Case 21 A neonate with abnormal movements

A 3-week-old boy, Oliver, presents to the ED on Friday morning with abnormal movements. His mother noticed abnormal movements of the arms on one occasion and of one leg on another. Oliver seems unresponsive when having these episodes. There is no cyanosis and the longest episode has lasted for 30 seconds. There have been 6 episodes in the past 24 hours. Oliver has not had a fever but has been feeding less well than usual and has also been lethargic.

His mother was well in pregnancy and he was born by vaginal delivery following an uneventful labour. There was no prolonged rupture of membranes.

Oliver’s mother is not on medication and there is no history of drug abuse. The parents are not consanguineous.

On examination Oliver has a temperature of 37.9°C, a saturation of 97% in air and is not dehydrated. There is no rash. The anterior fontanelle is flat and there are no neurological signs. There are no signs in the other systems.

A bedside blood glucose is 4.3 mmol/L. The registrar who sees an episode feels that Oliver is fitting and discusses him with the consultant.

What investigations and treatment would you recommend?

The consultant suggests doing a full septic screen excluding a CXR (Oliver has no respiratory symptoms or signs), U and E’s, bone chemistry, Mg, LFTs, a laboratory glucose and to subsequently start iv penicillin and gentamicin.

The lumbar puncture is performed but only 3 drops of CSF are obtained. The CSF result is as follows:

• WBC 290/mm3 (normal ≤ 20/mm3) of which 70% are polymorphs
  
• RBC 18/mm3
  
• Gram stain – negative
  
• Rapid antigen screen – negative
  
• Protein 1.8 g/L (normal < 0.7 g/L)
  
• Glucose 2.0 mmol/L (normal >60% simultaneous blood glucose).

The microbiology technician who phones the ward with the result states that because the sample was so small the figures are approximate and the Gram stain can sometimes be negative in cases of bacterial meningitis, especially with small samples.

What is your opinion of the CSF result?

Oliver continues to fit and is given a loading dose of phenobarbitone. The following morning he is still having intermittent fits.

What further treatment would you give for the fits?

Oliver is given a loading dose of phenytoin and commenced on regular iv phenobarbitone. Intravenous lorazepam is used for the episodic fits that occur during the day. A CT scan is performed and is normal. On Sunday evening, over 48 hours following admission, Oliver develops status epilepticus and requires intubation, ventilation and transfer to a PICU. There he is also given iv aciclovir. On Monday morning the CSF PCR returns as positive for type 2 herpes and a diagnosis of herpes encephalitis is made. Oliver’s parents are specifically asked about a history of herpes genitalis. Both state that they have not had this but they are referred to a genito-urinary clinic where serological tests confirm that they both have antibodies to herpes type 2 and therefore must have had this infection in the past. Oliver returns to the local hospital, having been successfully extubated but 10 days later again develops status epilepticus and requires re-intubation, ventilation and another transfer to the PICU.

EEG shows marked epileptiform activity and a MRI shows widespread cystic leucomalacia. Oliver subsequently develops severe learning difficulties.

His parents sue because of the delay in the diagnosis of the herpes encephalitis and the resultant complications.

Expert opinion

Herpes encephalitis is rare. In cases due to vertical transmission it usually occurs between 4 and 11 days of age, but can present as late as 4 weeks. Oliver’s mother should have been discreetly, specifically asked about a history of genital herpes but in most infants who present with this condition there is no clinical history of this illness even though the mother has serological evidence of the disease. In approximately 40% of cases there are no herpetic skin lesions.

In an older child a focal fit would have the same significance as a focal neurological sign and would make one consider a condition such as herpes encephalitis or a structural brain lesion. However, fits in neonates can be quite subtle and may appear to be focal even in cases where there is a more generalized problem such as meningitis. In some cases of bacterial meningitis, especially if there is little CSF to analyse, the Gram stain can be negative and the diagnosis may be made subsequently on the more sensitive culture or PCR. Though sometimes one does not see organisms on a Gram stain this is unusual and should have prompted the doctors to think of nonbacterial causes of meningitis or encephalitis. Though the CSF white blood cell differential suggests a bacterial cause, early on in viral meningitis there can be a predominance of polymorphs and in this case the result was in any case approximate due to the small sample size. The CSF glucose is often normal in viral meningitis but can be low as in this case. Furthermore, the rapid antigen screen was negative. The administration of aciclovir should therefore have been considered following the CSF result.

Oliver’s worsening condition should also have made the doctors review the diagnosis prior to the onset of status epilepticus on Sunday. However, whether this would have made a difference to the long-term outcome is difficult to determine.

Aciclovir is a very safe drug and where there is doubt about the diagnosis it is safer to administer it and to then discontinue it if the patient improves and the CSF herpes PCR proves to be negative. It would have been wise to discuss this rare case with a consultant microbiologist and/or a tertiary infectious diseases centre.

Legal comment

The Expert Opinion above shows that this is a complex, difficult case. The clinicians did start treatment quickly. They seem to have acted reasonably. However, an instructed expert may criticize them for failing to consider herpes encephalitis as a differential diagnosis. The real issue is whether aciclovir should have been administered earlier and whether, on the balance of probabilities, it would have prevented the child from developing learning difficulties. If the answer is ‘yes’ to both these questions, then the case could be worth several million pounds.

Whether the clinicians were negligent or not, a mistake was made. The case should, therefore, be viewed as an important lesson in considering all potential diagnoses.