Vertebral alveolar echinococcosis—a case report, systematic analysis, and review of the literature

Vertebral alveolar echinococcosis—a case report, systematic analysis, and review of the literature

Grand Round Vertebral alveolar echinococcosis—a case report, systematic analysis, and review of the literature Thomas Raphael Meinel, Bruno Gottstein...

2MB Sizes 0 Downloads 49 Views

Grand Round

Vertebral alveolar echinococcosis—a case report, systematic analysis, and review of the literature Thomas Raphael Meinel, Bruno Gottstein, Vanessa Geib, Marius Johann Keel, Ruggero Biral, Markus Mohaupt, Jan Brügger

Alveolar echinococcosis caused by Echinococcus multilocularis is an infrequent zoonosis with a high degree of disability, morbidity, and mortality, especially in disease clusters of the northern hemisphere. The diagnosis is complicated by extended incubation time, diverse clinical manifestations, and mimicking of differential diagnoses. The primary organ affected is the liver, but extrahepatic disease is possible, with vertebral involvement in only a few dozen cases described worldwide. Although vertebral alveolar echinococcosis seems to be rare, it might be under diagnosed, and it might be seen more often as the number of people with immunocompromised conditions increases. Recognition of this syndrome is crucial, because advances in medical and surgical management strategies since the introduction of benzimidazole in 1976 have controlled and relieved symptoms in most cases. In this Grand Round, we present the case of a 75-year-old woman who was referred for biopsy of a lumbar lesion 3 months after she was diagnosed with chronic myeloid leukaemia. The diagnosis of hepatic alveolar echinococcosis with metastasis to the lumbar spine and paravertebral region as well as the brain was confirmed by biopsy, PCR, and serology. The patient was given albendazole and referred for palliative surgery with the aim of pain control. Clinical features of the case are presented and discussed in the context of the literature. This case and review illustrate the complexity of extrahepatic alveolar echinococcosis manifestations and the necessity of an interdisciplinary approach.

Introduction Epidemiology

Echinococcus granulosus and Echinococcus multilocularis cause two distinct diseases: cystic echinococcosis upon infection with E granulosus during the larval (or metacestode) stage, and alveolar echinococcosis upon infection with E multilocularis, also during the larval stage.1 The term hydatid disease was historically used for both alveolar echinococcosis and cystic echinococcosis, but should no longer be used for alveolar echinococcosis.1,2 Alveolar echinococcosis is a potentially lethal zoonosis withanincreasingincidenceof0·03–8·1/100 000inhabitants per year depending on the risk of exposure and endemic area.3 Endemic areas are limited to the northern hemisphere, and high-risk clusters in Europe include Switzerland, eastern and central France, southern Germany, and western Austria.4 Trends over the past 20 years include increasing manifestations in China, Canada, and central Europe, and expansions from rural to urban areas.3,5 The mean age of diagnosis is 50–60 years, and women seem to be affected slightly less often than men.6 Risk factors for infection include vocational gardening, forestry, hunting, or simply living in a disease cluster or rural setting.7,8 The primary host is the red fox (Vulpes vulpes), with parasite prevalence rates reaching 50% or even more in close proximity to urban areas, but other definitive hosts such as domestic dogs might have a substantial role in the transmission to human beings.6,9 Up until the introduction of benzimidazole in 1976, prognosis was bad, with an average 10-year survival rate of 29% in untreated patients.10 However, enhanced surgical and medical therapies and an increased knowledge of the disease have substantially improved survival since the 1980s, so that 10-year survival rates are www.thelancet.com/infection Vol 18 March 2018

now about 90–94% in newly diagnosed alveolar echinococcosis cases.11

Pathophysiology After an incubation period of approximately 5–15 years, the primary organ affected is the liver, as is evident in more than 95% of alveolar echinococcosis cases.6,10 Extrahepatic involvement is rare and usually occurs by continuous growth originating from a hepatic lesion or through haematogenous spread, metastasising from the liver to the lungs, spleen, CNS, bones, lymph nodes, or muscle, in order of frequency.6,8,12 Data show that primary extrahepatic disease is probably very rare, and is seen in fewer than 4% of cases, but it might be under diagnosed and remains poorly understood.8 Distant metastases can occur via lymphatic or various haematogenous pathways—eg, retrogradely through the portal vein, passing or bypassing the liver via anastomoses (maybe particularly in the case of portal hypertension) without affecting it, or as a result of undiscoverable hepatic disease.12 Osseous manifestation is thought to be prevalent in 0·02–1·00% of alveolar echinococcosis cases, although specific and recent data are scarce.8,12 With respect to malignant growth patterns, a PNM staging system—incorporating liver involvement of the parasite lesion (P), neighbouring organ invasion (N), or remote metastases (M)—has been developed and validated, although some authors did not find a correlation with survival rates.11,13–15 Building on this overview, we present a case of extrahepatic active alveolar echinococcosis affecting the lumbar vertebrae, with further lesions of the liver and brain. We include an exhaustive review of all vertebral cases of alveolar echinococcosis published and discuss the aetiology and the state of the art in diagnosis and therapy. Written informed consent was obtained from

Lancet Infect Dis 2018; 18: e87–98 Published Online August 11, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30335-3 Department of Internal Medicine, Sonnenhofspital, Bern, Switzerland (T R Meinel MD, V Geib MD, Prof M Mohaupt MD, Jan Brügger MD); Institute of Parasitology, University of Bern, Bern, Switzerland (Prof B Gottstein PhD); Department of Orthopedic Surgery, Bern University Hospital, Inselspital, Bern, Switzerland (Prof M J Keel MD); Trauma Center Hirslanden, Clinic Hirslanden, Zurich, Switzerland (Prof M J Keel MD); and Institute of Pathology Länggasse, Bern, Switzerland (R Biral MD) Correspondence to: Dr Jan Brügger, Klinik für Innere Medizin, Sonnenhofspital, Buchserstrasse 30, 3007 Bern, Switzerland [email protected] lindenhofgruppe.ch

e87

Grand Round

A

B

D

E

C

F

Figure 1: Characteristics of the lumbar lesion: spine MRI and CT scan (A) Non-enhanced and (B) contrast-enhanced axial images show a multilobulated osteolytic cystic mass in the lumbar and paravertebral region, originating from the L3 and L4 vertebrae. In addition to the cystic components, with fluid-like intensity, thickened septa can be seen with mild contrast enhancement (arrows). (C) Contrast-enhanced coronal CT scan showing the multicystic lesion without calcifications of the paravertebral mass. The sagittal MRI image (D) shows the extent of the mass and spinal cord compression. (E) In diffusion-weighted imaging the lesion appears as hyperintense. (F) Coronal CT showing osteolytic changes in L3 and L4.

Figure 2: Microscopic pathological examination of the vertebral lesion caused by alveolar echinococcosis Periodic acid-Schiff-positive lamellar structures and granulomatous inflammation caused by Echinococcus multilocularis.

the patient for publication of this Grand Round and the corresponding images.

Case description In February, 2016, a 75-year-old woman presented with progressive back pain and substantial weight loss. Laboratory examinations showed leucocytosis and parapro­ teinaemia (IgG λ). When a CT scan showed osteolytic lesions in the lumbar vertebrae L3 and L4 (figure 1), multiple myeloma was suspected, and a bone marrow biopsy was done in June, 2016. Surprisingly, the biopsy e88

resulted in a diagnosis of BCR-ABL-positive chronic myeloid leukaemia, and the patient started treatment with nilotinib (150 mg twice daily, orally), which she tolerated well. She achieved a complete haematological response, but with persistently high amounts of BCR-ABL transcription. Due to the patient’s immobilising back pain despite high doses of analgesics (fentanyl 100 µg/h transdermally and metamizole 1 g every 6 h), a lumbar MRI was done. It showed a diffuse, infiltrative, vertebral and paravertebral, multicystic, slightly ring-enhancing mass protruding intraspinally and compressing the spinal cord at L1–L4 (figure 1). The suspected radiological diagnosis in the context of chronic myeloid leukaemia was extramedullary haemopoiesis. Hence, the patient was referred to our hospital for a diagnostic transpedicular biopsy of this lesion in September, 2016. The patient had a clinically reduced nutritional state, but otherwise her presentation was unremarkable, with no signs of spinal cord compression or other neurological symptoms. Intraoperatively, 40 mL of pus-like fluid was aspirated and sent for pathological and micro­ biological tests. Periodic acid-Schiff (PAS)-positive lamellar structures and granulomatous inflammation were identified microscopically, suggesting a diagnosis www.thelancet.com/infection Vol 18 March 2018

Grand Round

of parasitic disease, specifically echinococcosis (figure 2). PCR confirmed the diagnosis of alveolar echinococcosis in biopsy tissue. Serology was positive for E granulosus (64 AU/mL), but also for specific epitopes of E multilocularis (17 AU/mL against Em2 and 28 AU/mL against Em18). Laboratory results showed a slightly elevated C-reactive protein (CRP) concentration (8 mg/L), erythrocyte sedimentation rate (ESR; 36 mm/h), and γ-glutamyl­ transferase concentration (104 U/L). The complete blood count was normal, with no eosinophilia present (0·1%), and concentrations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase were normal, as well as the international normalised ratio. In a search for additional involved organs, a head-topelvic body CT scan was done. This revealed several small hypodense lesions in the liver (one of them calcified) and calcified structures in the left basal ganglia (figure 3). The best staging modality would have been PET imaging but this was steadfastly declined by the patient. Liver sonography showed several lesions, resembling small pseudocystic structures as described in the Echinococcosis multilocularis Ulm ultrasound classification.16 We did a test for tuberculosis (QuantiFERON, QIAGEN, Germantown, MD, USA) and serology for HIV (fourth generation enzyme-linked immunosorbent assay for antibodies [IgG and IgM] and p24 antigen) and syphilis (Treponema pallidum particle agglutination assay) to check for immune deficiency or an alternate diagnosis, but the results were negative. IgD concentrations were below normal. Gram-stained and auramine-stained biopsy specimens showed no bacilli on light microscopy, and cultures for aerobic, anaerobic, and mycobacterial pathogens showed no growth. Therefore, the diagnosis of stage IV active vertebral alveolar echinococcosis, as well as hepatic and inactive cerebral alveolar echinococcosis, was made with PNM-classification P1N0M1. The patient was started on albendazole (400 mg twice daily, orally) 2 weeks after the diagnostic biopsy. As a result of debilitating pain despite 2 months of albendazole treatment, the patient was offered palliative surgery for pain control and referred to a tertiary care centre (Bern University Hospital, Inselspital, Bern, Switzerland) for surgical management. First, a dorsal approach was chosen for cementaugmented stabilisation from the tenth thoracic vertebra (Th10) down to the ilium (figure 4). Second, a bilateral retroperitoneal pararectus approach allowed enough space to carefully dissect the lesion from the surrounding tissue including the cava vein and the aorta. Avoiding spillage was not entirely possible, and purulent fluid was observed intraoperatively when cyst rupture occurred. Due to adhesions, a minor aortic injury resulted, and 10·5 L of blood had to be transfused during the surgery. Finally, en-bloc resection of the L3 and L4 vertebral bodies www.thelancet.com/infection Vol 18 March 2018

A

B

Figure 3: Results of the head CT scan and liver sonography (A) Axial non-contrast-enhanced CT showing calcifications in the left basal ganglia. (B) Liver sonography showing an exemplary 8 mm lesion (arrow) with a hyperechoic, irregular rim that is non-vascularised and a hypoechoic central zone. The red and blue structures are hepatic vessels.

A

C

B

D

Figure 4: Surgical management of the vertebral lesion caused by alveolar echinococcosis (A) Dorsal view with instrumentation in place. (B) The resected lesion seen from a caudal perspective with the vertebral body and (C) the rest of the intervertebral disc and small daughter cysts (arrows). (D) The implanted tantalum cage (right image) with postoperative lateral x-ray control (left image).

with the surrounding lesion was possible and a large tantalum cage was placed. At a follow-up appointment 7 months after the surgery, the patient showed dramatic improvement, was almost pain free and now able to walk with a walker. Imaging showed correct placement of the posterior and anterior implants. Neurologically, the quadriceps had bilateral paresis (grade 2–3 on the UK Medical Research Council muscle scale); therefore, the patient continued treatment within a neurorehabilitation programme. e89

Grand Round

Review and discussion

Differential diagnosis

Classic hepatic alveolar echinococcosis and cystic echinococcosis are well characterised diseases, and diagnostic investigation, treatment, and follow-up are well established.17 However, because of its rare occurrence, lingering course, and diverse symptoms, extrahepatic alveolar echinococcosis is difficult to diagnose, and often a relevant diagnostic delay occurs, or patients might even receive treatment on the basis of a false diagnosis.8 For vertebral cystic echinococcosis, a comprehensive systematic, two-part review has been published,18,19 but whether the facts and implications are equally applicable to alveolar echinococcosis is unclear. Here, we present data from all vertebral cases of alveolar echinococcosis that we found in the literature. We have combined the characteristics of the patients in the following paragraphs, and detailed data is available in the table.8,12,15,20–37

For vertebral alveolar echinococcosis presenting as an osteolytic and paravertebral mass, the differential diagnoses include Pott’s disease (vertebral tuberculosis), bacterial or fungal abscesses, malignant or benign tumours or haematomas, and cystic echinococcosis. In our patient, the suspected radiological diagnosis of extramedullary haemopoiesis was made without considering alveolar echinococcosis as a differential diagnosis, even though the region where the patient lived is in a high-incidence cluster. Alveolar echinococcosis was probably not considered because the patient had been diagnosed with chronic myeloid leukaemia only a short time before, and alveolar echinococcosis had never been described in a patient with chronic myeloid leukaemia. Several patients in our cohort had been treated for a long time under a false diagnosis. One case32 is particularly interesting, because histological and serological evidence indicated that the patient had an inactive cyst from a former infection with cystic echinococcosis, but in fact the patient had had a relapse because the true diagnosis was alveolar echinococcosis.

History Bone infestation was first described by Bidloo in 1708.38 In 1807, Chaussier39 described the first case of vertebral infection and Reydellet40 is thought to have done the first surgery for spinal echinococcosis in 1819. Del Campo41 seems to have been the first to undertake curative surgery for vertebral hydatid disease. Since serological and molecular diagnostic tools have only become available in the past few decades and histological analysis is not always able to differentiate between alveolar echinococcosis and cystic echinococcosis, most case reports before 1960 do not specify the exact pathogen and are hence not included in this Grand Round.42

Symptoms Pain, as observed in our patient, is the most frequent symptom of vertebral alveolar echinococcosis (23 of 29 patients identified in our literature review) and is often associated with neurological deficits caused by medullary or root compression (14 of 29 patients). Nonspecific symptoms such as weight loss were also present in our patient and occurred in six of 29 patients in our cohort. Enlarged lymph nodes, abdominal or epigastric pain, or systemic inflammatory response might also be present.8,21,24,32

Risk factors Our patient was living in a rural area and had contact with dogs in the neighbourhood, but she had never kept a dog herself, and she did not pursue any outdoor activities. In this cohort, the most common risk factor was farming or simply living in a rural setting (eight of 29 patients). Alcohol abuse (three of 29 patients) and previous splenectomy (one of 29 patients) are mentioned in the table because of the suggestive pathophysiology, although they are not considered established risk factors. Unlike in the case of hepatic disease, women were affected more often than men (16 vs ten), and the mean age at diagnosis was 54 years (SD 14·7). e90

Location In vertebral cystic echinococcosis the location is predominantly lumbosacral.18 In the presented cohort of alveolar echinococcosis cases, the lower (Th7–12) thoracic spine (17 of 29 patients), paravertebral and retroperitoneal space (nine of 29), and upper lumbar spine (L1–3; seven of 29) were the most affected regions. The lower lumbar spine (L4–S1; three of 29) and upper (Th1–6) thoracic spine (three of 29) were involved less often. Usually one lesion is found, but multiple lesions are possible.20,24 Although some authors describe continuous growth from the hepatic lesion, some of the cases— including our case—more likely reflect a haematogenous spread.28 Rich vascularisation and slow blood flow might be reasons for the predisposition of the metaphysis of the vertebral body to be affected.43 One case was probably due to intradural drop metastases, but we included it in the cohort nonetheless.20 Braithwaite and Lees44 established five types of spinal manifestations of echinococcosis that can lead to neuro­ logical problems: (1) a primary intramedullary cyst, (2) an intradural extramedullary cyst, (3) an extradural intraspinal cyst, (4) echinococcosis of the vertebra, and (5) paravertebral echinococcosis. Nurick45 established a grading system evaluating a patient’s ability to walk and work based on spinal compression of any cause.

Immunosuppression Alveolar echinococcosis was shown to occur more frequently and be diagnosed at earlier stages in patients with an immunocompromised condition than in those who were not immunocompromised, followed by an aggressive disease course in some immunocompromised patients.46–48 Notably, serology might give a false negative result and the benefit of treatment seems to be increased www.thelancet.com/infection Vol 18 March 2018

F

Nourrisson et al (2014)21

www.thelancet.com/infection Vol 18 March 2018

54

Patient 2

F

M

39

Honma et al (1982)25

Kadioglu et 36 al (2005)26

Keutgens et al (2013)27

75

M

59

Patient 2

F

48

M

F

M

Patient 1

Georges et al (2004)24

73

Patient 1

Severe lower back pain

Albendazole

L3–L5, paravertebral soft tissues

Albendazole

Mebendazole for 1 year

Th7–Th10, Th12–L1 ··

Th10–Th11

Benzimidazoles only in the later phase

Flubendazole

Th7

Multiple thoracolumbar sites, retroperitoneal

Flubendazole

Albendazole 600 mg/day

Th8 with paraspinal abscess

Th9–Th11 Back pain, paraparesis, sphincter dysfunction

History of previous liver surgery, malaise, gait disturbance, mental disorder, cachexia

Back pain

Abdominal pain

Rapidly progressive spinal compression, paraparesis

Mixed spastic and flaccid paraplegia

Medical therapy

Multiple intracranial Albendazole and intraspinal lesions

Location

Subcostal pain (right L5 posterior side)

Headache, paraparesis, confusion

History and symptoms

Claudon et al (1987)22 and Weber et al (1988)23

82

F

Atalan et al 67 (2016)20

Sex Age at vertebral manifest­ ation (years)

Biopsy

Spinal decompression

Laminectomy of Th12–L1

Decompression, osteosynthesis

Surgical excision and drainage

Laminectomy

Decompressive laminectomy

None

None

Surgery

No

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

+ve serology; +ve PCR; +ve pathology

+ve pathology

+ve pathology

+ve PCR; +ve pathology

+ve serology; +ve pathology

+ve serology; +ve pathology

+ve serology; +ve pathology

+ve serology

+ve serology

Positive (+ve) Liver involve­ serology, PCR, and pathology ment?

Outcome

Died a few days after the diagnosis was established Numerous nodules in the lungs; false diagnosis of tuberculosis; hyper-γ-globulinemia; activity in PET-CT Alcoholic liver cirrhosis, type 2 diabetes

(Table continues on next page)

No immediate improvement after surgery

Died 5 months after surgery

Progressed slowly, with aggravation of the vertebral lysis despite albendazole

Died 17 years after initial symptoms from encephalopathy

Relapsed after 2 years, had a second laminectomy; 7 years after diagnosis the patient was able to walk despite paraparesis

Paraplegia worsened 5 months after surgery; patient died 13 months after diagnosis (unrelated)

After 6·5 years, pain had disappeared, serology was negative, PET showed activity at L5, but no other lesions, albendazole was stopped in 2014, 4 years after initiating treatment

Drainage of paravertebral cysts

Continuous spread from the liver, echinococcal meningoencephalitis

··

Skin fistulisation, false diagnosis of Pott’s disease

Appearance of neoplastic epiduritis operatively

Putrid liquid operatively

ESR 40 mm/h

Drop metastasis rather than Died shortly after diagnosis local invasion (ARDS, hypernatraemia)

Particular features

··

Rural area

Rural area

Rural area

Farmer

Farmer

Farmer, splenectomy

Shepherd

Risk factors

Grand Round

e91

e92

44

41

29

Patient 2

Patient 3

Patient 4

32

55

Savas et al (1999)31

Scheuring et al (2003)32

··

··

Patient 2

Patient 3

··

Patient 1

F

M

··

··

··

F

Reuter et al 51 (2000)12

Jain et al (2016)30

M

F

M

M

F

80

Nell et al (2011)29

70

Patient 1

Merkle et al (1997)28

(Continued from previous page)

Sex Age at vertebral manifest­ ation (years)

L1–L3

L4–S1

L2, psoas muscle (bilaterally)

Th12, L1, psoas muscle (right side)

L2, psoas muscle (left side)

Location

Albendazole 400 mg twice daily

··

··

··

··

Medical therapy

Chills, fever, weight loss, abdominal pain

Progressive paraparesis

Back pain, spastic paraplegia, Nurick grade 5

Back pain, spastic paraplegia, Nurick grade 5

Back pain, spastic paraplegia, Nurick grade 5

Already preop albendazole 7·5 mg/kg twice daily in cycles

Th6

Th11–Th12 and retroperitoneal space

Yes

Removal of mass No and partial rib, laminectomy

··

+ve serology; +ve PCR

+ve serology; +ve pathology

+ve serology; +ve pathology

+ve serology; +ve pathology

··

Laminectomy, instrumentation Th8–Th12 Laminectomy, instrumentation Th4–Th9

+ve serology; +ve pathology

+ve serology; +ve pathology

··

No

Laminectomy, instrumentation Th10-L2

None

+ve pathology +ve serology; +ve PCR; +ve pathology

Yes No

+ve pathology

+ve pathology

+ve pathology

··

Yes

Yes

Yes

Positive (+ve) Liver involve­ serology, PCR, and pathology ment?

Resection of the lesion and L1–L3 vertebrae

··

··

··

Surgery

None Albendazole 400 mg twice daily, trial of mebendazole, then albendazole again

Mebendazole

Already preop albendazole 7·5 mg/kg twice daily in cycles

Th10

Th7, extension to spinal canal

Already preop albendazole 7·5 mg/kg twice daily in cycles

Th12–L1

Mebendazole Sensorimotor spastic Th8–Th10, 4 g per day paraparesis, ataxia paraspinal and paravertebral lesion long-term

Abdominal pain, constitutional symptoms, positive psoas sign

Lumbar back pain

Lumbar back pain

Thoraco-lumbar back pain

Lumbar back pain

History and symptoms

Rural area

··

··

··

ESR 78 mm/h; false diagnosis of inactive cystic echinococcosis after history of previous livery surgery; progression of disease after interruption of albendazole

··

··

Armpit lesion, early wound infection after surgery

··

Alcoholic ·· liver cirrhosis

·· False diagnosis of bacterial abscess vertebrectomy L1–L3, filling with bone cement

··

··

··

··

Outcome

(Table continues on next page)

Still alive, pain controlled with ibuprofen 600 mg twice daily, stability of vertebral lesion infiltration 15 years after albendazole was started

Leg strength returned to normal after surgery with no further paraparesis

Patient improved to Nurick grade 3

Patient improved to Nurick grade 0

Improved to Nurick grade 4; disease recurred at >18 months and patient died

Asymptomatic for 18 months

Great improvement regarding mobilisation; inflammatory parameters declined

··

Spondylitis intraoperatively, ·· calcifications, rimenhancement

··

··

Particular features

··

··

··

··

Risk factors

Grand Round

www.thelancet.com/infection Vol 18 March 2018

www.thelancet.com/infection Vol 18 March 2018

56

37

53

Kunze et al (1992)35

Iaroslavskii et al (1956)36

Faucher et al (2017)37

M

M

F

F

F

F

F

F

F

Vertebrae and paravertebral muscles

Th11–Th12

Location

Albendazole Abdominal adenopathy then vertebrae and renal area

Flubendazole, later albendazole

Albendazole, nitazoxanide

Mebendazole for 1 year

Medical therapy

Th7–Th8 with lytic appearance and compression fracture

C4–Th8

Back pain, paraplegia Th4

Subscapular pain, ascending spastic paraparesis

6 years of abdominal Th10–Th11 pain

Back pain, general malaise, kyphosis, spastic paraparesis

Albendazole

None

Mebendazole

Flubendazole

Albendazole Back pain for 7 years, Th12–L2, colio­ mesenteric nodular 400 mg twice cachexia, morning mass, adrenal gland daily stiffness (right side)

Epigastric pain, enlarged lymph nodes, dorsalgia

Back pain, Vertebrae radiculalgia, paralysis

Back pain

Back pain

History and symptoms

Resection of the lesion and Th4 vertebra

None

··

Laminectomy

··

Incomplete surgery

Five incomplete resections

Incomplete resections

Laminectomy

Surgery

No

No

Yes

No

Yes

··

··

··

Yes

Table: Detailed characteristics of all published cases of vertebral alveolar echinococcosis

+ve serology; +ve pathology

+ve pathology

+ve serology; +ve pathology

+ve serology; +ve pathology

+ve serology; +ve pathology

··

··

··

+ve pathology

Positive (+ve) Liver involve­ serology, PCR, and pathology ment?

ARDS=acute respiratory distress syndrome. L=lumbar. ESR=erythrocyte sedimentation rate. Th=thoracic. CRP=C-reactive protein. C=cervical.

54

Gaucher et al (1983)34

64

Patient 3

63

56

Patient 2

Toussaint et al (2001)15

49

Patient 1

Piarroux et al (2011)8

Sengul et al 36 (2008)33

(Continued from previous page)

Sex Age at vertebral manifest­ ation (years)

Alcoholic hepatic cirrhosis

··

··

··

··

··

··

··

··

Risk factors

Alive 10 years after diagnosis

Died 8 years after diagnosis was established

Alive 7 years after diagnosis

Neurological status improved after the operation; at 2 years the patient had not relapsed

Outcome

Died after 5·5 months

Slowly recovered and was able to walk after 2 years and work again after 4 years; no activity (radiology, serology) 2 years after albendazole was stopped, good outcome 7 years after diagnosis False diagnosis of osteomyelitis, albendazole 80 mg twice daily sufficient; albendazole stopped 5 years after initial treatment because PET and MRI showed no recurrence

Substantial improvement after mebendazole

Two relapses in the first year despite flubendazole

Elevated protein in cerebral spinal fluid

ESR 78 mm/h, aortic infiltration

Aspect of neoplastic epiduritis; eosinophilia

ESR 72 mm/h, CRP 22 mg/L, At 4 months the patients had gained weight and was pain free; false diagnosis of ESR and CRP declined and tuberculosis radiological lesions were stable

False diagnosis of tuberculosis

False diagnosis of cystic echinococcosis

··

Rural area

Particular features

Grand Round

i n

e93

Grand Round

patients with an immunocompromised condition.8,9,47,49 Whether the controlled chronic myeloid leukaemia should be considered as an immunocompromised condition in our patient is debatable. However, we also found that our patient has IgD concentrations below normal, and paraproteinaemia was detected, which could be linked to specific antibodies of E multilocularis. We ruled out other causes of immunodeficiency, although doing so is not obligatory in newly diagnosed patients with alveolar echinococcosis.50 The prevalence of immunocompromised conditions is increasing because of the expanded use of novel and mostly biological therapeutics, especially in rheumatology and oncology, and the proportion of patients with immunocompromised conditions in developed countries is estimated to be as high as 3% of the population.51,52 In our patient, the immunosuppression associated with the newly diagnosed chronic myeloid leukaemia might have contributed to increased metacestode tissue expansion and hence associated symptoms. We speculate that an immunocompromised condition will increase the incidence of symptomatic alveolar echinococcosis, because seroprevalence is much greater than the prevalence of the manifested disease.53–56

Imaging Sonography offers useful tools for screening and— combined with a contrast medium—assessment of vitality at follow-up of hepatic alveolar echinococcosis, but might not be helpful in extrahepatic disease.16,57 Active hepatic lesions in alveolar echinococcosis show multiple irregular, ill-defined lesions that are hypoattenuating on CT scans and hyperintense on T2-weighted MRI.13,58,59 Extrahepatic lesions have a multicystic, honeycomb appearance, with septations and sometimes clustered microcalcifications or plaque-like calcifications.59,60 Rim enhancement can be present (figure 1). The finding of vertebral infiltration with appearance as a paravertebral abscess should suggest echinococcosis, especially when calcifications are found.43 Differentiation between alveolar echinococcosis and cystic echinococcosis does not seem to be possible even with advanced imaging techniques for extrahepatic lesions, except in the case of cerebral manifestations.28 The hyperintensity in diffusion-weighted imaging as described in our patient has been analysed in hepatic lesions.61 PET-CT and PET-MRI offer tools to distinguish inactive from active lesions,62,63 but these were refused by our patient. Although not confirmed, we interpret the cerebral calcifications in our patient to most likely be spontaneous inactive alveolar echinococcosis lesions, as proposed by others.28 Further imaging would have been necessary to determine the activity of the hepatic lesions. Recommendations for follow-up of patients with extrahepatic alveolar echinococcosis undergoing medical treatment are scarce, and decisions should be made on an individual basis considering the location and local e94

threat of the lesion. However, monitoring should include liver sonography at individual intervals and PET-MRI or PET-CT every 2–3 years.

Pathology Differentiation between alveolar echinococcosis and cystic echinococcosis using biopsy specimens is sometimes possible when assessed by experienced diagnosticians, but it is especially difficult in the case of a bone biopsy. PAS-positive, narrow, bizarre lamellar structures of thin diameters, with diffuse expansion, extensive necrosis, and sparse lymphocytic inflammation seem to be suggestive of alveolar echinococcosis. In cystic echinococcosis, the PAS-positive structures are broader, a well defined capsule and massive granulomatous inflammation are present, and hydatid sand can be seen, but usually necrosis is not present.42 In our patient, the pathologist was not able to specify the pathogen by microscopy alone, but was certain about the diagnosis of echinococcosis. In our cohort, pathology was able to confirm the diagnosis of alveolar echinococcosis in 23 of 29 patients.

PCR and serology For a long time, serology has been the mainstay of non-invasive diagnosis in alveolar echinococcosis, and Em2-ELISA has yielded sensitivity of up to 97% and specificity—differentiating alveolar echinococcosis from cystic echinococcosis—of up to 74% or higher.50,64 Whether the same rates apply to extrahepatic alveolar echinococcosis is unclear. Furthermore, in immuno­ compromised patients, in whom serology is more often negative and occurs in unusual presentations, diagnosis by PCR—preferably on native biopsy material or nonstained sections of paraffin-embedded formalin-fixed specimens—is reliably feasible and especially helpful.24,47,65 The problem of biopsy-related disease dissemination does not seem to be a contraindication for biopsy in this cohort of patients, because those who underwent biopsy or incomplete resection did not have cutaneous or subcutaneous spread while receiving medical therapy during follow-up. However, prophylactic treatment with albendazole before biopsy is recommended, but albendazole was not administered to our patient because alveolar echinococcosis was not diagnosed until several days after the procedure. The additional use of Em18ELISA (formerly EmII/3-10-ELISA) provides the best information to assess and follow up the viability status of hepatic alveolar echinococcosis lesions.66 Overall, in our cohort 17 of the 29 cases were confirmed by serology and only four of 29 by PCR.

Laboratory No blood eosinophilia was present in our patient. Some authors suggest prevalence of blood eosinophilia in osseous echinococcosis of up to 70%.43 However, for patients with alveolar echinococcosis the real figure seems to be much lower, at about 15%. ESR and CRP can www.thelancet.com/infection Vol 18 March 2018

Grand Round

also be slightly altered, as in our patient. In this cohort, only one of the 29 case reports mentioned eosinophilia, and four of the 29 mentioned elevated ESR.

Liver Some authors have reported or suggested that hepatic manifestation always occurs in alveolar echinococcosis and the spread would always occur by continuous growth originating from a hepatic lesion.28 Subsequently, other researchers showed that hepatic involvement is not obligatory and that there are other mechanisms of extra-hepatic manifestation.12,24,25,28,29,31 Piarroux and colleagues8 found in their register that 60% of patients with remote metastasis had a proven liver infection—as did our patient—and 40% did not. Overall, regional spreading of the disease around the liver was almost twice as frequent as distant dissemination. In vertebral alveolar echinococcosis we found very similar numbers, with 15 of the 29 patients having proven hepatic infection and eight having explicit sparing of the liver. No general recommendations have been made regarding how and whether to check for liver involvement in patients with extrahepatic alveolar echinococcosis. However, given the high infection rate of about 95%, either sonography or CT seem to be indicated. In our patient, we chose to use head-to-pelvic CT, which has high sensitivity for all organs affected by alveolar echinococcosis, and sonography was used as a follow-up procedure. However, the calcified lesion in our patient’s liver was only visible in thin sections and was nearly missed in reconstructed images. This poor visibility of the calcified liver lesion in our patient adds to the theory of subclinical liver infection in so-called primary extrahepatic alveolar echinococcosis.

Medical therapy and monitoring Albendazole is the mainstay of drug therapy (as indicated in 14 of the 29 patients in our cohort) and is given at a dose of 10–15 mg/kg per day divided into two daily doses.17 Monitoring of haemopoiesis and liver enzymes is recommended at the beginning of treatment and pregnancy is a contraindication.50,67 We were concerned that our patient might have increased myelosuppression due to the underlying chronic myeloid leukaemia, but the controls showed that she had a normal complete blood count with slight postoperative anaemia. When albendazole is not well tolerated, mebendazole (six of the 29 patients) is a viable option at a daily dose of 40–50 mg/kg per day divided into three doses. Nitazoxanide (one of the 29 patients), amphotericin B, bortezomib, etanercept, and mefloquine have been tried, but failed in preclinical or clinical settings.68–73 Imatinib—another tyrosine kinase inhibitor—has been studied in vitro as a novel therapeutic option in alveolar echinococcosis.74 However, our patient received nilotinib for chronic myeloid leukaemia for 3 months without substantial benefit before albendazole treatment was started. www.thelancet.com/infection Vol 18 March 2018

In the case of incomplete resection of extrahepatic alveolar echinococcosis or incomplete palliative surgery of hepatic alveolar echinococcosis, long-term benzimidazole treatment is safe and should be given over several years, with follow-ups over a minimum of 10 years to rule out possible recurrence.14,32,50,75 Reliable criteria for parasite death in these patients are missing. Disappearance of anti-Em18 antibodies, with greater than 50% of the lesion calcified at initial diagnosis and a negative PET, has been described as a rationale to discontinue therapy for hepatic alveolar echinococcosis and has also been applied to extrahepatic alveolar echinococcosis cases.37,76 In case of a putative intolerance to albendazole or possible interactions, plasma level concentrations of albendazole should be checked, because these can reach subtherapeutic or toxic levels— eg, following concomitant medication with protease inhibitors, among others.48

Surgery Since the growth of the lesion is achieved by the local erosion of bone, the pressure on the blood vessels of the bone marrow can result in vascular necrosis, and therefore pus-like fluid is often observed in surgery.43,77 Different surgical techniques have been described, but not specific differences between cystic echinococcosis and alveolar echinococcosis.43,78 The best treatment is a radical resection with safety margins of 2 cm, which is almost never possible in patients with vertebral diseases. However, in vertebral alveolar echinococcosis the need for decompression to avoid paralysis sometimes needs to be weighed against the potential risks of the surgery. In most of the patients in our cohort, pure decompressive techniques were applied (17 of 29), and only one report mentioned vertebral body resection, as was done in our patient. After an exhaustive interdisciplinary discussion with the patient, the decision to undertake palliative surgery was made after considering the refractory, excruciating pain, non-existent quality of life, radiological risk of vertebral fracture, and absence of effect of albendazole on the pain. The result was mixed, leading to drastic improvements in pain, but also bilateral paresis. Puncture, aspiration, injection of hypertonic saline, and reaspiration has been proposed in patients with cystic echinococcosis but only for inoperable lesions or uncomplicated cystic echinococcosis.50,79 For alveolar echinococcosis, however, this technique cannot be recommended.

Outcome In some of the vertebral cases presented here, the disease was well controlled with medical therapy.12,14,15,21,29,43 Others reported the disease to be slowly progressive.22 A fatal outcome was associated with extensive and intradural disease.24,25,27,36 Overall, in this cohort, the mean reported follow-up was 5·7 years for controlled disease (nine of 29), and eight of the 29 patients died, with an average e95

Grand Round

Search strategy and selection criteria Data for this Grand Round were identified through a PubMed (MEDLINE), Ovid, Embase, and Google Scholar search of the literature published, without start date restrictions, up to April, 2017, incorporating articles going as far back as 1708, using the key words “echinococcosis” OR “hydatidosis” OR “multilocularis” OR “alveolar echinococcosis” AND “spinal” OR “vertebral”. Cross references were also included and authors contacted for additional information. We excluded all cases in which the pathogen was not clearly proven to be Echinococcus multilocularis by pathology, PCR, or serology. A few case collections were not included in the table because of incomplete data on the patients, but they were accounted for in the discussion.

survival of 43 months after diagnosis. In hepatic alveolar echinococcosis, indefinite medical treatment after incomplete surgery was associated with lower relapse rates than medical treatment for 2 years or less.14 PET-CT and serology are good tools for following up patients—at least for those with hepatic alveolar echinococcosis—and can potentially be used to determine when to stop longterm medical treatment, but only in immunocompetent individuals.37,66

Discussion We present a highly unique case of hepatic alveolar echinococcosis with distant metastasis to the spine and brain. To the best of our knowledge it is the first reported case of chronic myeloid leukaemia associated with alveolar echinococcosis. Other unique features include active extrahepatic disease and cerebral metastasis, and the existence of concomitant paraproteinaemia and IgD deficiency. Additionally, we reviewed the data from all available literature referring to cases of proven vertebral alveolar echinococcosis and discussed their unique features. With the number of patients with immunocompromised conditions increasing, hepatic and extra-hepatic alveolar echinococcosis will be encountered more often, and doctors should be aware of this condition. This holds especially true for areas where the number of cases of alveolar echinococcosis is increasing, such as in urban regions and new disease clusters like eastern Europe and China. Back pain and signs of spinal compression are the most frequent symptoms of vertebral alveolar echinococcosis, although non-specific findings such as weight loss might be present. The lower thoracic spine, lumbar spine, and paravertebral region are the predominant locations of vertebral alveolar echinococcosis. Hepatic involvement was only present in about half of the cases in our cohort, and the predisposition for vertebral infection remains poorly understood. The differential diagnosis should include other infectious diseases—especially e96

tuberculosis—and neoplasms. When the response to treatment of those diseases is inadequate, alveolar echinococcosis should be considered and ruled out using appropriate serological tests, PCR, or both. Other laboratory signs—such as eosinophilia, elevated ESR, or CRP—might be present but are unreliable and hence obsolete. A standard of care should be established for primary extrahepatic disease; we suggest head-to-pelvic CT scan. Medical therapy is crucial and well tolerated in long-term treatment. Nevertheless, new parasiticidal drugs are needed because therapy remains parasitostatic and requires that patients be immunocompetent. Complete resection of the lesion is the treatment of choice for easily accessible lesions, with preoperative, perioperative, and postoperative use of benzimidazoles. However, surgery in vertebral alveolar echinococcosis is associated with operative complications and the spread of disease, and palliative procedures should be reserved for situations in which the quality of life is otherwise not tolerable. A medical trial should be attempted first, because pain control can also be possible solely with medical therapy. Providing long-term medical treatment is very important in case of incomplete resection, as are long-term follow-ups. When reporting cases, the exact pathogen should be clearly specified, because cystic echinococcosis and alveolar echinococcosis are very distinct diseases. Despite substantial advances in diagnostic investigations, and medical and surgical treatment, vertebral alveolar echinococcosis remains a challenging disease associated with a high degree of morbidity, disability, and mortality. In endemic areas, alveolar echinococcosis and cystic echinococcosis should be considered in the investigation of any otherwise unexplained lesion with suggestive radiological features in any location. Interdisciplinary discussion is needed to provide tailored management for each patient. Contributors TRM, VG, and JB were the patient’s internal medicine physicians. TRM and JB wrote the initial draft, did the review of the literature, and edited the manuscript. BG, VG, and MM reviewed and edited the manuscript. MJK did the surgery, provided intraoperative images, and edited the manuscript. RB provided images of the biopsy samples, edited the manuscript, and was the consulting pathologist for the case. Declaration of interests We declare no competing interests. Acknowledgments Freelance editor Jeannie Wurz (Bern, Switzerland) proofread the manuscript. We kindly thank C Nourrisson, G Sengul, and J Rockstroh for sharing long-term follow-up data. References 1 Eckert J, Gemmell MA, Meslin FX, Pawlowski ZS. WHO/OIE manual on echinococcosis in humans and animals: a public health problem of global concern: Paris, France: World Organisation for Animal Health; 2001. http://apps.who.int/iris/bitstream/10665/424 27/1/929044522X.pdf (accessed Apr 3, 2017). 2 WHO. Fact sheet echinococcosis. 2017. http://www.who.int/ mediacentre/factsheets/fs377/en/ (accessed Apr 3, 2017). 3 Gottstein B, Stojkovic M, Vuitton DA, Millon L, Marcinkute A, Deplazes P. Threat of alveolar echinococcosis to public health—a challenge for Europe. Trends Parasitol 2015; 31: 407–12. www.thelancet.com/infection Vol 18 March 2018

Grand Round

4 Vuitton DA, Demonmerot F, Knapp J, et al. Clinical epidemiology of human AE in Europe. Vet Parasitol 2015; 213: 110–20. 5 Kern P. Clinical features and treatment of alveolar echinococcosis. Curr Opin Infect Dis 2010; 23: 505–12. 6 Kern P, Bardonnet K, Renner E, et al. European echinococcosis registry: human alveolar echinococcosis, Europe, 1982–2000. Emerg Infect Dis 2003; 9: 343–49. 7 Kern P, Ammon A, Kron M, et al. Risk factors for alveolar echinococcosis in humans. Emerg Infect Dis 2004; 10: 2088–93. 8 Piarroux M, Piarroux R, Giorgi R, et al. Clinical features and evolution of alveolar echinococcosis in France from 1982 to 2007: results of a survey in 387 patients. J Hepatol 2011; 55: 1025–33. 9 Oksanen A, Siles-Lucas M, Karamon J, et al. The geographical distribution and prevalence of Echinococcus multilocularis in animals in the European Union and adjacent countries: a systematic review and meta-analysis. Parasit Vectors 2016; 9: 519. 10 Ammann RW, Eckert J. Cestodes. Echinococcus. Gastroenterol Clin North Am 1996; 25: 655–89. 11 Torgerson PR, Schweiger A, Deplazes P, et al. Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years. J Hepatol 2008; 49: 72–77. 12 Reuter S, Seitz HM, Kern P, Junghanss T. Extrahepatic alveolar echinococcosis without liver involvement: a rare manifestation. Infection 2000; 28: 187–92. 13 Graeter T, Kratzer W, Oeztuerk S, et al. Proposal of a computed tomography classification for hepatic alveolar echinococcosis. World J Gastroenterol 2016; 22: 3621–31. 14 Krochmann NP. Alveoläre echinokokkose—validierung der WHO PNM-Klassifikation. PhD Thesis, University of Ulm, Ulm, Germany, 2012. 15 Toussaint F, Pere P, Le Chaffotec L, Grandhaye P, Pourel J, Chary-Valckenaere I. Alveolar echinococcosis of the spine. J Clin Rheumatol 2001; 7: 248–51. 16 Kratzer W, Gruener B, Kaltenbach TEM, et al. Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: Echinococcosis Multilocularis Ulm classification-ultrasound. World J Gastroenterol 2015; 21: 12392–402. 17 Kern P, Menezes da Silva A, Akhan O, et al. The echinococcoses: diagnosis, clinical management and burden of disease. Adv Parasitol 2017; 96: 259–369. 18 Neumayr A, Tamarozzi F, Goblirsch S, Blum J, Brunetti E. Spinal cystic echinococcosis–a systematic analysis and review of the literature: part 1. Epidemiology and anatomy. PLoS Negl Trop Dis 2013; 7: e2450. 19 Neumayr A, Tamarozzi F, Goblirsch S, Blum J, Brunetti E. Spinal cystic echinococcosis–a systematic analysis and review of the literature: part 2. Treatment, follow-up and outcome. PLoS Negl Trop Dis 2013; 7: e2458. 20 Atalan G, Sivrioglu AK, Sonmez G, Celik M, Simsek B. A case of alveolar echinococcosis presenting as cerebral and spinal intradural metastases. Eurasian J Med 2016; 48: 149–52. 21 Nourrisson C, Mathieu S, Beytout J, Cambon M, Poirier P. Osteolytic bone lesion: vertebral alveolar echinococcosis in a patient with splenectomy. Rev Med Interne 2014; 35: 399–402. 22 Claudon M, Bracard S, Plenat F, Regent D, Bernadac P, Picard L. Spinal involvement in alveolar echinococcosis: assessment of two cases. Radiology 1987; 162: 571–72. 23 Weber M, Vespignani H, Jacquier P, et al. Neurological manifestations of alveolar echinococcosis. Rev Neurol (Paris) 1988; 144: 104–12 (in French). 24 Georges S, Villard O, Filisetti D, et al. Usefulness of PCR analysis for diagnosis of alveolar echinococcosis with unusual localizations: two case studies. J Clin Microbiol 2004; 42: 5954–56. 25 Honma K, Basano N, Andoh N, Iwai K. Hepatic alveolar echinococcosis invading pancreas, vertebrae, and spinal cord. Hum Pathol 1982; 13: 944–46. 26 Kadioglu HH, Malcok UA, Senguli G, Aydin IH. Alveolar hydatid disease of the spine causing paraplegia. Neurosciences (Riyadh) 2005; 10: 180–82. 27 Keutgens A, Simoni P, Detrembleur N, et al. Fatal alveolar echinococcosis of the lumbar spine. J Clin Microbiol 2013; 51: 688–91.

www.thelancet.com/infection Vol 18 March 2018

28 Merkle EM, Kramme E, Vogel J, et al. Bone and soft tissue manifestations of alveolar echinococcosis. Skeletal Radiol 1997; 26: 289–92. 29 Nell M, Burgkart RH, Gradl G, et al. Primary extrahepatic alveolar echinococcosis of the lumbar spine and the psoas muscle. Ann Clin Microbiol Antimicrob 2011; 10: 13. 30 Jain S, Jaiswal M, Gandhi A, Mittal RS. Primary spinal alveolar hydatid disease: a case series with review of literature. World Spinal Column Journal 2014; 5: 12–20. http://www.wscj.org/ text.php3?id=115 (accessed Oct 10, 2016). 31 Savas R, Calli C, Alper H, et al. Spinal cord compression due to costal Echinococcus multilocularis. Comput Med Imaging Graph 1999; 23: 85–88. 32 Scheuring UJ, Seitz HM, Wellmann A, et al. Long-term benzimidazole treatment of alveolar echinococcosis with hematogenic subcutaneous and bone dissemination. Med Microbiol Immunol 2003; 192: 193–95. 33 Sengul G, Kadioglu HH, Kayaoglu CR, Aktas S, Akar A, Aydin IH. Treatment of spinal hydatid disease: a single center experience. J Clin Neurosci 2008; 15: 507–10. 34 Gaucher A, Vinet E, Pere P, Plenat F, Ethgen D, Pourel J. Alveolar echinococcosis with spinal localization. Presse Med 1983; 12: 1366 (in French). 35 Kunze V, Layer G, Brüning R, Nägele M. “Metastasizing” echinococcus alveolar of the liver. Radiologe 1992; 32: 444–47 (in German). 36 Iaroslavskii VE. Primary alveolar echinococcosis of spinal canal. Sov Med 1956; 20: 81–83 (in Russian). 37 Faucher J-F, Descotes-Genon C, Hoen B, et al. Hints for control of infection in unique extrahepatic vertebral alveolar echinococcosis. Infection 2017; 45: 365-68. 38 Bidloo G. Exercitationum anatomico-chirurgicarum decades duae. Lugdunum Batavorum: J Luchtmans, 1708; 216: 10–26 (in Latin). 39 Chaussier M. Paralysie des membres inférieurs causée par un kyste vermineux penetrant de la poitrine dans le rachis. In: Corvisart, Leroux, Boyer, eds. Journal de médecine, de chirurgie et de pharmacie, etc. 14th edn. Paris, France: Migneret, Méquignon 1807; 231–37 (in French). 40 Reydellet M. Moelle épinière, medulla spinalis ou dorsalis. Dictionaire des sciences médicales, par une société des médecins et de chirurgiens. Paris: C. L. F. Panckoucke, 1819: 33: 538–68. 41 del Campo JC. Vertebral echinococcosis; total resection of the fifth lumbar vertebra. Arch Urug Med Cir Espec 1950; 36: 337–57 (in Spanish). 42 Stark LG. Erhebung und vergleichende histologische analyse des archivierten gesamtkollektivs von Echinococcus multilocularis und Echinococcus granulosus am Institut für Pathologie der Universität Ulm im Zeitraum 1989–2010. Dissertation, University of Ulm, 2012. 43 Herrera A, Mateo J, Lobo-Escolar A, Ibarz E, Gracia L. Hydatidosis of the spine: diagnosis and treatment. Berlin: Springer-Verlag Berlin Heidelberg, 2014: 99–119. 44 Braithwaite PA, Lees RF. Vertebral hydatid disease: radiological assessment. Radiology 1981; 140: 763–66. 45 Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain 1972; 95: 87–100. 46 Sailer M, Soelder B, Allerberger F, Zaknun D, Feichtinger H, Gottstein B. Alveolar echinococcosis of the liver in a six-year-old girl with acquired immunodeficiency syndrome. J Pediatr 1997; 130: 320–23. 47 Chauchet A, Grenouillet F, Knapp J, et al. Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppression-associated conditions. Clin Infect Dis 2014; 59: 1095–104. 48 Zingg W, Renner-Schneiter EC, Pauli-Magnus C, et al. Alveolar echinococcosis of the liver in an adult with human immunodeficiency virus type-1 infection. Infection 2004; 32: 299–302. 49 Geyer M, Wilpert J, Wiech T, et al. Rapidly progressive hepatic alveolar echinococcosis in an ABO–incompatible renal transplant recipient. Transpl Infect Dis 2011; 13: 278–84. 50 Brunetti E, Kern P, Vuitton DA. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 2010; 114: 1–16.

e97

Grand Round

51 Harpaz R, Dahl RM, Dooling KL. Prevalence of immunosuppression among US adults, 2013. JAMA 2016; 316: 2547–48. 52 Novosad SA, Winthrop KL. Beyond tumor necrosis factor inhibition: the expanding pipeline of biologic therapies for inflammatory diseases and their associated infectious sequelae. Clin Infect Dis 2014; 58: 1587–98. 53 Romig T, Kratzer W, Kimmig P, et al. An epidemiologic survey of human alveolar echinococcosis in southwestern Germany. Romerstein study group. Am J Trop Med Hyg 1999; 61: 566–73. 54 Gottstein B, Saucy F, Deplazes P, et al. Is high prevalence of Echinococcus multilocularis in wild and domestic animals associated with disease incidence in humans? Emerg Infect Dis 2001; 7: 408–12. 55 Craig PS, Rogan MT, Allan JC. Detection, screening and community epidemiology of taeniid cestode zoonoses: cystic echinococcosis, alveolar echinococcosis and neurocysticercosis. In: Baker JR, Muller R, Rollinson D, eds. Advances in Parasitology. Cambridge, MA, USA: Academic Press, 1996: 169–250. 56 Yang YR, Craig PS, Vuitton DA, et al. Serological prevalence of echinococcosis and risk factors for infection among children in rural communities of southern Ningxia, China. Trop Med Int Health 2008; 13: 1086–94. 57 Zhang H, Liu ZH, Zhu H, Han Y, Liu J, Deng LQ. Analysis of contrast-enhanced ultrasound (CEUS) and pathological images of hepatic alveolar echinococcosis (HAE) lesions. Eur Rev Med Pharmacol Sci 2016; 20: 1954–60. 58 Farrar J, Hotez P, Junghanass T, Kang G, Lalloo, D. Manson’s tropical diseases, 23rd edn. London: Elsevier Saunders, 2014. 59 Srinivas MR, Deepashri B, Lakshmeesha MT. Imaging spectrum of hydatid disease: usual and unusual locations. Pol J Radiol 2016; 81: 190–205. 60 Polat P, Kantarci M, Alper F, Suma S, Koruyucu MB, Okur A. Hydatid disease from head to toe. Radiographics 2003; 23: 475–94; quiz 536-37. 61 Becce F, Pomoni A, Uldry E, et al. Alveolar echinococcosis of the liver: diffusion-weighted MRI findings and potential role in lesion characterisation. Eur J Radiol 2014; 83: 625–31. 62 Azizi A, Blagosklonov O, Lounis A, et al. Alveolar echinococcosis: correlation between hepatic MRI findings and FDG-PET/CT metabolic activity. Abdom Imaging 2015; 40: 56–63. 63 Kaltenbach TEM, Graeter T, Mason RA, et al. Determination of vitality of liver lesions by alveolar echinococcosis. Comparison of parametric contrast enhanced ultrasound (SonoVue(R)) with quantified 18F-FDG-PET-CT. Nuklearmedizin 2015; 54: 43–49. 64 Gottstein B, Jacquier P, Bresson-Hadni S, Eckert J. Improved primary immunodiagnosis of alveolar echinococcosis in humans by an enzyme-linked immunosorbent assay using the Em2plus antigen. J Clin Microbiol 1993; 31: 373–76. 65 Trachsel D, Deplazes P, Mathis A. Identification of taeniid eggs in the faeces from carnivores based on multiplex PCR using targets in mitochondrial DNA. Parasitology 2007; 134: 911–20. 66 Ammann RW, Stumpe KD, Grimm F, et al. Outcome after discontinuing long-term benzimidazole treatment in 11 patients with non-resectable alveolar echinococcosis with negative FDG-PET/CT and anti-emII/3-10 serology. PLoS Negl Trop Dis 2015; 9: e0003964.

e98

67 Steinmetz S, Racloz G, Stern R, et al. Treatment challenges associated with bone echinococcosis. J Antimicrob Chemother 2014; 69: 821–26. 68 Kuster T, Stadelmann B, Rufener R, Risch C, Muller J, Hemphill A. Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin. Int J Antimicrob Agents 2015; 46: 546–51. 69 Weiner SM, Krenn V, Koelbel C, Hoffmann HG, Hinkeldey K, Ockert D. Echinococcus multilocularis infection and TNF inhibitor treatment in a patient with rheumatoid arthritis. Rheumatol Int 2011; 31: 1399–400. 70 Stadelmann B, Aeschbacher D, Huber C, Spiliotis M, Muller J, Hemphill A. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes. PLoS Negl Trop Dis 2014; 8: e3352. 71 Hemphill A, Stadelmann B, Rufener R, et al. Treatment of echinococcosis: albendazole and mebendazole–what else? Parasite 2014; 21: 70. 72 Tappe D, Muller A, Frosch M, Stich A. Limitations of amphotericin B and nitazoxanide in the treatment of alveolar echinococcosis. Ann Trop Med Parasitol 2009; 103: 177–81. 73 Kern P AP, Abboud P, Kern WV, et al. Critical appraisal of nitazoxanide for the treatment of alveolar echinococcosis. 57th Annual Meeting of ASTMH; Sheraton New Orleans, LA, USA; Dec 7–11, 2008. 402 (abstr). 74 Hemer S, Brehm K. In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae. Int J Antimicrob Agents 2012; 40: 458–62. 75 Bardonnet K, Vuitton DA, Grenouillet F, et al. 30-yr course and favorable outcome of alveolar echinococcosis despite multiple metastatic organ involvement in a non-immune suppressed patient. Ann Clin Microbiol Antimicrob 2013; 12: 1. 76 Crouzet J, Grenouillet F, Delabrousse E, et al. Personalized management of patients with inoperable alveolar echinococcosis undergoing treatment with albendazole: usefulness of positron-emission-tomography combined with serological and computed tomography follow-up. Clin Microbiol Infect 2010; 16: 788–91. 77 Rayport M, Wisoff HS, Zaiman H. Vertebral echinococcosis: report of case of surgical and biological therapy with review of the literature. J Neurosurg 1964; 21: 647–59. 78 Kamat AS, Thompson C, Ben Husien M. Staged surgical management in the treatment of primary epidural hydatidosis of the spine: a case series and review. Cureus 2015; 7: e401. 79 Spektor S, Gomori JM, Beni-Adani L, Constantini S. Spinal echinococcal cyst: treatment using computerized tomography-guided needle aspiration and hypertonic saline irrigation. Case report. J Neurosurg 1997; 87: 464–67.

www.thelancet.com/infection Vol 18 March 2018