ORIGINAL ARTICLE

Recurrent cerebral fever in the seventeenthand twenty first centuries

A.N. Williamsa,*, R. Sunderlandb

aCDC, Child Health Directorate, Northampton General Hospital, Cliftonville, Northampton NN1 5BD, UKbBirmingham Children’s Hospital, Steelhouse Lane, UK

10do

16

KEYWORDSThomas Willis;Coma;Venous Sinus;Thrombosis;Paediatric coma

90-3798/$ - see front matter Q 200i:10.1016/j.ejpn.2004.07.005

* Corresponding author. Tel.: C4404-545988.E-mail address: anw@doctors.org.u

Summary The development of modern neuroscience away from the concepts ofHippocrates and Galen can be traced to the writings of some 17th century clinicians,especially Thomas Willis. His exceptional skills in observation and description allow awindow into the experiencesofourmedical forebears. His approach to themanagementof infection-related coma in a child is amenable to modern interpretation andcomparison with modernmanagement because of the clarity of his clinical descriptions.Modern clinicians may benefit from this historical perspective into influences on theorigins of neuroscience. The different outcome for a child presenting in the 17th and21st century encourage grateful reflection on our current privileged position.Q 2004 European Paediatric Neurology Society Published by Elsevier Ltd. All rightsreserved.

Introduction

Thomas Willis (1621–1675) was Sedleian Professorof Natural Sciences at Christchurch Oxford and aFellow of the Royal Society. Described by Lord Brainas ‘the Harvey of the Nervous System’, he isremembered for his work in clinical neuroscienceand immortalized by the arterial anastamosis at thebase of the brain (the circle of Willis) whosefunction he described.1,2 Willis wrote widely inother areas of medicine. He clarified what wouldultimately be identified as the cranial, spinal,autonomic and peripheral nerves, which led acentury later to understanding the workings ofthese structures. His greatest contribution mayhave been not in anatomy but in creating the ideas

4 European Paediatric Neurolo

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k (A.N. Williams).

that led to the science of physiology and hence tounderstanding motor, sensory and higher corticalfunctions.

Willis created the concept and term ‘neurology’and possibly ‘psychology’. He introduced the ideaof reflex functions and gave this important subjectits initial syntax. He is responsible for replacing thecurrent Galenic concept of higher cerebral func-tions occurring by flux and flow residing in theventricles. His careful anatomical studies of nervebundles and the ganglia of the cerebrum, brainstem and cerebellum led to the realisation thathigher functions derived from the activities of theseneuronal structures.

Willis’ clinical work and hence his writings dealtprincipally with adults. Only recently have hismedical writings concerning children started toattract interest and for Willis to be regarded as apioneer of paediatric neurology.3,4 He made import-ant original contributions to the understanding of

European Journal of Paediatric Neurology (2004) 8, 307–312

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A.N. Williams, R. Sunderland308

conditions such as myasthenia gravisand (see below) infections of the nervous system.This paediatric practice led to realisation of theeffects of compression on the optic thalamus as acause of blindness and possible corpus striatumcompression in the pathogenesis of paralysis. Hisviews on corpus striatum compression so profoundlyinfluenced neurophysiological research that it wasnot until the second half of the 19th century that hisviews on the connections of the optic nerves withthe thalamus were followed up.5

Childhood coma is seen infrequently in routinemedical practice and remains a serious cause forconcern. Kirkham has recently reviewed themodern management of non-traumatic coma.6 Wepresent the history and post mortem findings ofcase of relapsing febrile coma described in detail byThomas Willis and offer a modern interpretationby reference to a recent case.

Seventeenth century childhood ‘palsey’

Willis in his Practice of Physick (a 1685 Englishtranslation of parts of his earlier works, which werewritten in Latin) after relating his experience inadults, in the chapter ‘On the Palsey’, relates thefinal illness of a three-year-old child. This boy hadbeen previously well, had a febrile illness with anapparent recovery after a week, subsequentlyfollowed by the development of paralysis and visualimpairment before falling into a terminal coma.Willis relates the history, his management, his vainattempts to save him and the subsequent postmortem.

“A child little more than three years of age, of amoist brain, as it appeared by sore inflammation ofhis eyes, and watery pushes of his face (to which hehad sometimes been obnoxious) at the beginning ofAutumn being ill, with a slow fever, and a dejectedappetite, became very drowsy and sleepy, so thathe slept almost continually day and night: but beingawakened he knew standers by, and answered aptlyenough to things asked.”

“That within six or seven days the diseased beingfree from his fever, waking sufficiently and desiringfood, seemed to recover and scarce to have anymore need of physical help. But in a short whileafter (I do not know on what occasion) undergoing arelaps, and being drowsie again, he was presentlyaffected with a great stupefaction, for that beingwith difficulty to be awakened, he scarce knewanything, or did any thing with knowledge: the nextdays after being utterly stupid tho being pinchedhard, he would open his eyes and roul them this

way, and that, he saw nothing: and within a day ortwo a palsey of the whole right side followed. Theformer remedies being prescribed to him. Didnothing: but the diseased after he had lain so fortwo or three days insensible, the Pulse andRespiration at length failing, he dyed.”7

Post mortem findings

“The scull being opened, the foremost region of thebrain, almost as far as the insertion of the fourthsinus, was swollen being covered with a limpidwater shining through the membranes, which uponthe dissection of the meninges presently flowedforth: moreover, at that place the portions of thebrain cut off by piece-meal appeared too moist, andalmost without red and bloody specks: but in thehindmost part of the brain the vessels were red withblood, and the cortical substance appeared morelow and firm without a tumour, or being floatedwith water: from these things (as we have con-cluded before) it will manifestly appear that thecause of the lethargy depends on a watery glut offilth in the outward part of the brain. The brainbeing cut off piece-meal, and a hole being madeinto the foremost cavity, sprouting with a lympha,the limped water sprung forth as tho it had beenpent up in too narrow a space before: whose mightstore had filled all the ventricles to the top, and (asit seemed) by compressing the Thalami Optici hadcaused the blindness, and by entering or compres-sing one corpus striatum, or its pores, had broughtthe Palsey. The Plexus Choroeides appeared asparboiled, somewhat white, and almost withoutblood, its probable that all the Lympha, or thegreatest part of it, wherewith the ventricles of thebrain were floated, distilled from those vessels: thoin this case (as some think) the watery latex sinkinglower from the cortex of the brain, at length havingwholly palsied the brain, could fall into thosesinuses a reason may not uneasily be thencetaken, therefore, the lethargy seeming first to becured, and by being more violent returned again,with a blindness and a palsey joined with it, to wit,as at first the store of soporiferous matter fell fromthe cortex of the brain into its cavity, the animalfunction grew a little clear: but afterward, when anew matter sprung in the cortex of the brain andthis falling into the sinuses was gathered togetherto a fullness, thereupon a relapse of the formerdisease happened with the addition of the blindnessand the palsy.

Now tho the dropsy of the inner part of the brain,or an inundation of its ventricles, by compressing

Recurrent cerebral fever in the seventeenth and twenty first centuries 309

the corpora striata or thalami optici causes a palseyor blindness or by twitching the origins of the nerves,convulsive affects: yet it most evidently appeared bya late observation, that the lethargy does not arisefrom such a cause, but only from the outward part ofthe brain being floated or compressed.”

One of the interesting aspects of this case isWillis’ concentration on the relationship of possiblecorpus striatum compression as the pathogenesis ofparalysis, and of the nearby optic thalamus as thesource of blindness. Willis postulated that thecorpus striatum was involved in both movementand sensation. Movement was mediated throughthe passage of animal spirits, which travelled onthrough the striatum and medulla, and on to theperipheral nerves. Willis speculates in this patientthat it is the impediment of these animal spirits thatleads to the paralysis and blindness.

The description of the child’s relapseand insensitivity to pain allow estimation of thecoma scale even after this great time. The clinicaldifferential diagnosis then and now would includesinusitis, preseptal periorbital cellulitis, tuberculo-sis and cerebral abscess secondary topneumococcal pneumonia. The ensuing course ofthese infections was (and remains)thrombophlebitis of a venous sinus and develop-ment of cerebritis or a subdural abscess—which is sopoorly contained as to form a subdural empyema.8,9

The likeliest organisms were and still areStreptococci or Staphylococci. Haemophilus andmeningococci do not usually follow this clinicalcourse. Although we cannot exclude tuberculosis, itis less likely given Willis’ description of theventricular contents as being ‘limpid water’.

The post mortem description of raised fluidpressure indicates the development of hydrocepha-lus. It may be of special significance given Willis’interest in the thalami and corpus striatum. Willis’final quoted paragraph indicates his interest in thedifference between ventricular dilatation (dropsyof the inner part of the brain) and cerebralinfarction (the outward part of the brain beingfloated or compressed). He writes confidently thatblindness arises from the former leading to com-pression of the optic thalamus (or corpus striatum)but lethargy only arises from the latter. The‘watery glut of filth’ in particular regions probablydelineates areas of cerebral infarction, secondaryto ischaemia and meningeal infection. The loss of‘red and bloody specks’ in parts of the brain thatwere ‘too moist’ is an apt description of infarctedautolysing cerebral substance. Then and nowcorrelation between structure and function can bemade from such observations. This child’s death

allowed further exploration of the origin of highercerebral functions.

A 21st century case (Birmingham 2001)

A 9-year-old girl presented with a 3-day history ofswelling of her left eye, fever with hallucinations,dysuria and abdominal pain. A few days earlier heryounger brother had hit her on the eye. When theeye became inflamed she was given oral co-amoxiclav by her GP. Approximately 12 h later,she was brought to casualty, where there wasswelling of the upper eyelid, full eye movements,no abnormality of the pupil reflexes and nodischarge from the eye. The abdomen was diffuselynon-specifically tender. The initial diagnosis wascellulitis involving the left upper eyelid andtemporal region. She was treated with i.v. cefur-oxime 60 mg/kg/day for 2 days then intravenousmetronidazole 22.5 mg/kg/day and flucloxacillin24 mg/kg/day (to cover possible anaerobes andStaphylococci) from days 3 to 8 when microbiologyadvice recommended using metronidazole andcefotaxime 200 mg/kg/day for 5 days followed by7 days oral co-amoxiclav 5 ml tds of 250/62 syrupand metronidazole 300 mg tds. Her haemoglobinwas 12.6 gm/dl, white count 4.6 with normaldifferential, electrolytes and liver function normalwith CRP 252 mg/l. Her temperature settled over-night but the swelling of the eye increased withpreservation of normal pupils reflexes and eyemovements. Late in this second day she began tohallucinate that a pop group were on the ward butwould not perform for her. Over the next day shedeveloped increasingly severe headache with neckstiffness and refused to drink because of sorethroat.

Imaging of the brain (Fig. 1) showed extensivepre-septal oedema of the left eye and cheek withextensive sinus disease bilaterally and destructionof the left ethmoid plate. There was a small area ofgas in the right forehead scalp and a small externalabscess in the right frontal area.

As she had already received i.v. antibiotics for 3days, surgical and microbiological opinion was thatlumbar puncture would not assist and carried asmall but significant risk of complications. Inkeeping with current practice, lumbar puncture(LP) was not done. We appreciate this is contro-versial as LP would have assisted in differentiatingmeningitis from meningismus and organisms mighthave been identified from gram stain.

ENT and Ophthalmic surgical opinion confirmedthe need for ethmoidectomy, which grew

Figure 1 MRI demonstrating extensive pre-septal oedema of the left eye and cheek, bilateral extensive sinus diseaseand destruction of the left ethmoid plate.

A.N. Williams, R. Sunderland310

Streptococcus anginosus, sensitive to penicillin,erythomycin and cefotaxime. The eye swellingresolved, the inflammatory markers settled (CRP38 mg/l, WBC 8.5!109/l) and her mental statereturned to normal. Ophthalmic and ENT reviewswere satisfactory and she was discharged home

Figure 2 MRI demonstrating loculated subdural em

after 13 days i.v. antibiotics with 7 days supply oforal coamoxiclav and metronidazole.

Three weeks later there was a gradual onset ofmild right-sided weakness of her upper arm with noother neurological abnormality and no fever.Because of the immediate past history the brain

pyema over the left frontal and parietal lobes.

Recurrent cerebral fever in the seventeenth and twenty first centuries 311

was scanned again (Fig. 2) which showed aloculated subdural empyema over the left frontaland parietal lobes.

These were drained via a left fronto-parietalcraniotomy and she had a further 1-week course ofintravenous cefotaxime 200 mg/kg/day and metro-nidazole 22.5 mg/kg/day. There was no re-accumu-lation on subsequent scanning, the inflammatorymarkers resolved (CRP 19 mg/l) and there was fullneurological recovery with no relapse after pro-longed follow up.

Twenty first century interpretation

Willis presents a fascinating window into childhealth long before the antibiotic age. Mortalitywas high and clinical medicine largely ineffective indealing with infectious disease. In neurologicalinfectious diseases morbidity and mortality remaintragically high despite antibiotics and safe inter-ventional surgery. Because of the clarity of hisclinical descriptions we are able to speculate on thelikely diagnosis for his 3-year-old patient. Willisclearly describes an obstructive hydrocephalus with

Figure 3 Section of the brain taken from Willis’ “De Animpermission from Birmingham University.

visual impairment and insidious coma. Withoutantibiotics and surgical drainage, obstructivehydrocephalus was a not uncommon consequenceof bacterial or mycotic meningitides, where thecerebro-spinal fluid flow is obstructed by adhesionsprecluding drainage. The causes were usuallyinfectious either blood borne, extension of middleear disease through the petrous bone or through theethmoid or frontal sinuses in the facial bones.Propagation of phlebitis into the vein of Galen orvenous sinus thrombosis secondary to pyogenicmeningitis also needs to be remembered. Thesediseases are still seen in the developing world anddeath is inevitable without modern treatments.

It is unclear whether Willis’ patient was blind orvisually inattentive. Blindness would indicatecavernous sinus thrombosis, damage to the visualpathways or occipital infarction. The relevance tothe development of Willis’s thinking and our under-standing of neurophysiology has been made above.

The white choroid plexus, ‘almost without blood’may have been due to an infectious fibrosis,phlebitis, ischaemia or secondary to compressionas a consequence of the hydrocephalus. The postmortem description confirms the appearances of

a Brutorum” 1672 (not from the patient discussed) with

A.N. Williams, R. Sunderland312

pyogenic adhesions leading to acute hydrocephalus.It is unclear whether the final insult was cerebralischaemia, massive infarction or tonsillar hernia-tion from a combination of cerebral oedema,hydrocephalus and accumulated ‘putrid wateryglut’. Our more recent case had a happier outcome(Fig. 3).

Conclusion

Non-traumatic childhood coma in childhood is aserious condition. Willis’ astute observations plusthe clarity of his clinical and post mortem descrip-tions enable us to gain understanding of thepathophysiology and natural progression of adisease which is now rarely seen in the developedworld. This case provides a fascinating window intoWillis’ thoughts concerning brain function andlocalization at a time when neuroanatomy wasbeginning to be defined and the first seriousattempts to understand functional cerebral local-ization were being made. These cases remind us ofour privileged position in history and the seriousimplications for continued indiscriminate or inap-propriate use of available therapies. We may findourselves equally powerless should micro-organ-isms develop widespread antibiotic resistance10 andexperience the tragic aspects of clinical practicethat Willis described with such humility and grace.

Acknowledgements

We would like to thank Dr Robert Rust MD for hiscomments, the library staff at the Cripps Postgradu-ate Medical Centre, Northampton and the Centrefor the History of Medicine, Birmingham.

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