Pseudomyxoma peritonei (PMP) is a rare, slow growing mucinous ascites, typically associated with primary appendiceal or ovarian neoplasm [1]. Mucinous material fills the peritoneal cavity, causing enlargement of the abdomen and has been described as “jelly belly”, due to its appearance at laparotomy [2]. The symptoms of PMP are often non-specific and vague, causing difficulties in diagnosis. Further, diagnostic imaging is not always able to detect the disease prior to surgery. The clinical implications of this are that PMP is not commonly considered a differential diagnosis in patients with these symptoms, which may then delay the diagnosis being made. This causes a potential delay in treatment, which has been shown to worsen the morbidity and mortality associated with PMP [3,4].

Introduction

Pseudomyxoma peritonei (PMP) is a rare, slow growing mucinous ascites, typically associated with primary appendiceal or ovarian neoplasm [1]. Mucinous material fills the peritoneal cavity, causing enlargement of the abdomen and has been described as “jelly belly”, due to its appearance at laparotomy [2]. The symptoms of PMP are often non-specific and vague, causing difficulties in diagnosis. Further, diagnostic imaging is not always able to detect the disease prior to surgery. The clinical implications of this are that PMP is not commonly considered a differential diagnosis in patients with these symptoms, which may then delay the diagnosis being made. This causes a potential delay in treatment, which has been shown to worsen the morbidity and mortality associated with PMP [3,4].

Case

A 48-year-old female presented to her general practitioner with a two-month history of increasing abdominal girth and a feeling of pelvic “fullness”. Importantly, she had not been unwell, did not have any infective symptoms, no loss of weight or appetite, and no nausea or vomiting. Her bladder and bowel function was normal, her periods were regular, and her Pap smears were up to date and normal.

The patient had a past medical history of primary hypothyroidism and depression, both of which were clinically stable. She had no known allergies. Her regular medications were Fluoxetine (20 mg daily) and thyroxine sodium (100 mg daily). She lived with her 16-year-old daughter, and worked full time in a delicatessen. Her family history included bowel, prostate, and breast cancer.

Her GP ordered various investigations (Table 1). Her borderline high CA-125 level (38 kU/L, reference range < 36 kU/L) and the imaging findings suggested a possible gynaecological malignancy.

Table 1: Initial investigation results

• *RR: reference range
• ^Ca125: cancer antigen 125, CEA: carcinoembryonic antigen, Ca19.9: cancer antigen 19.9. These are common tumour markers used in conjunction with clinical examination and other investigations to aid cancer diagnosis.

She was referred to an outpatient gynaecological oncology clinic for further evaluation and formulation of a management plan. On examination in the clinic, the patient looked well and was afebrile. Her abdomen was distended, with a palpable, non-tender mass in the right iliac fossa. Mild ascites was present. She was also obese (BMI 37). Per vaginal examination revealed a palpable mass, with noted fixation of the right adnexa. Her uterus was mobile, non-tender, and of normal size and morphology.

The patient was discussed at the multidisciplinary team meeting where it was recommended that she undergo a laparotomy for total abdominal hysterectomy, bilateral salpingo-oophrectomy, and omentectomy. At the time of the surgery, she was noted to have extensive mucinous material throughout her peritoneum, and within her uterus and cervix. The mass seen on imaging was found to be an enlarged appendix, which required concurrent general surgical consultation for removal. The specimens were sent to pathology for analysis (Table 2).

Table 2: Formal pathology results

The subsequent histopathological diagnosis was of a primary appendiceal malignancy, with rupture and extensive mucin extrusion into the peritoneal cavity.

She had an unremarkable post-operative course, and was discharged home on day 4. She was to be followed up with the pathology results for relevant discussion regarding her ongoing treatment, management, and prognosis.

Discussion

Pathology

The underlying pathology in PMP has been a controversial area for some time [6]. The pathological process was originally thought to be due to a foreign body reaction after mucus containing cysts ruptured into the peritoneum [7]. However, it has now been re-defined to embrace a spectrum of cells from benign to malignant that produce abundant mucinous fluid. Within the ascitic fluid, there may be a few, if any, neoplastic cells seen, as the mucinous exudate is believed to spread further than any potential malignant cells within the peritoneum [8]. Malignant cells that produce PMP are often described as histologically borderline, as they do not show invasion of surrounding structures since they adhere rather than invade. Haematogenous or lymphatic metastasis is unusual, and most cases are found to originate from the appendix, with the most common being primary appendiceal mucinous neoplasia [6]. Rarely, however, the origin may be from the ovary, stomach, gallbladder, pancreas, urinary bladder, uterus, or fallopian tubes [1]. The mucinous tumour cells form cysts that increase intraluminal pressure within the organ of origin, and eventually cause the luminal wall to rupture [8]. The cells are then able to leak into the peritoneum. They are transported passively by peritoneal fluid flow and absorption, and by gravity to adhere to both abdominal and pelvic structures. Even if PMP is of a benign cell origin, the slow but relentless increase of gelatinous fluid in the peritoneal cavity causes compression of intra-abdominal organs, and mechanical and functional gastrointestinal obstruction [8].

Clinical presentation

Symptoms of PMP vary and will depend on the extent of the disease. Most commonly, patients report increasing abdominal girth or enlarging incisional, umbilical, or inguinal hernias [2]. Women may be diagnosed incidentally during routine pelvic examination or may present with infertility [2]. Patients may also report early satiety, as the space within the peritoneal cavity for the stomach to expand decreases, or with a clinical picture of acute appendicitis [9]. However, PMP is still often diagnosed incidentally at laparotomy, with symptoms sometimes inaccurately labeled as irritable bowel syndrome for years prior to diagnosis [1,2].

Utility of diagnostic imaging in PMP

Multiple imaging modalities have been reviewed with regard to PMP. Plain abdominal x-rays have been found to be of little diagnostic use, however, it may help to diagnose intestinal obstruction, a late complication of PMP [10]. Ultrasound may be utilised, with reported findings including homogenous tumour deposits, separated ascites, scalloping of the liver edges, and echogenic masses [11]. CT scans are the most widely used imaging technique for intra-abdominal pathology. Findings suggestive of PMP include scalloping of organs, ascitic septations and loculi, curvilinear calcifications, and omental thickening [10].

A review of CT scan use in 17 cases of PMP reported that early disease is easier to diagnose than more advanced disease. The authors urged radiologists to look for a pattern of mucinous ascites accumulation, rather than the appearance of individual deposits of disease on the image [12]. These authors were based at a surgical hospital and had experience with PMP. It may be difficult to expect a radiologist to detect this diagnosis without having had a similar level of experience. Ultrasound requires similar expertise, where it has been reported that familiarity with the features of PMP are required for accurate diagnosis [13].

Clinical implications

Despite being uncommon, PMP is a possible diagnosis that may occur in patients. It is worth keeping this disease as a differential diagnosis for patients that present with abdominal fullness. Imaging may help with the diagnosis but is not definitive. Without treatment, the prognosis for this condition is poor, with a ten-year survival rate of approximately 32% [14]. Treatments such as peritonectomy, intra-peritoneal chemotherapy at the time of surgery, and radical de-bulking of tumour deposits have been shown to improve the recurrence free survival time in these patients and decrease overall mortality [3,4]. Further, surgery that does not definitively de-bulk the condition contributes to increased difficulty in managing PMP effectively later on, through the creation of adhesions that can facilitate spread of PMP to the small bowel [3]. Early diagnosis is therefore important to help expedite care, allow for appropriate surgical and oncology management to occur, and improve outcomes in patients with PMP.

This case highlights that although it is most commonly horses when you hear hooves, very occasionally, it may actually be a zebra.

Consent declaration

Informed consent was obtained from the patient for publication of this case report.

Conflicts of interest

None declared.

References

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[5] Mann WJ, Wagner J, Cumas J, Chalas E. The management of pseudomyxoma peritonei. Cancer. 1990;66:1636-40.

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[14] Gough DB, Donohue JH, Schutt AJ, Gonchoroff N, Goellner JR, Wilson TO, et al. Pseudomyxoma peritonei: long term patient survival with an aggressive regional approach. Ann Surg. 1994;219(2):112-119.

This case report describes a fourteen year-old male who presented with a relapse of steroid-dependent focal segmental glomerulosclerosis (FSGS). FSGS is responsible for 10-15% of cases of idiopathic nephrotic syndrome (INS) in children, with the majority of cases attributed to minimal change disease. Prednisolone is first line for the induction of remission, with the majority of INS cases responding to initial therapy. Those who fail to achieve remission within four weeks of corticosteroid therapy are labeled “steroid-resistant”. Of those who do remit with corticosteroids, 80% have a relapse, with 50% of these patients having “frequently relapsing disease”. Those patients who relapse while on corticosteroids, or within two weeks of cessation of corticosteroids, are labeled “steroid-dependent”. The aim of this article is to review the literature available on the management of FSGS, particularly steroid-resistant, steroid-dependent, and frequently relapsing disease.

Case Study

ML, a fourteen year-old male, presented to a rural paediatric department with a one-month history of increasing oedema of his face, sacrum, and lower limbs; lethargy; and oliguria on a background of known steroid-dependent focal segmental glomerulosclerosis (FSGS).

ML first presented with nephrotic syndrome in late 2014, which was initially responsive to corticosteroids, but relapsed following steroid cessation. A renal biopsy was performed in early 2015 and ML was diagnosed with FSGS. At this time, he was started on cyclosporin 125 mg OD and was managed by a general paediatrician and nephrologist.

Approximately one month prior to his admission, ML commenced 50 mg doxycycline at night for acne and the cyclosporin was consequently reduced to 100 mg daily due to concerns that doxycycline may increase the cyclosporin concentration. Soon after, his symptoms of nephrotic syndrome began to return and the cyclosporin was increased to 110 mg daily. ML had also started ramipril 1.25 mg at night prior to his admission.

ML had a history of partial seizures, diagnosed in 2008, which were well controlled by valproate 400 mg twice daily. Developmental history was unremarkable. He had no known allergies and had received his routine childhood vaccinations. Due to the immunosuppressive nature of relapsing nephrotic syndrome, he also received the pneumococcal vaccine and an annual influenza vaccine. There was a family history of epilepsy in his grandmother, but no family history of renal disease. ML was an only child, a non-smoker, and a non-drinker, who lived with his mother in a major regional centre.

On examination, ML was pale and lethargic, with marked periorbital oedema. His vital signs were within normal limits. He had cold peripheries, indicating intravascular depletion but central capillary refill was normal. His jugular venous pressure (JVP) was not elevated, but he had pitting oedema extending to the upper legs, as well as sacral, periorbital, and scalp oedema. His abdomen was distended and ascites was demonstrated by shifting dullness. The abdomen was otherwise non-tender and bowel sounds were present. Heart sounds were dual with no murmurs. His chest was clear with resonant percussion, excluding pulmonary oedema.

Investigations included urine dipstick; urine microscopy, culture, and sensitivity (MCS); spot protein-creatinine ratio; full blood examination (FBE); urea, electrolytes, and creatinine (UEC); liver function tests (LFTs); and a cyclosporin level. Urinary investigations revealed heavy proteinuria, but no haematuria, and all other investigations were unremarkable.

ML was admitted for management of his acute relapse, which included fluid and salt restriction, daily weighs, and daily urine dipstick. The ramipril was ceased. He was administered 75 mg of intravenous 20% albumin over six hours, with 40 mg of intravenous frusemide given at mid-infusion and post-infusion.

ML lost four kilograms overnight and was discharged on a five-day course of oral frusemide, with a 40 mg dose on the first day, then 20 mg for four days.

Discussion

Background

FSGS is a histopathological pattern of glomerular injury seen under light microscopy, in which sclerosis occurs in segments of only some of the glomeruli [1]. This pattern of injury can occur in all age groups and is the most common cause of adult nephrotic syndrome [2]. FSGS is also identified in 10-15% of cases of idiopathic nephrotic syndrome in children, with the majority of cases attributed to minimal change disease [3].

In most cases of FSGS, the underlying cause is unknown – termed “primary FSGS” [4]. However, secondary FSGS may develop as a response to previous renal injury. Underlying causes of secondary FSGS include reflux nephropathy, infections (for example, HIV), obesity, medications (for example, interferon), genetic mutations, surgical resection of renal tumours, congenital renal dysplasia, and intrauterine growth restriction [5].

Primary FSGS presents with a typical nephrotic syndrome, including foamy urine and extensive oedema [6], particularly periorbital oedema. Nephrotic syndrome is confirmed with a spot urine protein creatinine ratio >0.2 g/mmol [3]. Secondary FSGS is more variable in its presentation, with proteinuria often below nephrotic levels and patients being less likely to present with overt oedema [5].

In children who present with overt nephrotic syndrome, a renal biopsy is not appropriate, because the majority of these cases will be due to minimal change disease. Only when they are unresponsive to corticosteroids, or develop a frequently relapsing or steroid-dependent pattern of disease, is a renal biopsy justified [6]. For indistinct presentations (for example, proteinuria below nephrotic levels), a renal biopsy may be considered on the initial presentation [7]. The risks and benefits of the renal biopsy must be evaluated, with post-biopsy bleeding being a major risk to consider [6].

The following discussion will focus on the treatment of primary FSGS. Secondary FSGS is best treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers to lower the intraglomerular pressure and treatment of the underlying cause, when possible [2].

Immunosuppressive treatment: corticosteroid

Corticosteroids are first-line in treatment of idiopathic nephrotic syndrome (INS) for the induction of remission. Between 80-90% of cases of INS are responsive to initial corticosteroid therapy [3]. Those patients who fail to achieve remission within four weeks of corticosteroid therapy are labeled “steroid-resistant”. Of those patients who respond initially, there is an 80% chance of relapse, with 50% of those having frequently relapsing disease, defined as two or more relapses in the first six months or four or more relapses in any twelve-month period [3,8]. Those who relapse while on corticosteroids or within two weeks of cessation of corticosteroids are labeled “steroid-dependent” [3].

Immunosuppressive treatment: non-corticosteroid

In steroid-resistant, steroid-dependent, and frequently relapsing disease, non-corticosteroid immunosuppressive agents are utilised. The available evidence for each of the commonly used non-corticosteroid immunosuppressive agents will be explored to determine if cyclosporin is the best treatment to prevent relapse in a patient like ML, who has steroid-dependent FSGS.

Calcineurin inhibitors, with or without low dose prednisolone, are first line [1]. The majority of evidence is with cyclosporin. Cochrane Reviews have demonstrated that cyclosporin increases the rate of remission in children with steroid-resistant disease [9] and reduces relapses in steroid-dependent disease, compared with prednisolone alone [8]. Cyclosporin was superior to intravenous cyclophosphamide in steroid-resistant disease [9]. However, in steroid-dependent disease, relapse was reduced with an eight-week course of alkylating agents, cyclophosphamide, or chlorambucil, while cyclosporin required a prolonged course and its effects were not always sustained following treatment cessation [8]. Therefore, cyclophosphamide plays no role in steroid-resistant disease, but may be used in the treatment of steroid-dependent FSGS when cyclosporin has failed or in patients with higher risk of calcineurin nephrotoxicity due to extensive interstitial fibrosis or vascular disease [1].

Mycophenolate motefil may be useful as an alternative medication for relapsing disease, however, the evidence is limited to a few smaller trials [8]. It may be used in combination with corticosteroids when calcineurin inhibitors have been unsuccessful or are contraindicated. Rituximab is another alternative, which has had some success in steroid-dependent disease, but the evidence does not support its use in steroid-resistant disease [8,10,11]. Subcutaneous natural adrenocorticotropic hormone (ACTH) therapy has also had some success in pilot studies, however, the treatment is expensive and further randomised trials are required to confirm the results [12,13].

Non-immunosuppresive treatment

The evidence clearly supports the use of ACE inhibitors or angiotensin receptor blockers in children with steroid-resistant nephrotic syndrome and secondary FSGS [7]. The use of these agents in steroid-dependent or frequently relapsing disease has not been specifically studied. However, guidelines on the use of anti-hypertensive agents in children with chronic kidney disease from any cause suggest that children should be started on an ACE inhibitor or angiotensin receptor blocker when their blood pressure is consistently above the 90^th percentile for their age, sex, and height [14]. Treatment should aim to reduce blood pressure to at or below the 50^th percentile, unless limited by symptomatic hypotension [14]. Blood pressure-lowering drugs should be used when indicated, irrespective of the level of proteinuria [14]. In primary FSGS, blood pressure-lowering therapy may slow progression to end-stage renal disease, however, it rarely results in remission without concurrent immunosuppressive treatment [15].

Hyperlipidaemia is a common complication of nephrotic syndrome. Combined with the higher cardiovascular risk of patients with chronic kidney disease, this calls for lipid-lowering therapy with a statin [1,16]. While lipid-lowering agents have been successful in lowering lipids in adults with nephrotic syndrome, no studies have looked at the mortality and morbidity benefits of a statin [16]. The use of statins in children with nephrotic syndrome is controversial, with small studies showing that statins reduce lipid levels and are well tolerated, however, there is a lack of evidence regarding long-term safety of statins in paediatric patients [17].

Renal transplantation

Over ten years, 60% of cases of FSGS progress to end-stage renal failure [18]. These patients will need dialysis or renal transplantation. However, there is a high rate of graft failure, with recurrence of FSGS in 30% of allografts [19,20]. The graft survival is lower in children than in adults [19].

Therapeutic plasmapheresis, used for a number of antibody-mediated conditions, is a process that removes the antibody-containing plasma from the patient’s blood and replaces it with unaffected plasma or a plasma substitute [21]. Therapeutic plasmapheresis may be used in FSGS prophylactically before transplantation or in the treatment of established recurrence in an allograft [19]. Studies show that 49-70% of children with recurrent FSGS who receive plasmapheresis enter complete or partial remission of proteinuria [19]. A small study demonstrated that early and intensive daily plasmapheresis in patients with recurrence was beneficial in obtaining complete remission [20].

Future novel therapies

Adalimumab and galactose versus conservative therapy with lisinopril, losartan, and atorvastatin is currently being studied in the “Novel therapies for resistant focal segmental glomerulosclerosis (FONT)” trial. [22] If successful, these treatments may form part of the treatment of FSGS in those patients who have failed other immunosuppressive therapies.

Conclusion

This case report describes a patient with steroid-dependent nephrotic syndrome, diagnosed on renal biopsy as FSGS. The patient was commenced on cyclosporin, which is first-line in steroid-dependent disease. Alternative immunosuppressive agents, rituximab and mycophenolate motefil, require larger-scale trials to confirm their efficacy. Current guidelines suggest that patients’ ramipril should be restarted if their blood pressure is above the 90^th percentile for their age, sex and height. However, further research is needed to create specific guidelines for the use of anti-hypertensive agents in children with steroid-dependent nephrotic syndrome. The evidence for the safety of statins in children is insufficient, therefore these drugs should be avoided.

References

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[2] Reiser J. Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis [Internet]. Waltham (MA): UpToDate; 2016 [updated 2015 Dec 4; cited 2016 Jun 12]. Available from: http://www.uptodate.com/contents/epidemiology-classification-and-pathogenesis-of-focal-segmental-glomerulosclerosis?source=search_result&search=Epidemiology%2C+classification%2C+and+pathogenesis+of+focal+segmental+glomerulosclerosis&selectedTitle=1~134

[3] Royal Children’s Hospital Melbourne. Nephrotic syndrome [Internet]. Melbourne: Royal Children’s Hospital Melbourne; 2016 [cited 2016 Mar 19]. Available from: http://www.rch.org.au/clinicalguide/guideline_index/Nephrotic_Syndrome/

[4] Goddard J, Turner AN. Kidney and urinary tract disease. In: Walker BR, Colledge NR, Ralston SH, Penman ID, editors. Davidson’s principles and practice of medicine. 22^nd ed. Edinburgh: Elsevier Limited; 2014. p.461-523

[5] Kiffel J, Rahimzada Y, Trachtman H. Focal segmental glomerulosclerosis and chronic kidney disease in paediatric patients. Adv Chronic Kidney Dis [Internet]. 2013 [cited 2016 Jun 12];18(5):332-8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709971/

[6] BMJ Best Practice. Assessment of nephrotic syndrome [Internet]. London: BMJ Publishing Group Limited; 2015 [cited 2016 Jun 12]. Available from: http://bestpractice.bmj.com/best-practice/monograph/356.html

[7] Kidney Disease Improving Global Outcomes (KDIGO). KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl [Internet]. 2012 [cited 2016 Jun 12];2(2):139-274. Available from: http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-GN-Guideline.pdf

[8] Pravitsitthikul N, Willis NS, Hodson EM, Craig JC. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev [Internet]. 2013 [cited 2016 Mar 19];(10):CD002290. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002290.pub4/abstract

[9] Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev [Internet]. 2010 [cited 2016 Mar 18];(11):CD003594. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003594.pub4/abstract

[10] Kronbichler A, Kerschbaurn J, Fernandez-Fresnedo G, Hoxha E, Kurschat CE, Busch M, et al. Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: a systemic review. Am J Nephrol [Internet]. 2014 [cited 2016 Mar 18];39(4):322-30. Available from: http://www.karger.com/Article/Abstract/360908 DOI: 10.1159/000360908

[11] Magnasco A, Pietro R, Edefonti A, Murer L, Ghio L, Belingheri M, et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol [Internet].  2012 [cited 2016 Mar 12];23(6):1117-24. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358759/

[12] Bomback AS, Canetta PA, Beck Jr. LH, Ayalon R, Radhakrishnan J, Appel GB. Treatment of resistant glomerular disease with adrenocorticotropic hormone gel: A prospective trial. Am J Nephrol [Internet]. 2012 [cited 2016 Mar 12];36(1):58-67. Available from: http://www.karger.com/Article/Abstract/339287

[13] Hogan J, Bomback AS, Kehta M, Canetta PA, Rao MK, Appel GB, et al. Treatment of idiopathic FSGS with adrenocorticotropic hormone gel. Clin J Am Soc Nephrol [Internet]. 2013 [cited 2016 Mar 12];8(12):2072-81. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848392/

[14] Kidney Disease Improving Global Outcomes (KDIGO). KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl [Internet]. 2012 [cited 2016 Jun 12];2(5):337-414 Available from: http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO_BP_GL.pdf

[15] Korbet SM. Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. Semin Nephrol [Internet]. 2003 [cited 2016 Mar 12];23(2):219-28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12704582

[16] Massy ZA, Ma JZ, Louis TA, Kasiske BL. Lipid-lowering therapy in patients with renal disease. Kidney Int [Internet]. 1995 [cited 2016 Mar 12];48(1):188-98. Available from: http://www.sciencedirect.com/science/article/pii/S008525381559056X DOI: 10.1038/ki.1995.284

[17] Prescott WA, Streetman DD, Streetman DS. The potential role of HMG-CoA reductase inhibitors in paediatric nephrotic syndrome. Ann Pharmacother [Internet]. 2004 [cited 2016 Jun 12];38(12):2105-14. Available from: http://aop.sagepub.com/content/38/12/2105.full.pdf+html

[18] South M, Isaacs D. Practical paediatrics. 7^th edition. Sydney: Elsevier; 2012. p.651

[19] Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transplant [Internet]. 2009 [cited 2016 Mar 13];25(1):25-31. Available from: http://ndt.oxfordjournals.org/content/25/1/25.full

[20] Straatmann C, Kallash M, Killackey M, Iorember F, Aviles D, Bamgbola O, et al. Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients. Pediatr Transplant [Internet]. 2013 [cited 2016 Mar 13];18(1):29-34. Available from: http://onlinelibrary.wiley.com/

[21] Fridey JL, Kaplan AA. Therapeutic apheresis (plasma exchange or cytapheresis): indications and technology [Internet]. Waltham (MA): UpToDate; 2016 [updated 2015 Jul 29, cited 2016 Jun 12]. Available from: http://www.uptodate.com/contents/therapeutic-apheresis-plasma-exchange-or-cytapheresis-indications-and-technology?source=search_result&search=therapeutic+apheresis&selectedTitle=1~150

[22] Trachtman H, Vento S, Gipson D, Wickman L, Gassman J, Joy M, et al. Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design. BMC Nephrol [Internet]. 2011 [cited 2016 Mar 19];12(8). Available from: http://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-12-8

A fit 40-year-old man presented to hospital with signs and symptoms consistent with a large anterior stroke. He underwent intravenous thrombolysis and later developed cerebral oedema, which was managed with a decompressive hemicraniectomy. Investigation findings revealed the patient had tight mitral stenosis most likely due to rheumatic heart disease. The report discusses the pathogenesis of stroke due to rheumatic heart disease and compares the use of intravenous thrombolysis and mechanical thrombectomy in the treatment of ischaemic stroke.

Introduction

Cerebrovascular disease is the second leading cause of death and the leading cause of disability in Australia [1]. This case report describes a 40-year-old who presented with symptoms consistent with a large anterior stroke. The report illustrates the causes of stroke in a young person, and outlines the pathogenesis of stroke due to rheumatic heart disease. It also highlights the serious complication of cytotoxic and ionic cerebral oedema that can occur after a large stroke, and the use of hemicranectomy in its management. The case report also discusses and compares the use of intravenous thrombolysis and mechanical thrombectomy in the treatment of ischaemic stroke.

Case Description

A 40-year-old man collapsed at home and was transported by ambulance to the emergency department (ED) of a regional hospital. En route to the hospital he was confused and was noted to have left sided weakness and facial droop. He emigrated from India at age 13, had no known medical conditions, and was on no regular medications. There was no family history of stroke or any prothrombotic conditions. He reportedly did not smoke or drink alcohol, he exercised regularly, and was not overweight.

On examination in the ED, he had a Glasgow Coma Score (GCS) of 13, left-sided facial droop, dysarthria, complete flaccid paralysis of the left upper limb, and left lower limb weakness (unable to resist gravity). He was assessed as having a National Institute of Health Stroke Score (NIHSS) of 14. On auscultation, his chest was clear and heart sounds were reported as being dual with no murmurs. An ECG was performed, which showed he was in sinus rhythm. A computerised tomography (CT) brain scan showed an area of hypodense brain tissue corresponding to the right middle cerebral artery (MCA) territory and a dense right MCA sign, representing increased attenuation of the proximal portion of the MCA (Figure 1). There were no signs of acute haemorrhage on the CT scan. A CT angiogram was not performed. These findings were consistent with a large right MCA ischaemic stroke. Since all inclusion criteria were met with no contraindications to therapy, the patient was treated with alteplase within four hours of symptom onset. The patient was observed for signs of bleeding; and vital signs, cardiac rhythm, blood glucose, and neurological function were checked regularly following alteplase administration. Approximately three hours later, the patient’s GCS dropped to 11. A CT brain scan was repeated, which showed further development of cerebral oedema and effacement of the sylvian fissure, but no acute haemorrhage. Due to his neurological deterioration and worsening cerebral oedema, he was transferred to a tertiary hospital to undergo a decompressive hemicraniectomy.

Figure 1: A non-contrast CT scan of the brain showing a dense right middle cerebral artery sign [32].

On examination in the intensive care unit, post-hemicraniectomy, the patient’s neurological function had improved to a GCS of 14. He still had a dense left hemiparesis, reduced left sided sensation, facial droop, dysarthria, and left-sided neglect. The intensivist identified a diastolic murmur with an opening snap that had not been picked up on previous examinations. The patient was extensively investigated to find the cause of the stroke. This included a full blood count (FBC); urea, electrolytes, and creatinine (UEC); coagulation studies; fasting lipids and glucose; ESR and CRP; syphilis serology; vasculitis screen; prothrombotic screen; chest x-ray; ECG; and carotid artery doppler scan. These results were all normal.  An echocardiogram showed tight mitral stenosis (MS) with a mitral valve area of 1.8 cm², thickened and restricted valve leaflets, and a large dilated left atrium measuring 49 mm. The systolic pulmonary artery pressure was also measured during echocardiogram which demonstrated no significant pulmonary hypertension.

It was hypothesised by the intensivist that the stroke resulted from a thrombus forming in the large, dilated, left atrium due to paroxysmal atrial fibrillation (AF) caused by the MS. Even though no significant childhood illness was reported by the patient or his family, the MS was believed to be the result of rheumatic heart disease (RHD) based on his echocardiogram findings and the patient’s emigration history.

The patient was reviewed by cardiology and was commenced on warfarin with a target INR of between two to three. It was also recommended that he receive intramuscular penicillin injections of 900 mg monthly for the secondary prevention of RHD. A follow-up echocardiogram and cardiology appointment was booked for six weeks’ time to determine whether a percutaneous balloon mitral valvuloplasty would be indicated to treat his MS. A follow up neurosurgery appointment was also planned for discussion of a future cranioplasty. Once stable, the patient was transferred to a rehabilitation facility to undergo an intensive multi-disciplinary program consisting of physiotherapy, speech therapy, and occupational therapy with the aim of maximising his physical, psychological, social, and financial independence.

Discussion

Young patients with minimal risk factors who have suffered a stroke require more extensive investigations in order to find an underlying cause. Conditions associated with ischaemic stroke in young adults include cardiac abnormalities, premature atherosclerosis, hypertension, vasculopathy including arterial dissection, recent pregnancy, other hypercoagulable states, smoking, illicit drug use, metabolic disorders, and migraine with aura [2]. A meta-analysis by Schurks et al. [3] found migraine with aura to be an independent risk factor for developing ischaemic stroke, but the absolute increase in the risk of stroke was found to be small. The pathophysiology underlying migraine as a possible cause of stroke is not yet clear [3]. Several metabolic conditions are also associated with acute ischaemic stroke in young adults. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a metabolic condition which leads to progressive degeneration of smooth muscle cells in the vessel wall [4]. Patients with CADASIL may present with migraine, transient ischaemic attack, or ischaemic stroke in late childhood or early adulthood [4]. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is another metabolic condition that causes stroke-like episodes in young adults, leading to progressive neurologic dysfunction and dementia. The hallmarks of this syndrome are episodes of hemiparesis, hemianopia, or cortical blindness [5]. Cardiac defects such as patent foramen ovale (PFO) and atrial septal defect (ASD) have also been implicated in the pathogenesis of stroke in younger adults [6]. The mechanism is via an embolus that originates in the systemic venous circulation and enters the systemic arterial circulation through the cardiac defect. Emboli can originate from the lower extremity or pelvic veins, tricuspid vegetations, or right atrial thrombi [6]. Many of these conditions only account for a very small percentage of stroke in young adults. A large cohort study by Putaaya et al. [7] looked at patients aged 15-49 with their first ever ischaemic stroke. They found the most common aetiologies were cardioembolism and cervicocephalic atrial dissection.

Atrial fibrillation is a common causes of cardioembolic stroke, with around 25% of ischaemic stroke patients in Australia having AF [8]. Coronary artery disease, hypertension, heart failure, and valvular heart disease are the most common causes of AF [9].  In this case report the patient’s thrombus was hypothesised to have been caused by paroxysmal AF due to rheumatic MS.  Rheumatic heart disease is a result of cardiac inflammation and scarring triggered by an autoimmune reaction to infection with group A streptococci [10]. This can result in thickened and restricted valve leaflets, leading to valve stenosis and/or regurgitation [10]. Rheumatic heart disease is the most common cause of MS [11]. One of the most common complications of rheumatic MS is AF [12]. In rheumatic MS, AF may initially be paroxysmal, but eventually it becomes chronic as the MS and left atrial dilatation progress [11]. AF may cause systemic embolism from mural thrombus development in the left atrium leading to stroke. Patients with MS and AF should therefore receive long-term prophylactic anticoagulation. Left atrial thrombus can occur in MS, even when sinus rhythm is present. This is due to left atrial dilatation, low blood velocity, and disorganised blood flow. Therefore, prophylactic anticoagulation should also be considered for patients with MS and a dilated left atrium even if in sinus rhythm [12]. The 2014 American Heart Association (AHA) guidelines on management of valvular heart disease recommends the use of warfarin in patients with MS and at least one of the following conditions: paroxysmal AF, permanent AF, prior embolic event, or proven left atrial thrombus [13]. Newer oral anticoagulants are now approved for the prevention of systemic embolism in adults with non-valvular AF. However, they are not approved for use in patients with MS, as this patient group was excluded in clinical trials [13].

Another treatment option for MS is percutaneous balloon mitral valvuloplasty. This procedure involves a balloon catheter being inserted via the femoral vein and placed in the left atrium. The balloon is positioned across the stenotic mitral valve and inflated, thereby separating the stenotic leaflets along the commissures. The criteria for percutaneous balloon mitral valvuloplasty in an asymptomatic patient with MS is a mitral valve area ≤1.0 cm², favorable valve morphology, absence of moderate to severe mitral regurgitation, and no left atrial thrombus [13]. The patient in this case report did not meet the AHA criteria and therefore is unlikely to undergo valvuloplasty. In asymptomatic patients with MS, follow-up echocardiography is recommended every three to five years, if the mitral valve area is >1.5 cm² [13]. The patient in this case report should therefore undergo regular echocardiograms to monitor the progression of his MS.

One of the serious complications of a large MCA stroke is the development of cytotoxic and ionic cerebral oedema. Cerebral oedema is the result of cells being unable to maintain ATP-dependent Na⁺/K⁺ membrane pumps which are responsible for a high extracellular and low intracellular Na+ concentration [14]. When energy falls due to cerebral ischaemia, these pumps cease to operate and Na⁺ accumulates in the cell, drawing with it Cl^– and water along an osmotic gradient [14]. Space-occupying cerebral oedema can elevate intracranial pressure and lead to brain herniation [15]. The development of space-occupying cerebral oedema due to a large infarction leads to neurologic deterioration with signs that typically include decreased arousal, pupillary changes, and worsening of motor responses [16]. These neurological signs are indicators of the need to intervene urgently. Decompressive hemicraniectomy and durotomy is a surgical technique used to relieve the increased intracranial pressure and brain tissue shifts that occur in the setting of large cerebral hemisphere space-occupying lesions. The technique involves removal of bone tissue and incision of the restrictive dura mater covering the brain, allowing swollen brain tissue to herniate upwards through the surgical defect rather than downwards to compress the brainstem [16]. In patients with malignant MCA infarction, decompressive surgery undertaken within 48 hours of stroke onset reduces mortality and increases the number of patients with a favorable functional outcome [17].

The immediate aim in the management of acute ischaemic stroke is to recanalise the occluded vessel as quickly, safely, and effectively as possible to restore blood supply to the ischaemic brain region [18]. Thrombolytic therapy is an effective strategy for salvaging ischaemic brain tissue that is not already infarcted following ischaemic stroke [19]. However, there is a risk of haemorrhage, a narrow window during which it can be administered, and multiple contraindications to its use [18]. The indications for administering thrombolysis include the onset of ischaemic stroke within the preceding four-and–a-half hours in Australia and Europe, and within three hours in the United States. There must also be no signs of haemorrhage on the brain CT scan [18]. Where available, assessment of ischaemic brain injury with either diffusion and perfusion MRI or with perfusion CT should be performed if the findings are likely to influence treatment decisions. However, these should be used rather than CT only if it does not delay treatment with intravenous alteplase [20]. A 2014 meta-analysis by Emberson et al. [21] evaluated individual patient data from 6756 subjects who were allocated to intravenous alteplase or control within three to six hours of acute ischaemic stroke onset. The primary outcome measure was the proportion of patients achieving a good stroke outcome at three or six months as defined by a modified Rankin scale score. The modified Rankin scale measures the degree of disability or dependence in the patient’s daily activities [21]. The results of Emberson’s analysis showed that the sooner intravenous alteplase treatment is initiated, the more likely it is to be beneficial, and that the benefit extends to treatment started within four-and-a-half hours of stroke onset [21]. It was found that beyond five hours, harm may exceed benefit as alteplase increased the risk of symptomatic intracranial haemorrhage (6.8% vs 1.3% control) and fatal intracranial haemorrhage within seven days (2.7% vs 0.4% control) [21]. A recent systematic review by Wardlaw et al. [22] found similar results, that treatment with intravenous alteplase within three hours of stroke was substantially more effective in reducing death or dependency than therapy given up to six hours after stroke onset.

Intra-arterial mechanical thrombectomy is another treatment option for patients with ischaemic stroke. Five large randomised control trials [23-27] demonstrated that early intra-arterial treatment using mechanical thrombectomy devices is superior to standard treatment with intravenous thrombolysis alone for large proximal vessel ischaemic stroke in the anterior circulation. The inclusion criteria for mechanical thrombectomy include a CT brain scan ruling out intracranial haemorrhage, angiography demonstrating a proximal large artery occlusion in the anterior circulation, and thrombectomy initiated within six hours of stroke onset [23]. One problem that limits the widespread clinical use of mechanical thrombectomy is that only an estimated ten percent of patients with acute ischaemic stroke have a proximal large artery occlusion in the anterior circulation and present early enough to qualify for mechanical thrombectomy [18]. Another issue that limits its widespread use is that it is restricted to major stroke centres that have specialist interventional radiology resources and expertise able to perform the procedure [18]. The Queensland Health Policy Advisory Committee on Technology published a report in December 2015 that looked at mechanical thrombolysis for ischaemic stroke [29]. They found that mechanical thrombectomy can only be safely performed in experienced centres with appropriate support in terms of imaging and multidisciplinary care, and that only large tertiary centres with stroke units are able to provide this service. They noted that this may have implications for patients who are not near to these services, especially given the time frame within which the procedure can be performed. This has implications for accessibility for rural and remote patients, and associated costs if transferring patients to tertiary centers is required [29]. Another issue is that transferring patients to tertiary centres can delay the onset of stroke treatment. However, eligible patients can receive standard treatment with intravenous alteplase if they present to hospitals where thrombectomy is not an option. Those patients with qualifying anterior circulation strokes can then be transferred to tertiary stroke centers where intra-arterial thrombectomy is available [30].

In this case report, the patient was discussed at an interventional radiology meeting at the tertiary hospital. The radiologist commented that if this patient had initially presented to the tertiary hospital rather than the regional hospital, the patient would have undergone a mechanical thrombectomy instead of, or as well as, the intravenous thrombolysis. Similar views are expressed in a 2015 editorial by neuroradiologists Pierot and Derdeyn [31]. They conclude that endovascular treatment has now been proven effective for a well-defined subset of patients with acute stroke, provided there is careful patient selection, time to reperfuse, and reperfusion rate is optimised. This illustrates that mechanical thrombectomy is now the treatment of choice for proximal, anterior, ischamic stroke if the resources and personnel are available.

Consent Declaration

Informed consent was obtained from the patient and next-of-kin for publication of this case report and accompanying figures.

Conflicts of Interest

None declared.

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