She received HPV vaccination at the age of 15 years and three years later, she mavirus Vaccination Syndrome. Case Re- ports in Clinical Medicine, 8, 239-244. developed intermittent arthralgia, meralgia, and numbness in limbs. There https://doi.org/10.4236/crcm.2019.89029 were no orthostatic dysregulation symptoms. She had hypertelorism, and brachydactyly in both the hands, and revealed mild cubitus varus deformity Received: August 15, 2019 with lateral instability. X-ray examination disclosed hypoplasia of the humer- Accepted: September 3, 2019 Published: September 6, 2019 al capitellum and trochlea in elbow joints. G-banded chromosomes were shown to be composed of 48, XXXX. She was, therefore, diagnosed with XXXX syn- Copyright © 2019 by author(s) and drome, which explained the reason for her limb symptoms. Although some Scientific Research Publishing Inc. girls with HPV vaccination complain of various symptoms including limb This work is licensed under the Creative Commons Attribution International pain and numbness, exact underlying cause of these symptoms needs to be License (CC BY 4.0). ascertained carefully for reaching a final diagnosis. http://creativecommons.org/licenses/by/4.0/ Open Access Keywords XXXX Syndrome, Tetrasomy X, Human Papillomavirus Vaccine, Arthralgia, Complex Regional Pain Syndrome

1. Introduction

Human papillomavirus (HPV) vaccine was introduced for the prevention of ute- rine and cervical cancer [1]. Subsequently, in several countries, a significant num-

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ber of adolescent girls with HPV vaccination complained of possible adverse effects, such as general fatigue, chronic headache, arthralgia, limb pain and weakness, and difficulty in learning [2]-[9]. This post-HPV vaccination syndrome is explainable by a combination of orthostatic dysregulation, chronic regional pain syndrome (CRPS), and brain cognitive dysfunction [10]. Additionally, some patients reported having developed other diseases after HPV vaccination [11] [12]; however, the relationship between HPV vaccination and the onset of other diseases remains unclear. Here, we report a case wherein the patient was diagnosed with XXXX syndrome during examination for suspected post-HPV vaccination syndrome. We obtained the patient’s consent for publishing this case report.

2. Case Report

A 19-year-old Japanese woman was referred to our hospital with a compliant of persistent joint pain, especially with both the elbows. She had a history of postural hand tremor and her father experienced a similar disorder. Further, she reported of a delay in verbal development, learning disability, school refusal, and had been suffering from depression requiring multidrug therapy during child- hood. She received three injections of HPV vaccine at the age of 15 years; the first dose of HPV vaccine (Cervarix®) in September 2011 and third dose in March 2012. After three years, she developed intermittent meralgia, arthralgia, and numbness in the limbs, which occasionally hindered her daily activities. Al- though she visited several hospitals with her mother, her diagnosis was obscure. Finally, her mother suspected that these symptoms were related to HPV vaccination and thus, they consulted us in November 2015. On examination, she was 172.0 cm tall and weighed 51 kg. She had hypertelorism, midfacial hypoplasia, a high palate, and bilateral brachydactyly with nail hypoplasia (Figure 1(A)). Both the elbows had lateral instability with cubitus varus deformity in the elbow joints bilaterally, which was revealed upon elevat- ing the arms (Figure 1(B)). However, neither swelling nor redness was seen in any of these joints. X-ray examination indicated hypoplasia of the humeral capitellum and trochlea in both the elbow joints (Figure 2). Routine laboratory tests did not reveal any abnormal findings. The serum C-reactive protein and anti-matrix metalloproteinase (MMP) levels were 0.04 mg/dl and 13.2 ng/ml (normal: 17.3 - 59.7 ng/ml), respectively. The results of antibody tests for rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies were also

Figure 1. Brachydactyly in foot (A) and cubitus varus (B).

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negative. G-banded chromosomal analysis disclosed 48, XXXX (Figure 3), and she was diagnosed with XXXX syndrome. The patient underwent regular medical examinations in neurology, orthopedic surgery, and genetic counseling de- partments. Elbow supporters, analgesic drugs, and rehabilitation effectively re- duced patient’s limb pain and psychosocial support relieved her mother’s anxie- ty. The patient continues to receive rehabilitation and did not require any pain-relieving medication in 2018.

Figure 2. X-ray of the elbow showing hypoplasia of the humeral capitellum and trochlea (arrowheads).

Figure 3. G-banded chromosomal analysis showing 48, XXXX.

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3. Discussion

XXXX syndrome is a rare sex chromosomal abnormality, which is characterized by tall stature, facial dysplasia (midfacial hypoplasia, hypertelorism) and limb deformity (radioulnar synostosis), intellectual disability, and speech and beha- vioral problems [13]. Cases with polysomy X accompanied with systematic lupus erythematosus (SLE) were reported and it is likely that X-chromosome polysomy plays a role in higher incidence of autoimmune diseases [14]. Contrarily, it is also surmised that HPV vaccination can induce autoimmune diseases, including SLE and rheumatoid arthritis [8]. Our present case developed arthralgia and meralgia of unknown cause, three years after HPV vaccination. We previously reported patients with arthritis after HPV vaccination [15]. Incubation period of three years is rather long to consider a post-HPV vaccination syndrome as a cause for her limb pain [3], and clinical manifestations without any orthostatic dysregulation symptoms were atypical for this syndrome [2] [10]. The patient was accidentally diagnosed with XXXX syndrome and we hypothesized that this congenital disorder may be responsible for her limb pain including arthralgia and meralgia. Although some cases with polysomy X have been reported, most of them without SLE did not complain of pain including arthralgia [14] [16] [17]. Recent evidence has shown that autoantibodies against adrenergic and cholinergic receptors play an important role in the appearance of both orthostatic dysregulation and CRPS [18] [19]. The relationship between HPV vaccination and positive serum autoantibodies against autonomic nerve receptors have already been described in the previous three cases [20] [21] [22]. Thus, it cannot be completely ruled out that HPV vaccination worked as a trigger for inducing limb pain. Finally, we emphasize that it is very important to carefully check for other disorders, such as a congenital disorder, during examination of girls complaining of various symptoms after HPV vaccination.

4. Conclusion

A case with a rare congenital disorder, XXXX syndrome, was reported. Although the patient was initially suspected to be suffering from post-HPV vaccination syndrome, careful physical examination and chromosomal analysis led to the final diagnosis of XXXX syndrome. Suspected adverse effects following HPV immunization are complex conditions which might be due to certain disorders. A thorough investigation is required during examination of the patients with suspected post-HPV vaccination syndrome.

Funding

This study was supported by a grant from a Health and Labour Science Research Grant on Emerging and Re-emerging Infectious Diseases (Establishment of Treatments and Providing Information on Symptoms after HPV vaccination, H28-001) to S.I. from the Ministry of Public Heath, Labour and Welfare, Japan.

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Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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Campo, M., Eds., Smith’s Recognizable Patterns of Human Malformation, 7th Edi- tion, Elsevier Saunders, Philadelphia, 74-75. [14] Slae, M., Heshin-Bekenstein, M., Simckes, A., Heimer, G., Engelhard, D. and Ei- senstein, E.M. (2014) Female Polysomy-X and Systemic Lupus Erythematosus. Se- minars in Arthritis and Rheumatism, 43, 508-512. https://doi.org/10.1016/j.semarthrit.2013.07.014 [15] Abe, R., Kinoshita, T., Hineno, A. and Ikeda, S. (2016) Monoarthropathy or Po- lyarthritis in Adolescent Japanese Girls Who Received Immunization with the Hu- man Papillomavirus Vaccine. Case Reports in Clinical Medicine, 5, 109-114. https://doi.org/10.4236/crcm.2016.53020 [16] Tartaglia, N.R., Howell, S., Sutherland, A., Wilson, R. and Wilson, L. (2010) A Re- view of Trisomy X (47,XXX). Orphanet Journal of Rare Diseases, 5, 8. https://doi.org/10.1186/1750-1172-5-8 [17] Kara, C., Üstyol, A., Yılmaz, A., Altundağ, E. and Oğur, G. (2014) Premature Ova- rian Failure Due to Tetrasomy X in an Adolescent Girl. European Journal of Pedia- trics, 173, 1627-1630. https://doi.org/10.1007/s00431-013-2209-y [18] Yu, X., Stavrakis, S., Hill, M.A., Huang, S., Reim, S., Li, H., et al. (2012) Autoanti- body Activation of Beta-Adrenergic and Muscarinic Receptors Contributes to an “Autoimmune” Orthostatic Hypotension. Journal of the American Society of Hypertension, 6, 40-47. https://doi.org/10.1016/j.jash.2011.10.003 [19] Kohr, D., Singh, P., Tschernatsch, M., Kaps, M., Pouokam, E., Diener, M., et al. (2011) Autoimmunity against the β2 Adrenergic Receptor and Muscarinic-2 Re- ceptor in Complex Regional Pain Syndrome. Pain, 152, 2690-2700. https://doi.org/10.1016/j.pain.2011.06.012 [20] Blitshteyn, S. and Brook, J. (2017) Postural Tachycardia Syndrome (POTS) with Anti-NMDA Receptor Antibodies after Human Papillomavirus Vaccination. Im- munologic Research, 65, 282-284. https://doi.org/10.1007/s12026-016-8855-1 [21] Hendrickson, J.E. and Tormey, C.A. (2016) Human Papilloma Virus Vaccination and Dysautonomia: Consideration for Autoantibody Evaluation and HLA Typing. Vaccine, 34, 4468. https://doi.org/10.1016/j.vaccine.2016.05.029 [22] Schofield, J.R. and Hendrickson, J.E. (2018) Autoimmunity, Autonomic Neuropa- thy, and the HPV Vaccination: A Vulnerable Subpopulation. Clinical Pediatrics, 57, 603-606. https://doi.org/10.1177/0009922817728701

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Case Reports in Clinical Medicine, 2019, 8, 245-249 https://www.scirp.org/journal/crcm ISSN Online: 2325-7083 ISSN Print: 2325-7075

Can Wernicke’s Encephalopathy Be Precipitated by Administering Glucose before Thiamine in Severely Malnourished or Alcoholic Patients?

Joshua Altman, Matthew F. Ryan*

Department of Emergency Medicine, University of Florida, Gainesville, FL, USA

How to cite this paper: Altman, J. and Abstract Ryan, M.F. (2019) Can Wernicke’s Ence- phalopathy Be Precipitated by Administer- We discuss the safety and controversy regarding the administration of glu- ing Glucose before Thiamine in Severely cose before thiamine with regards to precipitation of Wernicke’s Encephalo- Malnourished or Alcoholic Patients? Case pathy in the severely malnourished and alcoholic patient population. Herein Reports in Clinical Medicine, 8, 245-249. https://doi.org/10.4236/crcm.2019.89030 we review clinical features, pathophysiology and the relevant literature to provide an evidenced-based recommendation that thiamine replacement Received: November 26, 2018 should not delay glucose administration acutely in the malnourished patient Accepted: September 15, 2019 population. Published: September 18, 2019

License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access 1. Introduction

Can Wernicke’s Encephalopathy be precipitated by administering glucose before thiamine in severely malnourished or alcoholic patients? The answer is not ob- vious and the bottom line is that physiologically, this can happen but most patients already have the manifestations of encephalopathy before they present to the emergency department. Moreover, the process does not happen immediately but rather evolves throughout a hospital course as documented in case reports and literature reviews. Current established guidelines are straightforward with the recommendation to not delay glucose administration while waiting for thiamine. In this article we review the current literature and case reports behind the controversy that still exists and make a case for why administration of glucose should not be delayed while waiting for thiamine in the emergency department

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or other acute care settings.

2. Discussion

Thiamine deficiency manifests itself as a disease of the central and peripheral nervous system, cardiovascular system, and the gastrointestinal tract. Wernicke’s Encephalopathy is a well known, serious complication of thiamine (Vitamin B1) deficiency characterized by a syndrome of altered mental status, ophthalmople- gia, and gait ataxia. Some other thiamine deficiency diseases are listed in Table 1. The pathophysiology behind the disease relates to thiamine’s key role in glucose metabolism. Thiamine is a cofactor for several enzymes in the TCA cycle including α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and transketolase. Thiamine is utilized after phosphorylation to thiamine pyrophosphate. In particular, a decrease in enzymatic activity leads to utilization of non-oxidative pathways for energy production and thus lactate accumulation in the brain, muscle and serum since pyruvate is not able to be shuttled into the TCA cycle. Severe lactic acidosis has been associated with thiamine deficiency [1] and wor- sened in these cases by glucose administrations. Although this may explain why thiamine deficiency is harmful, the association with causing Wernicke’s Ence- phalopathy after glucose treatment remains unclear. But it seems some association likely exists. In chronic alcoholics, thiamine absorption in the gut is inhibited for reasons that are not entirely clear. Subramanya and coworkers [2] recently described a mechanism of significant inhibition in carrier-mediated thiamine transport across the jejunal brush-border membrane associated with a significant reduc- tion in levels of expression of thiamine transporter-1 in rats that were chronically fed alcohol. This work is based on the previous discovery that thiamine absorption in human small intestinal brush-border membranes proceeds via a pH-dependent, electroneutral, carrier-mediated mechanism [3]. There are two reports [4] [5] citing acute encephalopathy in 5 profoundly malnourished patients after receiving IV glucose solutions. However, none of these patients developed symptoms after a single dose of glucose. Additionally these patients developed their symptoms over a course of days. Nevertheless, proponents of “thiamine before glucose” feel otherwise and conclude that if a blood glucose test reveals no hypoglycemia, thiamine should be administered

Table 1. Syndrome—hallmarks of disease.

Mental status changes, ocular abnormalities, Wernicke’s Encephalopathy gait ataxia Wet Beriberi High-output cardiac failure with edema

Dry Beriberi High-output cardiac failure without edema

Neuritic Beriberi Polyneuropathy

Gastrointestinal Beriberi Abdominal pain, lactic acidosis, vomiting

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before glucose if possible as part of therapy [6]. Patients in starvation states can still exhibit normal serum glucose levels however because degraded proteins are not replenished and serve as carbon sources for glucose synthesis. Koguchi and colleagues [7] describe a case in which a 61 year-old man with a significant history of alcoholism presented with altered mental status and after starting IV glucose, the patient fell into a coma. No time frame is given in the report, but the patient already had radiographic evidence of Wernicke’s Ence- phalopathy as evidenced on MRI imaging of the head during his hospitalization. As shown in Figure 1, MRI revealed hyperintense lesions of the mammillary bodies and horns of the fourth ventricles consistent with Wernicke’s Encepha- lopathy. Although the patient did not receive thiamine until Day 5 of his admis- sion and died 3 months later from pneumonia, the authors concluded that an infusion of glucose to patients with a known thiamine deficiency is potentially fatal. There also exists several cases of Wernicke’s Encephalopathy occurring in patients with hyperemesis gravidarum [8] [9], some indolently via IV glucose administration. For the most part, neurologic symptoms were already present before therapy. In these patients, body stores of thiamine can be depleted in weeks and chronically ill patients may already have critically low thiamine levels; RBC transketolase activity requires thiamine as a cofactor and an assay of enzymatic activity will reflect the robustness of thiamine stores. However in animal models, glucose loading had no significant clinical consequence when administered to rats fed a thiamine-deficient diet for 21 days. Advanced neurologic dysfunction with glucose administration was only seen in rats fed thiamine-deficient diets for 28 - 35 days and that ataxia and other neurologic sequela were clinically noted prior to glucose challenge [10] [Table 2].

3. Conclusions and Summary of Recommendations

Much controversy still exists regarding acute precipitation of Wernicke’s Ence- phalopathy by administering glucose before thiamine in severely malnourished and alcoholic patients. The bottom line is that physiologically, this can happen but in most documented case reports, patients already had the manifestations of encephalopathy before they presented to the emergency department or other

Figure 1. MRI image showing hyperintense lesions of the mammillary bodies and horns of the fourth ventricles consistent with Wernicke’s Encephalopathy [7].

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Table 2. Some causes of Wernicke’s Encephalopathy.

• Alcohol Abuse • AIDS • Malignancy • Hyperemesis gravidarum • Prolonged total parenteral nutrition • Post surgical patients • Iatrogenic glucose loading in any predisposed patient

acute care seetting. Moreover, the process has been shown to actually evolve throughout a hospital course, rather than the acute care and initial treatment in the emergency department. Even in one case example where acute decompensation is described, no actual time course is given, and thiamine administration was delayed until 5 days after glucose. The established recommendations are straightforward: do not delay glucose administration while waiting for thiamine. Furthermore, thiamine is best administered parentally, preferably IV versus IM, since GI absorption in malnourished patients is very low. The recommended dose is 250 - 500 mg although there is little to no evidence-based studies supporting any dose (even doses as low as 2 mg have been effective). In summary, Wernicke’s Encephalopathy can be hastened by glucose administration but not in the time frame of a typical single emergent care visit. More- over, glucose administration should not be delayed while waiting for thiamine administration. We did not uproot any studies reporting immediate findings of Wernicke’s Encephalopathy, coma or death from appropriately treating a malnourished patient. In these patients, glucose and thiamine, amongst other nu- trients, should be replaced via IV administration as soon as possible, but treatment with glucose should not be delayed if awaiting thiamine.

Conflicts of Interest

The authors have no conflicts of interest to report.

References [1] Klein, M., Weksler, N. and Gurman, G.M. (2004) Fatal Metabolic Acidosis Caused by Thiamine Deficiency. Journal of Emergency Medicine, 26, 301-303. https://doi.org/10.1016/j.jemermed.2003.11.014 [2] Subramanya, S.B., Subramanian, V.S. and Said, H.M. (2010) Chronic Alcohol Con- sumption and Intestinal Thiamin Absorption: Effects on Physiological and Molecu- lar Parameters of the Uptake Process. American Journal of Physiology-Gastrointestinal and Liver Physiology, 299, G23-G31. https://doi.org/10.1152/ajpgi.00132.2010 [3] Dudeja, P.K., Tyagi, S., Kavilaveettil, R.J., Gill, R. and Said, H.M. (2011) Mechanism of Thiamine Uptake by Human Jejunal Brush-Border Membrane Vesicles. Ameri- can Journal of Physiology: Cell Physiology, 281, C786-C792. https://doi.org/10.1152/ajpcell.2001.281.3.C786

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[4] Watson, A.J., Walker, J.F., Tomkin, G.H., Finn, M.M. and Keogh, J.A. (1981) Acute Wernickes Encephalopathy Precipitated by Glucose Loading. Irish Journal of Med- ical Science, 150, 301-303. https://doi.org/10.1007/BF02938260 [5] Drenick, E.J., Joven, C.B. and Swendseid, M.E. (1966) Occurrence of Acute Wer- nicke’s Encephalopathy during Prolonged Starvation for the Treatment for Obesity. The New England Journal of Medicine, 274, 937-939. https://doi.org/10.1056/NEJM196604282741705 [6] Hack, J.B. and Hoffman, R.S. (1998) Thiamine before Glucose to Prevent Wernicke Encephalopathy: Examining the Conventional Wisdom. JAMA, 279, 583-584. https://doi.org/10.1001/jama.279.8.583a [7] Koguchi, K., Nakatsuji, Y., Abe, K. and Sakoda, S. (2004) Wernicke’s Encephalopa- thy after Glucose Infusion. Neurology, 62, 512. https://doi.org/10.1212/01.WNL.0000099189.56741.A7 [8] Giugale, L.E., Young, O.M. and Streitman, D.C. (2015) Iatrogenic Wernicke Ence- phalopathy in a Patient with Severe Hyperemesis Gravidarum. Obstetrics & Gyne- cology, 125, 1150-1152. https://doi.org/10.1097/AOG.0000000000000557 [9] Ohkoshi, N., Ishii, A. and Shoji, S. (1994) Wernicke’s Encephalopathy Induced by Hyperemesis Gravidarum, Associated with Bilateral Caudate Lesions on Computed Tomography and Magnetic Resonance Imaging. European Neurology, 34, 177-180. https://doi.org/10.1159/000117034 [10] Zimitat, C. and Nixon, P.F. (1999) Glucose Loading Precipitates Acute Encephalo- pathy in Thiamin-Deficient Rats. Metabolic Brain Disease, 14, 1-20. https://doi.org/10.1023/A:1020653312697

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Spontaneous Bilateral Carotid Artery Dissection Revealing Multifocal Fibromuscular Dysplasia

W. Bnouhanna*, W. Fakir, M. Rahmani, M. Benabdeljlil, S. Aïdi

Department of Neurology A and Neuropsychology, Mohamed V University, Hôpital des Spécialités, Ibn Sina University Hospital, Rabat, Morocco

How to cite this paper: Bnouhanna, W., Abstract Fakir, W., Rahmani, M., Benabdeljlil, M. and Aïdi, S. (2019) Spontaneous Bilateral Background: Fibromuscular dysplasia (FMD) is a rare idiopathic segmental Carotid Artery Dissection Revealing Mul- non-arteriosclerotic and non-inflammatory arterial disease of small to me- tifocal Fibromuscular Dysplasia. Case Re- dium-sized vessels. Although it is considered a benign entity, FMD can lead ports in Clinical Medicine, 8, 250-257. https://doi.org/10.4236/crcm.2019.89031 to potentially severe cerebrovascular complications. We present an atypical clinical case of ischemic stroke (IS) caused by bilateral carotid dissection re- Received: August 22, 2019 vealing multifocal FMD. Case Report: A 43-year-old right-handed female Accepted: September 17, 2019 with no medical history suddenly developed somnolence with left-sided Published: September 20, 2019 weakness. Clinical examination revealed left hemiplegia and left central facial Copyright © 2019 by author(s) and paralysis with an NIHSS score: 22. Cerebral tomography (CT) with arterial Scientific Research Publishing Inc. angiogram revealed abilateralis of the middle cerebral arteries (MCA), a This work is licensed under the Creative double dissection of the internal carotids (IC), aneurysmal ectasia of the left Commons Attribution International License (CC BY 4.0). IC, and aneurysm of the M2 segment of the MCA. Brain magnetic resonance http://creativecommons.org/licenses/by/4.0/ imaging (MRI) with arterial angiography confirmed the bilateral dissection. A Open Access cerebral angiography (CA) revealed a radiological pattern of multifocal FMD. The angiography of the aorta and its branches showed adiffuse dysplasia of the renal arteries. The patient was put under antiaggregants. The modified Rankin score (mRS) after three months was three. Conclusion: Cerebrovas- cular FMD has typical angiographic features, the “string of beads” appearance being the most common. Although the risk of a stroke in patients with cervical FMD is low, it can lead to a severe stroke and the long-term risks are unknown. Patient registries should be encouraged to better understand the mechanisms and evolutionary profile of FMD and alert clinicians to this potentially disabling condition.

Keywords Fibromuscular Dysplasia, Carotid Disease, Stroke

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1. Introduction

Fibromuscular dysplasia (FMD) is a rare idiopathic segmental non-arteriosclerotic and non-inflammatory arterial disease of small to medium-sized vessels. The renal and cervical arteries are the most commonly affected, but all arterial territories can be involved. The cause and pathophysiology of FMD are still unknown. Clinical manifestations of FMD are primarily dependent on the affected vessels. Although FMD is usually considered as a relatively benign disease, cervical FMD can lead to potentially serious cerebrovascular complications. We present an atypical and rare clinical case of ischemic stroke (IS) caused by bilateral carotid dissection revealing multifocal Fibromuscular dysplasia (FMD at internal carotid and renal artery with an intracranial aneurysm).

2. Case Report

A 43-year-old right-handed Caucasian female with no medical history and with a low cardiovascular risk presented for three months unusual hemicranias and neck pain with recent aggravation. One week before her hospitalization, she ab- ruptly installed somnolence with weakness of the left side. Neurological examination revealed left hemiplegia, left central facial paralysis, left homonymous hemianopia, and dysarthria with an NIHSS score of 22, while cardiovascular including blood pressure and dermatological examinations were normal. Cerebral tomography (CT) with arterial angiogram revealed an ischemic stroke (IS) of both the middle cerebral arteries (MCA), a double dissection of the two internal carotids with irregularity of the arterial wall at the level of the middle third of the left internal carotid artery, aneurysmal ectasia of the left internal carotid, and aneurysm less than 10 mm of the M2 segment of the MCA. Brain magnetic resonance imaging (MRI) with arterial angiography and T1 FAT-SAT cervical axial section confirmed the bilateral dissection of the cervical carotids predominant on the right, associated with bilateral IS in the capsular-lenticular territory and the superficial territory of the right MCA (Figure 1). Neurointer- ventional radiologist was consulted and acerebral digital subtracted catheter angiography (DSCA) was performed showing radiological patterns of multifocal cervical FMD (string-of-beads aspect) in the left IC with bilateral IC dissection (Figure 2 and Figure 3). CT angiography of the aorta and its branches showed an appearance of diffuse arterial dysplasia of the renal arteries (Figure 4). The patient was put under antiaggregant therapy. For aneurysm of the M2 segment of the MCA, interventional treatment was not retained for our patient, instead, CT angiography monitoring was proposed. Motor rehabilitation and speech therapy were initiated during her hospitalization and continued after discharge. The follow-up is insured by a cerebrovascular disease specialist. After three months of treatment, the modified Rankin score (mRS) is three.

3. Discussion

The prevalence of cervical FMD in the general population is unknown. However,

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Figure 1. Encephalic MRI, diffusion weighted sequence showing ischemic stroke in the superficial and profound territories of the right ACM MCA and deep territory of the left ACM MCA.

Figure 2. Carotid arteries: digital subtracted catheter angiography. White arrow: Multi- focal fibromuscular dysplasia, with typical “string of beads” appearance. Red arrow: Pseudoaneurysm of the petrous segment of the left internal carotid artery.

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Figure 3. Carotid arteries: digital subtracted catheter angiography, shows a dissection in the right internal carotid artery, with typical “carotid string sign”.

Figure 4. Renal CT angiography; irregular appearance of the distal part of the renal artery arteries.

a study among 20,244 consecutive autopsies performed at the Mayo Clinic over 25 years found only 4 subjects with cervical FMD (0.02%) [1]. FMD is more common among women while less than 5% of patients have a family history [2]. The most common mode of revelation is an ischemic or hemorrhagic stroke, TIA, or subarachnoid hemorrhage [3] [4]. The rate of stroke in FMD is 0.75 to 4.9% [4] [5], which is due to the dissection of the cervical arteries or the rupture of aneurysms [6]. FMD has been identified in approximately 15% to 20% of bilateral dissection cases [7]. Mutations in the PHACTR1 (phosphatase and actin regulator 1) gene have recently been associated with cases of spontaneous cervical dissection and cases of DFM [8] [9] [10]. These entities may represent a

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spectrum of the same pathological process. FMD is often localized in the cervical and renal arteries, hence headaches and pulsatile tinnitus are common when it is manifested by a cervical dissection [11]. In a recent study in the United States, it was shown that one of three patients had FMD in 2 vascular beds [2]. Cerebral arteriography is the gold standard for the diagnosis of FMD. The typical angiographic aspect of a multifocal FMD is the “string of beads” one resulting from the alternation of stenosis with aneu- rismal dilatation, which is the most common aspect, found in 90% of cases. This aspect generally affects the medial and distal portions of the internal carotid artery and the V3-V4 segment of the vertebral arteries at the C1 and C2 vertebrae, areas usually unaffected by atherosclerosis [12]. In monofocal FMD, unifocal concentric (<1 cm in length) or tubular (≥1 cm) smooth narrowing can occur in any portion of the artery [12] [13]. The high prevalence of aneurysms and dissections in other arterial beds (including renal and aortic branch arteries) justify in patients diagnosed with cerebrovascular FMD head-to-pelvic vascular imaging [13]. In the absence of randomized trials, current medical and interventional strat- egies are based on observational data and expert opinion. The management of ischemic stroke secondary to FMD is similar to that of patients without FMD. In the acute phase, intravenous thrombolysis and/or mechanical thrombectomy are indicated; an antithrombotic agent must be prescribed later [12]. In the case of FMD without stroke complications, including associated asymptomatic cervical artery dissection, daily low-dose aspirin is often indicated to prevent throm- boembolic complications. For aneurysm in patients with FMD, similar management as in the general population should be proposed [14]. Securing an un- ruptured intracranial aneurysm by endovascular coiling or surgical clipping, if embolization is not feasible, must be discussed case by case [5] [12]. Besides, it is recommended to repeat brain magnetic resonance angiography every 5 to 10 years to evaluate the formation of new aneurysms if none have been detected on the baseline imaging (expert opinion). To our knowledge, there are no prognostic studies in patients with FMD compared to patients with spontaneous cervical dissection. The risk of incident and recurrent stroke in patients with cerebrovascular FMD remains uncertain. Longitudinal studies of patients with cerebrovascular FMD reported a risk of TIA or ischemic stroke during follow-up between 0.6% and 3.7% per year and a risk of intracerebral hemorrhage of less than 1% per year [5]. In the absence of stroke complications, the prognosis of isolated cerebrovascular FMD remains favorable [12]. Our observation is particularly interesting at several levels. First, the case of ischemic stroke due to a bilateral carotid dissection is a scarce situation. Secondly, the carotid dissection reveals a multifocal FMD which is also a rare case. In addition, our observation summarizes the main localizations of the FMD: internal carotid, intracranial aneurysm, and renal artery. Finally, we sum- marize the latest information about FMD.

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4. Conclusion

FMD is a rare vascular disease that affects mainly young women. Renal and cer- vico-encephalic arteries are the most frequently affected areas. FMD represents a cause of stroke in young people through dissection of the cervical arteries or aneurysm rupture. The string-of-beads aspect is the most common imaging find- ing of FMD. The management does not differ from that of spontaneous dissection. Patients diagnosed with cerebrovascular FMD should undergo head-to-pelvic vascular imaging. A better knowledge of this disease is critical to shorten the delay to diagnosis and to offer optimal therapeutic management. For that reason, large prospective studies that assess the risk of disease progression, death, and stroke are required to be able to define the best therapeutic strategy.

Conflicts of Interest

The authors had no financial support when writing this article.

Author’s Contributions

1) Wadi Bnouhanna • Conception of the work and Acquisition of data and Analysis of data and In- terpretation of data; • Drafting the work; • Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 2) Mounia Rahmani • Acquisition of data and Analysis of data and Interpretation of data; • Revising the work critically for important intellectual content; • Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 3) Wafa Fakir • Acquisition of data. 4) Maria Benabdeljlil • Acquisition of data and Analysis of data and Interpretation of data; • Revising the work critically for important intellectual content; • Final approval of the version to be published; • Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 5) Saadia Aïdi • Acquisition of data and/or Analysis of data and/or Interpretation of data; • Revising the work critically for important intellectual content; • Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately

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investigated and resolved.

References [1] Schievink, W.I. and Björnsson, J. (1996) Fibromuscular Dysplasia of the Internal Carotid Artery: A Clinicopathological Study. Clinical Neuropathology, 15, 2-6. [2] Olin, J.W., Froehlich, J., Gu, X., Bacharach, J.M., Eagle, K., Gray, B.H., et al. (2012) The United States Registry for Fibromuscular Dysplasia: Results in the First 447 Pa- tients. Circulation, 125, 3182-3190. https://doi.org/10.1161/CIRCULATIONAHA.112.091223 [3] De Bray, J.M., Marc, G., Pautot, V., Vielle, B., Pasco, A., Lhoste, P. and Dubas, F. (2007) Fibromuscular Dysplasia May Herald Symptomatic Recurrence of Cervical Artery Dissection. Cerebrovascular Diseases, 23, 448-452. https://doi.org/10.1159/000101470 [4] Corrin, L.S., Sandok, B.A. and Houser, O.W. (1981) Cerebral Ischemic Events in Patients with Carotid Artery Fibromuscular Dysplasia. Archives of Neurology, 38, 616-618. https://doi.org/10.1001/archneur.1981.00510100044005 [5] Pasquini, M., Trystram, D., Nokam, G., Gobin-Metteil, M.P., Oppenheim, C. and Touzé, E. (2015) Fibromuscular Dysplasia of Cervicocephalic Arteries: Prevalence of Multisite Involvement and Prognosis. Revue Neurologique, 171, 616-623. https://doi.org/10.1016/j.neurol.2015.02.011 [6] Kadian-Dodov, D., Gornik, H.L., Gu, X., Froehlich, J., Bacharach, J.M., Chi, Y.W., et al. (2016) Dissection and Aneurysm in Patients with Fibromuscular Dysplasia: Findings from the US Registry for FMD. Journal of the American College of Cardi- ology, 68, 176-185. [7] Béjot, Y., Aboa-Eboulé, C., Debette, S., Pezzini, A., Tatlisumak, T., Engelter, S., et al. (2014) Characteristics and Outcomes of Patients with Multiple Cervical Artery Dis- section. Stroke, 45, 37-41. https://doi.org/10.1161/STROKEAHA.113.001654 [8] Olin, J.W. (2017) Expanding Clinical Phenotype of Fibromuscular Dysplasia. Hyper- tension, 70, 488-489. https://doi.org/10.1161/HYPERTENSIONAHA.117.09646 [9] Debette, S., Kamatani, Y., Metso, T.M., Kloss, M., Chauhan, G., Engelter, S.T., et al. (2015) Common Variation in PHACTR1 Is Associated with Susceptibility to Cer- vical Artery Dissection. Nature Genetics, 47, 78. [10] Kiando, S.R., Tucker, N.R., Castro-Vega, L.J., Katz, A., D’Escamard, V., Tréard, C., et al. (2016) PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dyspla- sia Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genetics, 12, e1006367. https://doi.org/10.1371/journal.pgen.1006367 [11] Kadian-Dodov, D., Goldfinger, J.Z., Gustavson, S. and Olin, J.W. (2018) Natural History of Cervical Artery Fibromuscular Dysplasia and Associated Neurovascular Events. Cerebrovascular Diseases, 46, 33-39. https://doi.org/10.1159/000491437 [12] Touzé, E., Southerland, A.M., Boulanger, M., Labeyrie, P.E., Azizi, M., Bouatia-Naji, N., et al. (2019) Fibromuscular Dysplasia and Its Neurologic Manifestations: A Sys- tematic Review. JAMA Neurology, 76, 217-226. https://doi.org/10.1001/jamaneurol.2018.2848 [13] Varennes, L., Tahon, F., Kastler, A., Grand, S., Thony, F., Baguet, J.P., et al. (2015) Fibromuscular Dysplasia: What the Radiologist Should Know: A Pictorial Review. Insights into Imaging, 6, 295-307. https://doi.org/10.1007/s13244-015-0382-4 [14] American College of Cardiology Foundation/American Heart Association Task

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Force (2011) Guideline on the Management of Patients with Extracranial Carotid and Vertebral Artery Disease: Executive Summary. Journal of the American College of Cardiology, 57, 1002-1044.

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Case Reports in Clinical Medicine, 2019, 8, 258-273 https://www.scirp.org/journal/crcm ISSN Online: 2325-7083 ISSN Print: 2325-7075

Fabella Syndrome: A Typical Case of Misdiagnosis and Discussion

Mohammed H. Karrar Alsharif1,2,3*, Juman M. Almasaad2,4, Nagi M. Bakhit2,4, Khalid M. Taha5,6, Mohammed I. Eltahir2,3,7, Mamoun A. Alfaki1,3, Abubaker Y. Elamin2,3, Mohammed A. Noureddin8

1Department of Basic Medical Science, College of Medicine, Prince Sattam Bin Abdulaziz University, Al Kharj, KSA 2Department of Histology & Embryology, Medical Faculty, Ondukuz Mayis University, Samsun, Turkey 3Department of Anatomy, Faculty of Medicine, National University, Khartoum, Sudan 4College of Medicine, King Saud Bin Abdulaziz for Health Sciences University, Jeddah, KSA 5Department of Anatomy, Faculty of Medicine, El Deain University, El Deain, Sudan 6Department of Anatomy, Faculty of Medicine, University of Science and Technology, Khartoum, Sudan 7Department of Anatomy, Faculty of Medicine, University of Bahri, Khartoum, Sudan 8Department of Medicine, College of Medicine, Prince Sattam Bin Abdulaziz University, Al Kharj, KSA

How to cite this paper: Alsharif, M.H.K., Abstract Almasaad, J.M., Bakhit, N.M., Taha, K.M., Eltahir, M.I., Alfaki, M.A., Elamin, A.Y. Background: Fabella is a natural occurring sesamoid bone, cartilage or a and Noureddin, M.A. (2019) Fabella Syn- mixture of both that is usually located at the posterolateral corner (PLC) of drome: A Typical Case of Misdiagnosis and the knee [1]. Recently the PLC of the knee has been extensively investigated Discussion. Case Reports in Clinical Medi- cine, 8, 258-273. because it is a common site of injuries and diseases [2] [3]. The complexity of https://doi.org/10.4236/crcm.2019.89032 PLC anatomy needs to be fully understood because the fabella could be missed diagnosis as an osteochondral defect, osteochondritis dissecans (OCD), Received: August 27, 2019 Accepted: September 24, 2019 calcific tendinitis, or foreign body. We present a case report of fabella syn- Published: September 27, 2019 drome triggered by trauma and also performed a review of literature for the various diagnoses that might be confused with fabella syndrome. Case pres- Copyright © 2019 by author(s) and entation: A 29-year-old, Sudanese male presented to the trauma center in Scientific Research Publishing Inc. This work is licensed under the Creative King Khalid Hospital in KSA, complaining of pain and partial swelling in his Commons Attribution International left knee joint due to trauma. Fabella was detected in the posterior lateral License (CC BY 4.0). corner (PLC) of the knee joint embedded in the lateral head of the gastroc- http://creativecommons.org/licenses/by/4.0/ nemius muscle. All other pathological conditions were excluded. Conclusion: Open Access Fabella is sesamoid bone with variable size, found in the PLC. Commonly if present it causes periodic pain especially in the fully extended knee or it remains asymptomatic. Trauma, surgery, sports or heavy extreme activities may trigger the pain of asymptomatic fabella. Clinicians should consider that pain in the PLC of the knee can result from the presence of the fabella in a condition called fabella syndrome.

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Keywords Fabella Syndrome, Sesamoid Bone, Osteochondral Defect, Osteochondritis Dissecans, Calcific Tendinitis, Foreign Body

1. Introduction

Among the human body joints, the knee is the largest most, superficial and complicated joint. It takes place between the condyles of the femur proximally and the tibial plateau distally. It has been classified as a hinge type of synovial joint allowing flexion and extension; even so, the gliding, rolling and with rotation about a vertical axis movements are possible with little degrees [4]. The stability factors of knee joint are composed of 28 unique static and dynamic stabi- lizers (ligaments, tendons, meniscal structures, and strong muscles) [5] [6]. Re- cently the posterior-lateral corner (PLC) of the knee has been commonly investigated because of its importance in knee stability and considered as a common side of injuries and diseases [2] [3]. The complexity of PCL anatomy needs to fully understand because it can contribute to the misdiagnosis for orthopedic surgeons [4] [7]. The static components of PLC are the fibular collateral, fabellofibular and popliteofibular ligaments, and posterolateral capsule, whereas the dynamic components are the tendons of the popliteus, biceps femoris, lateral head of gastrocnemius and iliotibial tract; that together provide lateral knee stability [8]. PLC is a common side of injuries and abnormal condition such as fabella syndrome, osteochondral defect, osteochondritis dissecans, calcific tendinitis, and foreign body. All of these conditions will be reviewed briefly in this study. The current study aimed as well to report an unfamiliar morphology of posterior lateral corner of the knee (fabella syndrome) and its differential diagnosis in order to avoid misdiagnosis in such case.

2. Case Report

A 29-year-old, Sudanese male presented to the trauma center in King Khalid Hospital in KSA, complain from pain and partial swelling in his left knee joint due to falling down trauma. Physical examination of the patient showed a partial swelling with normal popliteal fossa. On palpation temperature was normal in the region and there was no tenderness around the knee joint. A general screen of the patient’s gait revealed no significant abnormalities. Changing position from sitting to standing and tolerance to either position was painless. The patient was asked if he has any similar symptoms before the trauma and the answer was no. Instability tests showed negative results and there were no abnormalities upon examination of distal neurovascular status. Although he visited two physicians during this time, the problem still re-

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mained due to misdiagnoses. Eventually in the hospital, after a precise examination, X-ray showed a fabella in close topographical relation to the posterior lateral femoral condyle embedded in the lateral head of gastrocnemius muscle (Figure 1). This result was confirmed by MRI findings as seen in Figure 2.

Figure 1. (a) Anteroposterior (AP), (b) Lateral view of plane radiograph showing fabella (arrows) located on the dorsal aspect of the lateral femural condyle.

Figure 2. MRI showing: a sagittal plane of knee joint at the lateral condyle of the femur. Arrow indicates the fabella associated with lateral head of gastrocnemius muscle.

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3. Discussion

Flabella is a small sesamoid bone found commonly in the lateral head of gastrocnemius muscle [1], but few studies reported that it can be found in the medial head [9] [10]. It is believed that the fabella is associated with the distal part of the short head of biceps femoris tendon [11] [12]. Also, it had been reported in the knee of the dogs, cats, and rabbits [13] [14]. Researchers were varied about the time of development of the fabella. Some authors noticed that it appeared at the age of 10 years and remains unossified until the age of 12 - 15 [15]. And some of them reported that it first appeared in the second trimester around 15th week of gestation [16]. fabella was developed when the plantaris and lateral head of gastrocnemius were entirely separated, but not when both muscles converge to a single belly [17]. The presence of fabella is widely variable. Table 1 demonstrates the prevalence of fabella on the previous studies including different ethnic groups [18]. Fabella could be pure osseous, cartilaginous or mixed in nature, forming its own joint with lateral condyle of the femur posteriorly [18] [19]. It has a variable size ranging from a very small dot with a 2.2 mm in diameter [19] [20] to large size measured 15 × 8 × 9 mm [21] 13 mm × 10 mm [22]. It’s larger in male than the female, which supports the theory of biomechanical role of fabella [11] [12]. Authors believe that the fabella is involved in the stability of the posterolateral aspect of the knee [23]. The functions of sesamoid are to protect the tendon of muscle from being damaged by friction, change the direction of the puling muscles and helping muscles in action [24]. During the transition from the quadrupedal posture to the bipedal, the fabella seemly starts to disappear, because the standing position in bipedal need more stability and less rotation [25] [26] so that the fabella variable absent and it classified as retrogressive anatomical that lost it function with an upright position in human.

Table 1. Prevalence of the fabella in the different ethnic groups.

Author Year Prevalence % Ethnic group

Yu et al. 1996 19.0 Caucasian American

Sarin et al. 1999 31.3 Caucasian America

Raheem et al. 2007 9.1 Caucasian Irish

Tim et al. 2010 3.1 Caucasian Brazilian

Phukubye and Oyedele 2011 23.5 Caucasian and African

Piyawinijwong et al. 2012 50.5 Asian Thailand

Tabira et al. 2012 68.6 Asian Japanese

Zeng et al. 2012 86.9 Asian Chinese

Chew et al. 2014 31.25 Asian, Singapore

O.F. Egerci et al 2016 22.8 Caucasian Turkish

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Asymptomatic fabella remains silence until it has been detected by accident in routine lateral knee radiograph. And this was accepted as normal anatomy without any complain pathology in knee that may confuse radiologist with other pathological conditions [27] [28] like osteophytes in osteoarthritis or intrame- niscal calcifications.

3.1. Fabella Syndrome

Fabella Syndrome describes traditionally posterolateral knee pain, occurring due to biomechanical pressure of the fabella against the lateral femoral condyle. Given its rarity, its diagnosis is often overlooked [29]. Fabella leads to many pathological conditions such as fabella syndrome and common fibular nerve palsy [30]. Also the presence of the fabella increases risk of osteoarthritis in the knee joint [31]. Due to its close anatomical association, authors believe that it may cause compression of popliteal artery [30] [32] or peroneal nerve at PLC of the knee [33] [34]. Pain at the posterior lateral part of the knee; which is augmented by full joint extension, is defined as fabella syndrome [35]. Authors referred this painful syndrome as the osteoarthritis [24] [36], degenerative arthritis and various deformity [37], dislocations [38], fracture [39] [40], and chondromalacia of the fabella [1] [28]. Absence of the fabella is a normal anatomical variation, clinicians and radiologist should know about the morphological features, position, and incidence of this bone. The fabella detected by different modalities of radiography such as X-ray, US, and MRI or by the cadaveric dissection.

3.2. Osteochondral Defect

Osteochondral defect is a common serious problem from which a large number of people around the world suffer [41]. About 63% of knees had been associated with chondral damage when investigated by means of arthroscopy, the full-thickness chondral lesion had been found in about 5% of cases [42]. The chondral lesion is the most common musculoskeletal defect that usually affects old age individuals [43]. Damage affecting chondral and bony part of the joint is called osteochondral defect, when solely articular cartilage is affected the term chondral injury or defect is usually applied [44] [45]. Articular cartilage damage may found isolated, but associated tissues are always involved [46]. Severity and progression of an osteochondral defect are largely affected by many factors such as weight, age, physical activity and genetic background of the individual [41] articular cartilage is avascular therefore it is the capability for regeneration are confined [47] [48]. Hyaline cartilage replaced by fibrocartilage as the joint subject to osteochondral defect, this change leads to joint’s deformation and immobility [49]. Osteochon- dral and even chondral damage can develop into osteoarthritis [50]. Osteoarthri- tis is a common complication of traumatic injuries that causes joint defects and disabilities [51]. According to the clinical findings joint injuries commonly in-

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volve articular cartilage, supporting tissues and capsule which cause joint degeneration [51]. Chondromalacia, chondral and osteochondral fractures, chondro- sis, chondral flaps and osteochondritis dissecans are types of articular cartilage lesion [52]. Data revealed that trauma is the most common cause of the articular cartilage damage and osteochondral deformities [53] [54]. The traumatic lesion is due to either direct stroke or contortion. Ligaments laceration is usually associated with traumatic injuries [52]. Etiology of the osteochondral lesions is also due to other causes rather than trauma such as metabolic defects, ischemia, joint degenerative disease, thromboembolism, corticosteroids or inflammatory diseases [45] [54]. Ankle and knee are the common joints that prone to the osteochondral injuries. Knee is the most frequently affected [44] [54] [55]. Femoral condyles are most common part of the knee impaired by osteochondral lesion and almost 58% of cases affect the medial femoral condyles [56]. In the ankle the talar dome is the frequent site of lesion [54]. Osteochondral injuries are always associated with pain, swelling, joint instability and dysfunction [57] [58] [59] [60]. Joints injuries disturb daily activities and joints immobility is common complication [61]. There are many imaging modalities used to diagnose chondral and osteochondral lesions, plain radiograph, CT, MRI and ultrasonography [59] [62] [63]. Plain radiograph doesn’t give a complete image of the lesion [64]. A Plain radiograph is useful to diagnose a fracture, subchondral cyst, osteochondral fragments and displaced osteochondral bodies [59]. To demonstrate articular cartilage sur- face using computerized tomography arthrography is the best choice, magnetic resonance is imaging technique through which demonstration of all tissue can be achieved (Figure 3) [59]. The US is used for assessment of both chondral and subchondral tissue components [62].

Figure 3. MRI showing: (a) Coronal plane of large osteochondral defect at the medial condyle of the femur; (b) Sagittal plane [65].

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3.3. Osteochondritis Dissecans of the Knee

Osteochondritis dissecans (OCD) is a separation of articular cartilage and underlying bone separate from the specific joint, due to a plane of cleavage through underneath bone (Figure 4 & Figure 5) [65]. König (1881) was first to describe Osteochondritis dissecans, He thought that a fragment separate as a result of dissecting inflammation followed necrosis caused by trauma [66]. Untreated OCD to the weight bearing bone may develop a degenerative joint disease [67]. According to the skeletal maturity of the patients, OCD is classified into juvenile and adult entities with open and close epiphyseal cartilage plates respectively [68] [69]. Among different joints including wrist, elbow, ankle, and hip, Knee is the commonest site for OCD [70] being engaged to approximately 75% of the cases, whereas, medial femoral condyle is the primarily affected site having more than 85% of the cases [67]. The clinical presentation is usually associated with nonspecific symptoms [71], including vague knee pain that is aggravated by certain activity like climb- ing stairs and may cause activity-related swelling and stiffness. Unstable lesions

Figure 4. Anteroposterior plane radiograph showing an osteochondritis dissecans lesion [70].

Figure 5. Echo MRI showing a rim of high signal intensity surrounding the osteochondritis dissecans lesion (arrows) [70].

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usually marked by physical symptoms such as locking or feeling of loose fragment [72] [73]. OCD of the knee is becoming increasingly more frequent in children, adolescent and young adult and is thought to be, due to earlier and increasingly sports endeavors [74] [75]. Despite much speculation, the etiology of OCD remains unclear [76]. A variety of theories have been suggested regarding the cause of OCD, including three main areas; trauma, vascular and genetic [74]. Microscopically, absent of the bone necrosis favour defects in the ossification centers, rather than ischaemia in the distal part of femur [67]. The diagnosis of OCD depends on patient data, physical examination, and radiographic appearance. MRI is considered as the best imaging modality for early detection of lesion [77]. Literature, classified OCD lesions as: grade 1, normal articular cartilage. These asymptomatic lesions and usually found accidentally during another index surgery; grade 2, fragmentation in situ. The overlying cartilage may look normal, but can feel soft to probing and can be indented more easily when compared to the surrounding normal cartilage; grade 3, partial detachment which can cause mechanical symptoms due to micro-motion of the fragment; and grade 4, is designated to an unstable lesion with complete detachment, loose body present, causing pain and mechanical symptoms [78] [79].

3.4. Calcific Tendinitis

Calcific tendinitis is also included in the differential diagnoses of fabella syndrome. In contrast to the posterolateral knee pain experienced in fabella syndrome, calcific tendinitis causes anterior knee pain [80]. It is atypical pain if experienced posterolateral aspect of the knee joint. Calcific tendinitis refers to a painful musculoskeletal disorder characterized by macroscopic calcium deposits in any tendon of rotator cuff [81] [82]. Calcium deposits can be single or multiple and may be found in subacromial bursa. These calcium deposits are composed of a crystalline calcium phosphate called as “hydroxyapatite”. It is different from dystrophic calcification, which develops at the edges or at the insertion site of non-viable and poorly vascularized or degenerative tendons. Calcific tendinitis affects 3% - 20% of the population; especially the adults whose age is 30 - 50 years. The most common rotator cuff involved in calcific tendinitis is supras- pinatus followed by infraspinatus, teres minor, and subscapularis tendons. Re- member, calcific tendinitis can affect any joint, but typically involves shoulder and hip joints. In the knee joint, patellar and quadriceps tendinitis are common [80] [83]. The exact pathogenesis of calcific tendinitis is yet to be revealed. However, recent literature on this condition reported that it is a cell-mediated process with four well-defined phases. These four phases of calcific tendinitis are formative, calcific, resorptive and reparative [84]. In the formative phase of calcific tendinitis, the tendons undergo a fibrocartilaginous transformation. In the calcific phase, calcification of the tendon occurs. Resorptive phase is painful and various

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inflammatory reactions take place within the calcium deposits. In the last phase of calcific tendinitis, fibroblasts restore the normal texture of tendons. In contrast, other authors suggest that matrix vesicles and degeneration of tendons are responsible for calcific tendinitis [85]. Calcific tendinitis may be asymptomatic in one-third of the patients. In oth- ers, it is painful, accounting for 7% of patients with shoulder pain, especially when inflammatory processes are undergoing in the calcium deposits. Osseous changes and calcium deposits can be visualized well with regional radiographs, CT and MRI. The size of calcium deposits may range from millimeters to centi- meters. Remember that an aggressive appearance on imaging films may confuse calcific tendinitis with infection or other diagnoses such as malignancies [86]. CT scan is the best modality to identify subtle osseous changes.

3.5. Foreign Body

Foreign body is referred to the substance or object that does not belong to the place where it is found [87]. Fabella might be taken as a foreign body in the knee joint. However, foreign body and fabella syndrome can be differentiated from each other by the shape and density of the object and also by the trauma history. History of trauma and wound of entry favors foreign body in the knee joint while bone-like density and advocates for sesamoid bone. In context with fabella syndrome, Driessen et al. [35] have demonstrated that foreign body can produce pain in the PLC of the knee joint. Foreign bodies in knee joints are rare. Authors reported an intraosseous metallic foreign body in the lateral [88] and medial [89] condyles of the femur associated with pain in the left knee. Low radiopaque objects are usually missed on imaging investigations. Therefore, accurate diagnostic protocol is required to detect these objects in order to avoid any pathological changes and complications. Thorns, wood, and sand are common foreign bodies get into the body during routine accidents. Radiography is the first investigation performed in detection of any foreign body. However, the disadvantage of radiography is that it is unable to provide exact size of foreign body as it is a 2-dimensional imaging modality. Therefore, further investigation using ultrasonography, CT scan and MR imaging are required to determine the exact size of the foreign body [90]. Determination of size of foreign body and more details are necessary to plan a therapeutic inter- vention. High frequency US is a safe, cheap and useful imaging modality to detect radiolucent foreign bodies such as wood and sand objects [91]. MRI is not considered a primary imaging modality for the detection of unknown foreign bodies as it is expensive and not easily available everywhere. Additionally, it is difficult to visualize foreign bodies of plastic, iron, glass and sand due to artefacts related to body’s composition, which may be encountered on MRI scan.

4. Conclusions

Fabella is a normal anatomical variant that may appear in PLC of the knee. It is

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often miss diagnosed in radiography [28]. Moreover, its variable size and nature (bone, cartilage, or mixed) [18] [19] may lead to confusion in the diagnosis of fabella syndrome with the following: 1) Osteochondral defect when it appears like isolated cartilage. 2) Osteochondritis dissecans which, if it is mixed, appears like a fragment of cartilage with underlying bone. 3) Calcific tendinitis when calcium deposit and osseous changes occur. 4) Foreign body especially after wounds injury. In general, all these conditions can be differentiated from fabella syndrome by taking proper patient history, focusing on the nature (type and site of the pain) and the history of trauma. Also, taking into consideration the size, density, shape, condition of the associated structures would assist in the diagnosis. Many reports pointed to the presence of the fabella, even though it is not described in most of the anatomy books. The exact role of the fabella in the knee joint and the consequence of its presence remain unclear and need to be clarified with further studies. We recommend giving more attention to this anomaly and the way it may affect the patient’s life style.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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Abbreviations

PLC: Posterolateral Corner OCD: Osteochondritis Dissecans CT: Computed Tomography MRI: Magmatic Resonance Imaging

DOI: 10.4236/crcm.2019.89032 273 Case Reports in Clinical Medicine

9 772325 707001 90