CLINICAL

AND

LABORATORY OBSERVATIONS

Pyomyositis Causing Temporary Quadriparesis During Induction Therapy for Acute Lymphoblastic Leukemia: Case Report and Review of the Literature Nazanin Montazeri, MD, BSc,* Uma H. Athale, MD, MSc, FRCPC,w Martha Fulford, MD, BSc, BEd, MA, FRCPC,* and Mark A. Tarnopolsky, MD, PhD, FRCPC*w

Summary: Pyomyositis (PM) is a purulent infection of skeletal muscle. It is often associated with immunosuppression in temperate climates. Herein, we report a case of PM causing temporary quadriparesis in a 14-year-old girl undergoing induction therapy for acute lymphoblastic leukemia and we review the reported pediatric cases associated with induction therapy for hematologic malignancies. Early symptoms of PM can be mistaken for the side effects of chemotherapeutic agents. Greater awareness of the clinical picture of PM will aid in early diagnosis and treatment. With appropriate medical therapy and timely abscess drainage, morbidity and mortality is greatly reduced. Key Words: pyomyositis, acute lymphoblastic leukemia (ALL), quadriparesis, induction therapy

(J Pediatr Hematol Oncol 2015;37:223–226)

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yomyositis (PM) is a purulent infection of skeletal muscle first described in detail by Scriba in 1885.1 Although primarily seen in tropical climates,2 PM has increasingly been reported in temperate areas, often in association with immunosuppression.3–6 Infection due to the human immunodeficiency virus accounts for nearly a quarter of the immunocompromised hosts5; however, hematologic malignancies and chemotherapy have also been implicated.6 The most common causative infectious agent is Staphylococcus aureus, which accounts for up to 75% of cases in temperate areas.5,7 Numerous other organisms, including fungi,8 have been reported as well. There have been several reports of PM in pediatric patients with hematologic malignancies.2,8–12 Herein, we report a case of PM causing temporary quadriparesis during induction therapy for acute lymphoblastic leukemia (ALL) and review the 5 reported pediatric cases associated with induction therapy for hematologic malignancies.

Received for publication September 5, 2013; accepted March 5, 2014. From the Departments of *Medicine; and wPediatrics, McMaster University, Hamilton, ON, Canada. The authors declare no conflict of interest. Reprints: Nazanin Montazeri, MD, BSc, Department of Medicine, McMaster University, Room MDCL—3101A, 1280 Main Street West, Hamilton, ON, Canada L8S 4K1 (e-mail: nazanin. [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.

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CASE REPORT A 14-year-old girl was admitted in February 2012 with a new diagnosis of precursor B-cell ALL. Presenting complete blood count showed white blood cell (WBC) count of 68.3 109/L, hemoglobin level of 75 g/L, and platelet count of 17109/L. Flow cytometry showed 88% blasts with dim CD10 + , CD19 + , dim CD22 + , CD 20 , CD34 , TdT , and aberrant CD5 expression. Eight percent of the blasts did not show CD5 expression. Cytogenetic study was normal and fluorescent in situ hybridization and molecular studies did not reveal MLL gene rearrangement or typical ALL-associated translocations. Cerebrospinal fluid was normal. She was categorized as high-risk (HR) (because of her age and presenting WBC count) precursor B-cell ALL and was started on chemotherapy as per the HR arm of Dana-Farber Cancer Institute ALL consortium protocol 05-001. The backbone of therapy was described earlier.13 In summary, the therapy consisted of steroid prophase with methylprednisone for the first 3 days, followed by induction therapy with prednisone, vincristine, doxorubicin, dexrazoxane, methotrexate, and PEG asparaginase. The patient also received day one intrathecal (IT) cytarabine on day 1 of therapy. She tolerated the initial treatment well and was discharged home after 2 weeks to be followed as an outpatient. However, on day 15 of the treatment she reported pain, swelling, and “spots” on her right hand. The next day, she developed left knee pain and her hand swelling and pain worsened. The pain progressed to involve all limbs and was described as a dull ache, worse on palpation. The patient rapidly developed weakness and had difficulty climbing stairs. She was admitted for pain management and further investigations. At the time of admission, her WBC count and absolute neutrophils were 0.7 109/L and 0.1 109/L, respectively. Shortly after, she experienced septic shock with subsequent confirmation of S. aureus bacteremia susceptible to cefazolin and oxacillin. She was initially treated with 2 doses of vancomycin and a 2-day course of piperacillin, tazobactam, and gentamicin. Subsequently, she received a 7-day course of ceftazidime and an 18-day course of cloxacillin. These were followed by 7 days of levofloxacin and 21 days of doxycycline. Cotrimoxazole was given for three weeks and overlapped with the doxycycline course. On initial examination, there was generalized proximal greater than distal weakness and areflexia. Mental status, cranial nerve, and sensory examinations were normal. Electrophysiological studies showed normal latencies, amplitudes, and conduction velocities for the sural (sensory), median, and peroneal (both motor) nerves. Laboratory tests showed a normal creatine kinase (CK) level, and this remained normal throughout her course in the hospital. On the basis of the symptoms, history of induction therapy, and bacteremia, PM was suspected and further imaging studies were performed. On day 23 after the start of chemotherapy, contrast MRI of the shoulders showed edema involving the rotator cuff muscles, more prominent on the right. On day 42 of therapy (27 d after the onset of symptoms), ultrasound imaging revealed an abscess measuring 4.8 2.5 1.5 cm in the left thigh, which was drained.

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ALL indicates acute lymphocytic leukemia; AML, acute myelogenous leukemia; N/R, not reported; PMN, polymorphonuclear leukocytes; WBC, white blood cell count.

27 Pain, swelling, 42 d after start of induction rash, rapid quadriparesis 14/F This study

ALL

10/F Kao et al9

Vincristine, doxorubicin, dexrazoxane, methotrexate, PEG asparaginase, methylprednisone, prednisone, intrathecal (IT) cytarabine

20 d after the start of induction Pain, fever

AML 15/F

ALL

ALL 10/M

Vincristine, epirubicin, prednisolone

Tenderness, 24 d after the diagnosis of AML subcutaneous nodules

15

14 Pain, limping

10

13.7 64% PMN 10.7 35% PMN N/R Patient treated for neutropenia 0.6 N/R 0.7 0.1 15 ALL 9/M

Corden and Morgan2 Corden and Morgan2 Chang et al8

Vincristine, daunorubicin, cytosine arabinoside, methotrexate, L-asparaginase, prednisone Vincristine, daunorubicin, cytosine arabinoside, methotrexate, L-asparaginase, prednisone Cytosine arabinoside, idarubicin

32 d after the start of induction

0.4 N/R ALL 12/M

Vincristine, daunomycin, L-asparaginase, prednisone

Pain, fever, rash

10

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16 d after completion of reinduction chemotherapy for a second hematologic relapse Pain, weakness 36 d after start of induction



Blatt et al10

Initial Symptom(s) Induction Chemotherapy Age (y)/ Hematologic Sex Malignancy References

DISCUSSION PM is most commonly associated with immunosuppression in temperate climates. Although the exact pathogenesis is unclear, it is believed to involve transient bacteremia, with muscle injury (myonecrosis) playing a possible role.5,9 In contrast, we suggest that it is unlikely that myonecrosis per se always occurs, given that at no time did our patient show elevated plasma CK activity. The observed quadriparesis in our patient may have been due to microscopic infection without subsequent abscess formation or possibly from a local cytokine or other myotoxin inhibiting muscle function. A number of cytokines have been identified and may play a role in the pathogenesis of idiopathic inflammatory myopathies, which manifest with muscle weakness.14 These include proinflammatory cytokines TNF-a and IL-1 a.14 Although not proven to play a role in PM, these and other cytokines may lead to muscle dysfunction observed clinically. Hematological malignancies and chemotherapy have been associated with PM, presumably by weakening the immune system. Herein, we reported a case of PM leading to rapid quadriparesis during induction therapy for ALL and reviewed other reported pediatric cases in association with induction therapy for hematologic malignancies (Tables 1, 2). The underlying hematologic malignancy was ALL in all but one of the cases, wherein acute myelogenous leukemia was implicated (Table 1). The symptoms of PM developed during or shortly after induction therapy in all cases. Pain or tenderness was the common initial symptom. Other symptoms include fever, subcutaneous nodules, rash, weakness, and limping. Our patient experienced pain, which spread from her hand to involve all 4 limbs. In addition, she experienced rapid quadriparesis and became bedridden. Interestingly, large abscesses were only discovered in her left hip and thigh, although her symptoms involved all limbs. Corden and Morgan2 reported a case

TABLE 1. Summary of Reported Pyomyositis Cases Associated with Induction Therapy for Hematologic Malignancies in the Pediatric Population (Part 1/2)

Gram stain and fluid cultures were negative. The next day, another ultrasound showed a superficial hypoechoic area measuring 0.2 0.2 0.1 cm and an echogenic area measuring 0.70.3 0.2cm in the left upper arm. On day 47 of therapy, a noncontrast MRI of bilateral hips suggested an abscess within the left iliopsoas muscle measuring 3.1 1.5 4.8 cm. This was confirmed with a contrast computed tomography (CT) and the abscess was drained. Again, no organisms were identified on Gram stain or on fluid cultures. On follow-up examination, 3 and a half months later, the patient had recovered well and had >grade 4/5 (MRC scale) power in all muscle groups. With regard to her ALL therapy, the day 18 therapy including day 18 triple IT therapy, was deferred because of septicemia and positive blood cultures. She received day 18 vincristine later; however, she did not receive day 18 triple IT therapy. She continued with daily prednisone and weekly vincristine. Her day 32 bone marrow examination revealed persistent leukemic blasts on flow cytometry and biopsy. Hence, she was categorized as induction failure and her therapy was switched to Children’s Oncology Group (COG) very HR protocol AALL 1131 and received 2 cycles of chemotherapy consisting of clofarabine, cyclophosphamide, etoposide, vincristine, and PEG asparaginase. She achieved remission in May 2012 and received a matched sibling donor stem cell transplant in July 2012. She was conditioned with cyclophosphamide and total body irradiation. Although the bone marrow was engrafted well, unfortunately, she went on to develop central nervous system relapse of ALL in October 2012 and passed away in December 2013.

Time From Onset of Symptoms to Initial WBC/ Time From Induction Therapy Identification of Abscess Neutrophils to Identification of Abscess (d) (109 L)

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Pyomyositis Causing Temporary Quadriparesis

TABLE 2. Summary of Reported Pyomyositis Cases Associated With Induction Therapy for Hematologic Malignancies in the Pediatric Population (Part 2/2)

References Blatt et

al10

Corden and

Morgan2

Corden and Morgan2

Chang et al8 Kao et al9 This study

Pathogen

Muscles Affected

Management

Outcome

Blood culture—S. aureus Abscess fluid—S. aureus Blood culture—S. aureus Abscess fluid—S. aureus Blood culture—not reported Abscess fluid—S. aureus

R calf L thigh Bilateral calf Bilateral thigh Bilateral thigh Bilateral lower extremities R shoulder/upper arm L buttock/pelvic region Bilateral calf

Antibiotics Incision and drainage Antibiotics Incision and drainage Antibiotics Incision and drainage

Successful

Antibiotics, drainage

Successful

R thigh L chest wall L thigh L Iliopsoas L upper arm

Antibiotics, drainage

Successful

Antibiotics, drainage

Successful

Blood culture—negative Abscess fluid—Acremonium species fungus Blood culture—S. aureus Abscess fluid—no growth Blood culture—S. aureus Abscess fluid—no growth

Successful Successful

L indicates left; R, right; S. aureus, Staphylococcus aureus.

with bilateral lower limb weakness; however, abscesses were later identified in the region. Magnetic resonance imaging (MRI) is the imaging modality of choice. It is able to distinguish abscess from swollen muscle and localize abscesses in the pelvic region. Still, ultrasound is the preferred screening modality because of its cost-effectiveness and availability. Computed tomography (CT) imaging can be used as well but it is less sensitive compared with MRI.5,7,15 Neutropenia delays abscess formation. Thus, irrespective of the modality chosen, imaging must be repeated once neutrophil counts improve. More than 1 abscess was identified in all cases; the lower limbs were most commonly affected (Table 2). Our patient developed 2 abscesses in the lower extremities (left thigh and left iliopsoas muscle). Superficial abscesses were found in the left upper arm. On average, it took 12.8 days (range, 10 to 15 d) from the onset of symptoms to the identification of an abscess (Table 1). In our case, this time period was considerably longer (27 d). However, as mentioned above, the early symptoms experienced by our patient were not at the site of the identified abscesses. This suggests that the weakness was not a manifestation of a physical myofibrillar displacement leading to the widespread weakness, but rather a more widespread contractile inhibition cotemporal with the presence of the bacteria in muscle. Aggressive and early systemic antimicrobial therapy, later imaging, neutropenia, or a delay in abscess formation may account for the longer time period seen in our case. S. aureus was implicated in all but one of the cases (Table 2). Our patient experienced S. aureus bacteremia with positive blood cultures; however, no organisms were identified from the abscess fluid and the cultures were negative. Treatment was successful in all cases and involved antibiotic therapy and abscess drainage (Table 2). Duration of antibiotic therapy should be tailored to individual patients but varies between 3 to 6 weeks.7,9,15,16 Repeated imaging can be used to monitor response to therapy. Early symptoms of PM can be mistaken for the side effects of chemotherapeutic agents. Specifically, vincristine is known to cause a dose-dependent neuropathy.17,18 Copyright

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Although primarily sensory in nature, motor and autonomic neuropathies have also been indicated. Sensory symptoms include pain, numbness, tingling of the hands and feet, and loss of deep tendon reflexes. Motor symptoms are rare but include weakness in the distal muscles and cramps.17,18 In our case, the proximal distribution of muscle weakness, normal nerve conduction studies, normal sensory examination, and history of S. aureus bacteremia, led to a high index of suspicion for PM as opposed to a drug-induced neuropathy. Left untreated, PM leads to septic shock, multiorgan failure, and death. Greater awareness of the clinical picture of PM (early and widespread proximal weakness often with antecedent pain, normal nerve conduction studies, and normal or minimally elevated CK) will aid in early diagnosis and treatment, greatly reducing morbidity and mortality. REFERENCES 1. Scriba J. A contribution, Etiology of acute myositis. [in German]. Deutsche Zeit Chir. 1885;22:497–502. 2. Corden TE, Morgan ER. Pyomyositis during induction chemotherapy for acute lymphocytic leukemia. J Pediatr Hematol Oncol. 1996;18:323–326. 3. Chiedozi LC. Pyomyositis. Review of 205 cases in 112 patients. Am J Surg. 1979;137:255–259. 4. Taksande A, Vilhekar K, Gupta S. Primary pyomyositis in a child. Int J Infect Dis. 2009;13:e149e51. 5. Agarwal V, Chauhan S, Gupta RK. Pyomyositis. Neuroimag Clin N Am. 2011;21:975–983. 6. Falagas ME, Rafailidis PI, Kapaskelis A, et al. Pyomyositis associated with hematological malignancy: case report and review of the literature. Int J Infect Dis. 2008;12:120–125. 7. Bickels J, Ben–Sira L, Kessler A, et al. Primary pyomyositis. J Bone Joint Surg Am. 2002;84-A:2277–2286. 8. Chang YH, Huang LM, Hsueh PR, et al. Acremonium pyomyositis in a pediatric patient with acute leukemia. Pediatr Blood Cancer. 2005;44:521–524. 9. Kao KL, Hung GY, Hwang B. Pyomyositis during induction chemotherapy for acute lymphoblastic leukemia. J Chin Med Assoc. 2006;69:184–188. 10. Blatt J, Reaman G, Pizzo PA. Pyomyositis in acute lymphocytic leukemia heralded by cutaneous vasculitis: brief communication. Med Pediatr Oncol. 1979;7:237–239.

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11. Yu CW, Hsiao JK, Hsu CY, et al. Bacterial pyomyositis: MRI and clinical correlation. Magn Reson Imaging. 2004; 22:1233–1241. 12. Karmazyn B, Kleiman MB, Buckwalter K, et al. Acute pyomyositis of the pelvis: the spectrum of clinical presentations and MR findings. Pediatr Radiol. 2006;36:338–343. 13. Silverman L, Stevenson K, O’Brien J, et al. Long-term results of Dana-Farber Cancer Institute ALL consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). Leukemia. 2010;24:320–334.

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14. Salomonsson S, Lundberg IE. Cytokines in idiopathic inflammatory myopathies. Autoimmunity. 2006;39:177–190. 15. Christin L, Sarosi GA. Pyomyositis in North America: case reports and review. Clin Infect Dis. 1992;15:668–677. 16. Crum NF. Bacterial pyomyositis in the United States. Am J Med. 2004;117:420–428. 17. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249:9–17. 18. Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol. 1986;1:421–427.

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2014 Wolters Kluwer Health, Inc. All rights reserved.

Pyomyositis Causing Temporary Quadriparesis During Induction Therapy for Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.

Pyomyositis (PM) is a purulent infection of skeletal muscle. It is often associated with immunosuppression in temperate climates. Herein, we report a ...
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