Cerebral venous sinus thrombosis as a complication of cranial melioidosis – a rare case report

Cerebral venous sinus thrombosis is a rare complication of cranial melioidosis. We report a case of an adult male who presented with skull osteomyelitis, transverse sinus thrombosis and multiple brain abscesses. His blood cultures grew Burkholderia pseudomallei . The patient finally succumbed after multiple recurrences of the infection despite surgical excision of the osteomyelitic bone and the recommended antibiotic treatment. The management of cerebral venous sinus thrombosis in patients with cranial melioidosis is discussed along with a brief review of the literature.


INTRODUCTION
Melioidosis is an infection caused by the soil-dwelling Gram-negative organism, Burkholderia pseudomallei [1,2]. Infection of the central nervous system (CNS) by this organism, known as cranial melioidosis (CM) is rare [1,3]. CM can involve any structure in and around the CNS [1,2,4]. The case we present is novel in that simultaneous occurrence of skull osteomyelitis, cerebral venous sinus thrombosis (CVT), multiple cerebral abscesses and systemic melioidosis in the same patient, is a clinical entity that has not been reported so far. Our case is also the fifth reported case of CVT in a patient with CM.

CLINICAL PRESENTATION
This 51-year-old male patient with diabetes mellitus (DM) was admitted six times at our centre for treatment, the details of which are summarized in Table 1. He had multiple admissions as there was recurrence of infection despite recommended treatment during each of these admissions.
In the first admission, contrast computed tomogram (CT) of the brain showed imaging features suggestive of focal osteomyelitis of the left occipital bone near the transverse sinus (Fig. 1a). Magnetic resonance imaging (MRI) of the brain showed focal pachymeningitis in the left occipital region (Fig. 1b). Magnetic resonance venogram showed left transverse sinus (TS) thrombosis (Fig. 1c). Blood and cerebrospinal fluid (CSF) cultures were sterile. Excision, biopsy and culture of the occipital bony lesion was planned. Patient and relatives were unwilling for any surgical procedure. Hence he was started on empirical intravenous antibiotics followed by oral antibiotics for a total duration of 7 weeks along with antiepileptic medications and blood thinners. He became afebrile and the retromastoid swelling subsided.
During the second admission, blood culture grew Pseudomonas aeruginosa. He was treated with culture specific intravenous antibiotics for 2 weeks with which he improved clinically.
He presented in a state of altered sensorium during the third admission. MRI of the brain showed progression of the bony erosion. He underwent left retromoastoid craniectomy and excision of the osteomyelitic occipital bone. The histopathology of the bone specimen was suggestive of chronic osteomyelitis. Blood culture grew B. pseudomallei. He was started on culture-specific OPEN ACCESS intravenous and oral antibiotics simultaneously. Intravenous antibiotics were given for 8 weeks and the oral antibiotics were continued for a total of 24 weeks. He remained asymptomatic for about 36 weeks from the time of discharge.
During the fourth admission, he presented with left hemiparesis. MRI of the brain showed multiple contrast enhancing ill-defined lesions involving grey and white matter of both cerebral hemispheres, cerebellum and brain stem (Fig. 2a, b). Blood and urine cultures were sterile. He was treated with empirical intravenous followed by oral antibiotics based on the previous positive B. pseudomallei culture sensitivity for a total of 6 weeks. His general condition and hemiparesis improved.  During the fifth and sixth admissions, the MRI of the brain showed progression of the ill-defined lesions with development of a large enhancing lesion in the right frontoparietal white matter (Fig. 2c). Blood and urine cultures remained sterile. He was treated with empirical antibiotics but lost to follow up and subsequently expired.

DISCUSSION
Melioidosis is endemic in Southeast Asia and Northern Australia [3]. Infection with this organism occurs via ingestion, inhalation or percutaneous inoculation [2,3]. CNS infection is believed to be secondary to hematogenous spread or direct spread from the nasopharynx [2].
Involvement of multiple tissue layers from the scalp to the brain parenchyma as reported by Pit et al. was seen in our case [9].
The previously reported four cases of CM with CVT and the case we present are summarized in Table 2. Niyasom et al. reported the first case of CM with CVT [8]. Patients with CM with CVT can have associated venous infarction in the cerebral hemispheres [8]. All patients were males with ages ranging from 23 to 69 [4,[6][7][8]. The commonest co-morbidity associated was DM [6,8,10]. The other risk factors include renal disease, thalassemia, previous trauma or surgery, pulmonary tuberculosis and malignancies [10]. Our patient had both DM and renal failure as co-morbidities. The venous sinus commonly involved was the superior sagittal sinus [6][7][8]. Two previously reported cases [4,8] showed TS involvement as seen in our case.
Delay in diagnosis is a major concern in patients with melioidosis [1]. The clinical and radiological features of CM can mimic other CNS pathologies like tuberculosis [1,4,11], other pyogenic infections [11] or malignancies [1]. In our patient also there was a delay in diagnosis as the organism could not be isolated in the first two admissions. This made us treat him for a shorter duration than the recommended prolonged antibiotic treatment. However, after the recommended culturespecific treatment he was disease free for about 9 months.
Cultures from the CNS specimen is the best way to establish a definite diagnosis of CM [12]. Diagnosis of the disease can also be done by culture of pus from the abscess [7], blood [6,8] or involved tissues [4] demonstrating the growth of the organism. CSF pictures can be variable in patients with CM. It can show lymphocytic pleocytosis [2,12], a CSF picture similar to tuberculosis or viral encephalitis. In about a third of patients, polymorphonuclear cell predominance can be seen [12] and rarely it can be acellular [6,8]. CSF also demonstrates high protein and normal glucose [12]. However, in our case, the CSF study was normal and CSF culture was negative.
The appropriate surgical intervention followed by antibiotic therapy is the recommended treatment for CM. The antibiotic of choice and its optimal duration of treatment are controversial [13]. Various authors recommend intravenous followed by oral antibiotic therapy in melioidosis. Duration of parenteral antibiotic therapy recommended by various authors ranges from 2 to 6 weeks [1-3] followed by oral antibiotics for 3-6 months [1,3]. The parenteral antibiotics used are ceftazidime [2,3] or meropenem [2]. Maintenance therapy with oral co-trimoxazole for 6 months following the initial parenteral antibiotic treatment has been recommended [1,2,4]. In patients who cannot tolerate co-trimoxazole, amoxicillin-clavulanate and/or doxycycline can be administered [3,4]. The choice of antibiotic should be based on the culture and sensitivity. CVT in these patients is treated with intravenous anticoagulants [4,8] along with antiepileptics [8].
Of the four previously reported cases of CM with CVT, all had good outcomes [4,[6][7][8]. When CM is seen associated with osteomyelitis or mass lesion, the mortality rate was about 25 % [1]. CM is known to recur due to non-compliance or suboptimal duration of antibiotic treatment [1]. We feel that the reasons for multiple recurrences and death in our case are (i) delay in diagnosis, (ii) inappropriate treatment due to lack of isolation of the organism during the initial two admissions, (iii) presence of co-morbidities like DM and renal failure and (iv) noncompliance to treatment.

CONCLUSION
Clinicians should be aware of this rare presentation of simultaneous CNS and systemic infection in association with CVT in patients with melioidosis.
Through this article, we recommend the following in patients with clinical presentation similar to ours (i) consider CM as one of the differential diagnoses in patients presenting with intracranial lesion, (ii) consider performing MR venogram in these patients as CVT can rarely be associated, (iii) consider long-term recommended antibiotic therapy and (iv) keep these patients on close clinical and radiological follow-up. If cranial imaging shows recurrence of infection and bacterial cultures remain negative, these patients should be treated again with antibiotics based on previous positive cultures for the recommended period of time.

Funding information
The authors received no specific grant from any funding agency.