Melioidosis of the nervous system: atypical presentation of a rare disease in a 48-year-old man

Abstract

A 48-year-old man who worked in mining in remote, northern Australia was transferred from a rural hospital 5 days after the onset of headaches, subjective fevers and flaccid paralysis of the left upper limb. Initial investigations demonstrated inflammatory cerebrospinal fluid (CSF) changes and a longitudinally extensive cervical cord lesion. Given two serial negative blood and CSF cultures, he was treated as inflammatory myelitis with intravenous methylprednisolone. Despite the initial improvement in pain and left arm power, the patient’s neurological deficit plateaued and then deteriorated with worsening neck pain, diaphragmatic dysfunction and dysphagia requiring intubation and respiratory support. A third CSF culture isolated Burkholderia pseudomallei confirming a diagnosis of neuro-melioidosis. Repeat imaging revealed the rostral extension of the original spinal cord lesion into the medulla and pons. Over the next 4 weeks, the patient’s neurological deficits slowly improved with continued intravenous antibiotic therapy with meropenem and oral trimethoprim/sulfamethoxazole.

Background

Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative soil and water bacterium endemic to tropical regions including northern Australia and Southeast Asia.^{1 2} Infections most commonly occur during the wet season and are acquired via percutaneous inoculation or inhalation.² Clinical manifestations can range from asymptomatic seroconversion to overwhelming sepsis and death. Any organ can be involved with pneumonia being the most common presentation.^{2 3} In Australia, neuro-melioidosis is rare, comprising only 3% of all cases.⁴ The overall mortality rate of melioidosis is approximately 10% in resource-rich countries; however, the case-fatality rate of neuro-melioidosis is much higher and in survivors is often associated with significant morbidity.⁵

Here, we present a case of neuro-melioidosis that mimicked an aseptic inflammatory disease and presented a diagnostic challenge, with multiple negative blood and cerebrospinal fluid (CSF) cultures.

Case presentation

A 48-year-old man from remote Queensland in northern Australia presented to a regional hospital after developing a 24 hours history of pain and swelling in his left arm which he attributed to an insect bite. No wound or eschar was seen. On the resolution of these symptoms, he developed a 2-day history of severe headache and neck pain, subjective fevers and photophobia, resulting in his presentation to hospital. He had no previous medical problems. He did not smoke but reported binge alcohol drinking. He lived on a farm with cattle and dogs and worked in a remote minesite clearing vegetations.

He was afebrile at that time with a normal neurological examination. A lumbar puncture performed at the rural hospital revealed normal opening pressure (18 cm H₂O) and predominant mononuclear (450 cells/mm³, 70%) pleocytosis with 1200 mg/L protein, glucose 2.6 mmol/L and a negative Gram stain. A provisional diagnosis of viral meningitis was made and treatment with intravenous aciclovir and analgesia was commenced. Two days later, he developed left arm flaccid paralysis and the decision was made to transfer him to the regional tertiary hospital for further management.

On initial examination at the tertiary hospital, his Glasgow Coma Scale score was 15 and he was haemodynamically stable. He had photophobia, and midline cervical and upper thoracic spinal tenderness, maximal at T2. His left upper limb weakness showed flaccid paralysis with the power of 3/5 across all muscle groups and absent reflexes. Power and reflexes in his other limbs were normal. The remainder of his cranial and peripheral nerve examination was unremarkable and no rashes, skin lesions or joint swelling were noted.

Investigations

Full blood count, urea and electrolytes, liver function tests and C-reactive protein were unremarkable on presentation at the rural hospital. Using the initial CSF, PCR for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus (VZV) and enterovirus were negative as was cryptococcal antigen.

A second lumbar puncture was performed on admission to the tertiary hospital and showed a mixed pleocytosis of 1120 cells/mm³ (polymorphonuclear 43%, mononuclear 57%), elevated protein of 1700 mg/L and glucose of 2.2 mg/L. Repeat PCR testing for HSV, VZV and enterovirus was negative and no organisms were isolated by culture. Trace oligoclonal bands were detected in CSF that were not present in serum. A serum autoimmune screen was negative.

Blood cultures were negative, and a CT brain scan and a chest X-ray were unremarkable.

MRI of the cervical spine (figure 1) showed an extended intramedullary ring-enhancing lesion within the right anterior aspect of the cord at level C5/C6 measuring 9 mm in transverse diameter. There was abnormal enhancement and abnormal high T2 signal within the cord superior and inferior to this level extending from C2/3 through to C7/T1.

Figure 1.

Initial MRI of the brain.

MRI of the brain was unremarkable.

Anti-aquaporin-4 antibodies were tested on the second CSF sample and returned a normal result 2 weeks later.

Differential diagnosis

The differential diagnosis for this presentation was wide. It included primary autoimmune, infectious and malignant aetiologies. Autoimmune causes were neuromyelitis optica, neurosarcoidosis and neuro-Behcet, which were ruled out after extensive investigations for autoimmune causes. The next group of presentation causes was infectious diseases. These included central nervous system (CNS) toxoplasmosis, tuberculous myelitis, viral meningitis, listeriosis, brucellosis, treponema myelitis and fungal myelitis. None of these organisms were isolated. Malignant differentials included CNS lymphoma. No malignant cells were identified on CSF cytology.

Treatment

Empirical intravenous acyclovir was started at presentation; however as HSV 1/2 and VZV PCR testing was negative, this was ceased after 2 days. With the provisional diagnosis of an autoimmune/inflammatory transverse myelitis, intravenous methylprednisolone was initiated.

On day 7 post admission (and day 5 of methylprednisolone treatment), the patient developed vomiting and worsening neck pain. Intravenous meropenem was initiated, and a lumbar puncture was repeated the following day.

A third CSF culture was performed and, on this occasion, isolated B. pseudomallei. Oral trimethoprim/sulfamethoxazole (TMP/SMX) was added.

A repeat MRI demonstrated rostral extension of the spinal cord lesion into the medulla and pons (figure 2).

Figure 2.

Second MRI of the brain showing progress of lesion.

Outcome and follow-up

From day 8 postadmission, the patient developed worsening headaches, hiccups and vomiting. The examination was consistent with autonomic dysfunction with labile blood pressure readings, left-sided facial droop and dysphagia with the inability to swallow saliva. The patient was transferred to the intensive care unit (ICU) and required intubation and ventilation to protect his airways from increased oral secretions which was followed later by tracheostomy.

He was treated with intravenous meropenem for 8 weeks and concurrent oral TMP/SMX followed by TMP/SMX for 6 months. His neurological symptoms plateaued and began to gradually recover. He remained in ICU for 3 weeks and received inpatient rehabilitation for a further 2 months. He was able to return home and is independent in most activities of daily living. On the last review, he has residual weakness in the left upper limb (3/5 proximally and 4/5 distally) and some left facial weakness. He has probable laryngospasm related to his long period of intubation and tracheostomy.

Discussion

This case provided a diagnostic dilemma as the initial clinical presentation was of an infection involving the nervous system; however, subsequent imaging and consistently negative cultures made an inflammatory, longitudinally extensive transverse myelitis more likely. It was only with further clinical evolution and a third lumbar puncture that the diagnosis of neuro-melioidosis became apparent.

Neurological involvement only accounts for 3% of cases of melioidosis.⁴ Disease can occur following a recent infection; however, latent infections have been described up to 62 years after exposure.⁶ Transmission most commonly occurs through percutaneous inoculation, inhalation and ingestion.⁶ Potential peripheral nerve route spread to the CNS is yet to be proven.⁷ Studies in mice showed that the rate of spread through the olfactory epithelium to the CNS can be as rapid as that through blood stream-related infection.⁸

The reported neurological presentations include fevers 76%, headaches 54%, unilateral weakness 38%, altered consciousness 39% and cranial nerve palsies 34%. Ring enhancing lesions and cerebral oedema are the most frequent MRI findings. CSF pleocytosis with mononuclear pleocytosis was found in 62% of cases with CNS melioidosis. B. pseudomallei was found in 92% of CSF cultures. Cerebral abscesses and micro-abscesses are the most common encountered finding. The mortality can reach 20%. About half of the affected patients recover completely, whereas one-third have persistent neurological deficits.^{9 10}

Treatment of melioidosis involves initial intensive therapy with intravenous antibiotics for 14 days which can be extended in critically ill patients to 4–8 weeks. Eradication treatment with meropenem or ceftazidime usually combined with TMP/SMX usually follows to decrease the rates of recurrence.¹ For neuro-melioidosis, the recommended minimum intravenous antibiotic treatment duration is 8 weeks followed by 6 months of eradication treatment with TMP/SMX.^{1 3}

This case demonstrates that, although rare, neuromelioidosis must be considered as a differential diagnosis in patients presenting with otherwise unexplained CNS disease in endemic areas.

Learning points.

• Neuromelioidosis can have unusual clinical and radiological presentations that mimic other inflammatory or infectious conditions.

• The theory of ascending neuronal infection along peripheral nerves and along white matter tracts is plausible in our patient but needs further study.

• There is no known clinical or radiological feature that is specific for neuromelioidosis.

• Early diagnosis and appropriate intravenous antibiotic treatment is essential to prevent mortality and significant neurological morbidity.