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Headache and visual aura in an immunocompromised patient

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6507 (Published 02 October 2012) Cite this as: BMJ 2012;345:e6507
  1. Hannah Tharmalingam, core medical trainee,
  2. Thomas C Morris, specialist registrar in infectious diseases,
  3. Joanna Farnsworth, specialty registrar in radiology,
  4. Edward J Kanfer, consultant haematologist
  1. 1Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK
  1. Correspondence to: H Tharmalingam hannahtharmalingam{at}doctors.org.uk

A 38 year old HIV negative South African man was diagnosed in 2007 with stage IVB Hodgkin’s lymphoma. Conventional chemotherapy and radiotherapy had no effect, so in March 2007 he underwent an autologous stem cell transplant. Relapses in 2009 and 2010 resulted in two allogeneic stem cell transplants, after he was conditioned with fludarabine, cyclophosphamide, and anti-thymocyte globulin. After his second transplant he developed grade four graft versus host disease that affected the liver and gut, and in December 2010 he was started on an immunosuppressive regimen of prednisolone and ciclosporin.

In June 2011 he re-presented with a one week history of fever, vomiting, and malaise, followed by severe headache and visual aura. On examination he was cachectic with mild ankle oedema and a fever (39.2°C). The rest of the examination was unremarkable. His peripheral white blood cell count was 0.7×109/L (normal range 4-11), neutrophils were 0.1×109/L (2-7.5), platelets 22×109/L (150-400), and haemoglobin 98 g/L (130-180). Liver function tests showed alanine transaminase 362 U/L (21-72), alkaline phosphatase 960 U/L (30-120), bilirubin 61 μmol/L (3-22; 1 μmol/L=0.06 mg/dL), and albumin 28 g/L (35-50). C reactive protein was raised at 2743 nmol/L (<45 nmol/L; 91 nmol/L=0.1 mg/L). In light of his neurological symptoms, he underwent magnetic resonance imaging (MRI) of the brain, the results of which are shown in fig 1.

Figure1

Fig 1 Axial T1 weighted magnetic resonance image of the brain with gadolinium contrast

Questions

  • 1 What does the contrast magnetic resonance image show?

  • 2 Given the clinical history and radiological findings what are the differential diagnoses?

  • 3 Aside from baseline blood tests, how would you investigate this patient?

  • 4 How would you manage this patient?

Answers

1 What does the contrast magnetic resonance image show?

Short answer

The contrast MRI of the brain shows a large ring enhancing lesion in the right parietal lobe. The rest of the image series showed similar lesions distributed throughout the cortex.

Long answer

This axial section of a contrast MRI of the brain shows a large ring enhancing lesion in the right post-central gyrus, measuring 25 mm in diameter (fig 2 red arrow). The rest of the image series showed several such cortically based ring enhancing lesions. No infratentorial masses were seen. A fluid attenuated inversion recovery (FLAIR) sequence showed severe white matter peri-lesional oedema and localised mass effect.

Figure2

Fig 2 Axial section of the contrast magnetic resonance imaging of the brain showing a large ring enhancing lesion in the right post-central gyrus, measuring 25 mm in diameter (arrow)

2 Given the clinical history and radiological findings what are the differential diagnoses?

Short answer

In immunocompromised patients, the main differential diagnoses are infections, such as tuberculosis, toxoplasmosis, fungal infection, and pyogenic abscess. Lymphoma and malignant metastasis are also a possibility, although these are more likely in an immunocompetent patient.

Long answer

Tuberculosis can occur even in mild immunodeficiency (table 1). Infection of the central nervous system occurs in about 1% of cases and is confirmed by lumbar puncture. Lymphocytes (rather than neutrophils) predominate in the cerebrospinal fluid (CSF); in addition, protein is raised and glucose is low (less than half of that seen in the serum). CSF culture is needed for a definitive diagnosis. Radiological features suggesting tuberculosis include hydrocephalus and basal enhancing exudates,1 as well as focal tuberculomas, which are often seen in the parietal lobes.2 About 3.6% of cases globally are multidrug resistant,3 so if preliminary CSF findings are non-diagnostic, consider stereotactic brain biopsy.

Table 1

 A guide to likely infecting organisms based on the type and severity of immune defect

View this table:

Toxoplasmosis is endemic in the United Kingdom and features high on the differential diagnosis in patients with severely impaired cell mediated immunity. Pathogenesis involves reactivation of a latent infection and can therefore be almost excluded in the absence of specific serum IgG. CSF polymerase chain reaction is about 50% sensitive. Imaging shows lesions with marked oedema and the presence of satellite lesions at the basal ganglia and corticomedullary junction.4 Toxoplasmosis is highly treatable, so a clinical and radiological response to treatment should be seen within two weeks.5

The most common fungal infection in severely impaired cell mediated immunity is with the capsulate yeast Cryptococcus neoformans. A high index of clinical suspicion is needed because the onset is indolent and all patients who are not treated will die within six weeks.6 Lumbar puncture results are deranged in 40-50% of cases, but this infection can often be difficult to distinguish from tuberculosis. However, the cryptococcal antigen latex agglutination test on blood or CSF is highly sensitive.7 Lesions on imaging are usually smaller than those seen here, but they can occasionally develop into larger pseudocysts.8 Filamentous fungal infections with organisms such as aspergillus should also be considered, and risk factors for these include neutropenia, corticosteroid use, and graft versus host disease.9

Pyogenic abscesses may be caused by direct spread from neighbouring sources (for example, otitis media) or from haematogenous dissemination. Factors that predispose to blood borne spread include bacterial endocarditis, suppurative lung disease, and a decreased capacity for phagocytosis secondary to cirrhosis or splenectomy. Causative agents include staphylococci, streptococci, nocardia, and listeria. Radiologically, pyogenic abscesses may be thin walled on the medial aspect and tend to be bright on diffusion weighted imaging.

Intracranial deposits of Hodgkin’s lymphoma are rare, occurring in only 0.25% of cases.10 A more likely diagnosis would be post-transplant lymphoproliferative disorder, where uncontrolled proliferation of B cells infected by Epstein-Barr virus can progress to non-Hodgkin’s lymphoma. Risk factors for the development of this disease include unrelated donor transplantation, use of anti-thymocyte globulin, acute graft versus host disease, and immunosuppression with calcineurin inhibitors.11 The incidence of post-transplant lymphoproliferative disorder after allogeneic stem cell transplantation is around 1%, but this may increase to 22% with three or more risk factors.12

Numerous studies have confirmed the increased risk of secondary cancer after allogeneic bone marrow transplantation,13 14 with skin cancers and cancers of the oral cavity being most common. Risk factors include older age, immunosuppression, total body irradiation, fludarabine based conditioning, and graft versus host disease.14 Radiologically, the enhancing rim of metastatic brain lesions is often thick and irregular. They are typically subcortical with severe perilesional oedema.

3 Aside from baseline blood tests, how would you investigate this patient?

Short answer

If safe (box), perform lumbar puncture and send CSF for Gram stain, cell count, protein and glucose, bacterial screen, tuberculosis and fungal culture, acid fast bacilli smear, cryptococcal antigen, polymerase chain reaction for toxoplasma and Epstein-Barr virus, cytology, and lactate dehydrogenase. Blood cultures, sputum cultures and HIV serology should also be sent. Perform chest radiography and consider echocardiography and computed tomography of the chest, abdomen, and pelvis.

Safety of lumbar puncture and computed tomography (CT) of the brain15

Indications for CT before lumbar puncture
  • Glasgow coma scale ≤13/15 (or falling rapidly)

  • Focal neurology (including speech or cerebellum)

  • Age >65 years

  • Immunocompromise

  • Known disease of the central nervous system

  • Recent fits (<1 week)

  • Papilloedema

Absolute contraindications after CT
  • Posterior fossa mass

  • Midline shift

  • Loss of basal or chiasmatic cisterns

  • Infected skin over puncture site

Relative contraindications after CT
  • Raised intracranial pressure

  • Coagulopathy

  • Spinal epidural abscess

Long answer

Table 2 summarises the initial investigations with indications. A definitive diagnosis of lymphoma or malignant metastasis requires a tissue biopsy.

Table 2

 Investigations that may be indicated in a patient presenting with ring enhancing lesions on magnetic resonance imaging of the brain

View this table:

4 How would you manage this patient?

Short answer

While awaiting the results of initial investigations, start empirical treatment according to risk factors and as tolerated by the patient, with careful selection of broad spectrum intravenous antibiotics, antituberculous drugs, and an antifungal agent or co-trimoxazole (or both).

Long answer

An appropriate empirical regimen here would be ceftriaxone and metronidazole, because the high C reactive protein points to bacterial infection and these drugs are well tolerated in liver dysfunction. The deranged liver function tests without features of extracranial tuberculosis make empirical treatment for tuberculosis less appealing. Quickly tailor treatment according to progress and the results of investigations. Twelve months of treatment is recommended for tuberculosis of the central nervous system,16 and corticosteroids improve survival in the first six weeks.17 Cryptococcus is best treated with two weeks of liposomal amphotericin and flucytosine,18 followed by fluconazole.19 Treat toxoplasmosis with pyrimethamine and sulfadiazine for three to six weeks. Cessation of immunosuppression is the mainstay of treatment for post-transplant lymphoproliferative disorder, although intrathecal chemotherapy may be needed for disease of the central nervous system.20

Imaging should be repeated at least twice a week. The absence of conclusive test results and a failure to respond clinically should prompt consideration of stereotactic brain biopsy.

Patient outcome

Tests were inconclusive—the CSF showed raised protein only and some resistant coliforms were grown from the sputum—so the patient was treated empirically with intravenous meropenem and metronidazole. Despite this, there was neurological deterioration and he sadly died. Persistent thrombocytopenia and an insufficient response to platelet transfusions precluded biopsy; none of the other investigations identified a diagnosis.

Notes

Cite this as: BMJ 2012;345:e6507

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References