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Encephalopathy in the oncology patient

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Shared care information

Paediatric oncology patients may fit, or present with an altered level of consciousness, for a variety of reasons (see below).

As for other children, stabilisation of the "ABC" is the first priority. A diagnostic work up should be performed on patients who are not suitable for transfer after discussion with the paediatric oncologist on call, looking for reversible causes. Rectal medications should be avoided in patients who may be neutropenic.

Altered level of consciousness

Causes

  • Drugs: narcotics and sedative agents. May be worse if co-existing renal (opiods) or hepatic (most other sedative agents) impairment. Chemotherapeutics e.g., ifosfamide.
  • Infection: usually in patients on therapy. Immunocompromised patients may develop typical or atypical infections including fungal and parasitic. May be localised or septicaemia.
  • Neoplasm: primary or secondary. This can be meningeal infiltration without mass effect and so MRI may be required.
  • Psychiatric
  • Metabolic: hypoglycaemia, hypernatraemia, uraemia, hepatic encephalopathy, hyperammonaemia
  • Vascular: intracranial haemorrhage, sinus venous thrombosis (especially if the child is on L-asparaginase), CVA
  • Other: raised ICP secondary to space occupying lesions, blocked VP shunts, Posterior reversible encephalopathy syndrome (PRES), toxicity secondary to IT therapy.

Clinical presentation

There may be subtle alterations in behavior or rapidly progressive decreased level of consciousness. Children can even initially appear "hyperactive" and agitated or irritable.

Diagnosis

Do not attempt LP without cranial imaging first in this setting

  • CBC, full biochemistry including glucose, calcium, LFTs, blood gas, ammonia (on ice), coag screen.
  • Full infection screen - write clearly on form what organisms are being considered, e.g.,fungus, so that microbiology can process appropriately.
  • Viral serology/PCR
  • Drug history
  • Tox screen (including alcohol in older children)
  • CSF for cytospin to haematology (leukaemia/lymphoma) or cytology (solid tumours). 
  • MRI preferably but CT may be more readily available after hours. In semi-conscious children this often requires a general anaesthetic.

Management

  • ABC - make sure the child is stable before instituting any specific management. Also make sure you chase the results of rapidly reversible causes such as hypoglycaemia, hyponatraemia.
  • GCS - even if this is normal contacting anaesthetics may be indicated if an urgent scan is likely to be required.
  • Full history, physical and neurological exam looking for: signs of infection, skin lesions (herpes, bacterial infection), bruising (abnormal coag), localising neurological signs.
  • If known brain tumour patient involve neurosurgeons early, especially if there is a VP shunt in situ.
  • If there is any fever or other signs of infection, consider first line antibiotic therapy, antifungals or antivirals as indicated after discussion with the paediatric oncologist on call.
  • Consider neurological opinion and EEG for non-convulsive status.
  • Consider psych input if all investigations are normal.

Encephalitis and Meningitis

Shared care information

Please discuss these patients with the paediatric oncologist on call as soon as they are stabilised. Depending on the patient's diagnosis and stage of treatment, different investigations may be required.

Cause

The differential diagnosis is broad but is usually between infective, neoplastic and toxic (i.e., chemotherapy induced) causes. Inflammatory conditions can also occur particularly post SCT.

Investigations

  • MRI head gives more clinical information in this setting than CT
  • Viral PCR for HSV, mumps, HIV, adenovirus, Polyomavirus, EBV on blood and CSF (once it has been determined than LP is safe - see warning above)
  • Serology for measles (post measles encephalopathy) toxoplasma, mycoplasma
  • Toxoplasma PCR
  • Cryptococcal staining and antigen
  • CSF for M,C+S and protein and glucose, mycology, mycobacterium stain and culture, if indicated
  • CSF for cytospin for haematology (leukaemia/lymphoma) or anatomical path (solid tumours)
  • Electroencephalogram (specific patterns may be seen in some cases)
  • Neurology opinion/Infectious Diseases opinion.

Management

  • Supportive care of ABC as indicated, discuss antimicrobial therapy with Oncology unit and Infectious Diseases team.
  • If no cause is apparent from initial investigations, consider empiric antiviral therapy after all investigations completed.
  • If symptoms persist, the repeat MRI may show changes not present initially and help with diagnosis.
  • Institute therapy for specific causes as indicated.

Ifosfamide induced encephalopathy

Ifosfamide is a pro-drug metabolised by cytochrome p450 to active alkylating species; other non-alkylating substances are formed:

  • choroethylamine - this conjugates with cysteine and is metabolised to thialysine ketamine which:
    • may have CNS effects on its own.
    • inhibits electron-binding flavoproteins in the mitochondrial respiratory chain. This has direct effects and alters the NAD/NADH balance which prevents dehydrogenation of aldehydes e.g., chloracetaldehyde.
  • chloracetaldehyde - produced by action of extrahepatic mono-amine oxidases. Chloracetaldehyde is closely related to known hypnotics.

Clinical features

The clinical picture can range from mild somnolence (quite commonly observed during and/or immediately after the infusion), agitation, confusion, hallucinations to deep coma. The acute organic psychosis usually remits within 2 - 7 days of discontinuation of ifosfamide. However, emotional lability may last longer. Deaths have been reported.

Risk factors

  • age - more common in older patients
  • oral administration
  • renal impairment and post-renal obstruction
  • short infusion time
  • prior CNS problems including brain tumours.

Prevention

  • give ifosfamide over at least 3 hours
  • if encephalopathy occurs with prior course of ifosfamide, consider:
    • substitution of ifosfamide with cyclophosphamide, or
    • continuing ifosfamide but give:
      -ifosfamide as continuous infusion and
      -methylene blue 0.8 mg/kg/dose (max 50 mg) over 15min IV 6 hourly for duration of infusion.

Methylene Blue

Methylene Blue has been shown to be effective in treating and preventing ifosfamide encephalopathy. It acts as an alternative electron acceptor, replacing inhibited flavoproteins, inhibits extrahepatic mono-amine oxidase and may oxidate NADH. Methylene blue does not inhibit the anti-cancer effect of ifosfamide.

Treatment

  • Severe encephalopathy: stop ifosfamide and give methylene blue 4 hourly IV
  • Mild/moderate encephalopathy: give methylene blue 0.8 mg/kg/dose over 15 min 4 hourly IV.

Dose of Methylene Blue

The adult dose is 50 mg methylene blue in a 1% aqueous solution. There is very little information on paediatric dosing. Therefore:

Dose = 0.8 mg/kg/dose IV over 15 minutes. Maximum dose is 50 mg.

Toxicity and Contraindications

Methylene blue is a redox agent. Although it is used as a reducing agent in methaemoglobinaemia it can also act as an oxidising agent. It is also a monoamine oxidase inhibitor.

Methylene blue may cause:

  • nausea
  • vomiting
  • abdominal and chest pain
  • headache, dizziness, confusion
  • sweating
  • dyspnoea
  • hypertension and
  • methaemoglobinuria
  • discoloured urine.

G6PD deficiency - methylene blue precipitates haemolysis.

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Document Control

  • Date last published: 03 March 2014
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network