After effects of bacterial meningitis and meningococcal disease: how

and why?

Dr Nelly Ninis

What happens in invasive bacterial infections

- Meningitis

- Septicaemia

- And afterwards

The Bacteria

Meningococcus

Pneumococcus

GAS

Pseudomonas / staphylococcus

Infection – the start

Viruses

Common colds

Flu

C’Pox

Toxins

Cause inflammatory explosion of immune system

More toxins in blood = worse disease

Antibiotics kill bacteria not toxins

Once toxins detonate the immune system – antibiotics, supportive care and time

SEPTICAEMIA

MENINGITIS

Prodrome

Cardiovascular failure

CNS failure

MD – disease development

Rash comes at some point

Meningitis

Complications

Brain swelling

Vessel ( vascular ) complications- stroke

Effusions

Obstruction of flow of CSF

Intracranial pressure

Septicaemia

Inflammation in the blood vessels throughout the body

Rapid onset multi-organ failure

Blood vessels are targetted

The Rash

Infection

Microbial Products(exotoxin/endotoxin)

Cellular Responses

OxidasesPlatelet

ActivationKinins

Complement

Coagulopathy/DICVascular/Organ System Injury

Multi-Organ Failure

Death

Endothelial damage Endothelial damage

CoagulationActivation

CytokinesTNF, IL-1, IL-6

Pathogenesis of Severe Sepsis: Inflammation/Coagulation are Linked

Table 3: Median times of onset of clinical features prior to hospital admission (redbars show age-specific median times of first presentation to a primary carephysician).

Age < 1 year Age 1 – 4 years Age 5 – 14 years Age 15 - 16 yearsHoursfromonset Median

(IQR)Median(IQR)

Median(IQR)

Median(IQR)

0 - 4 FeverMiserable/irritablePoor feedingNausea/vomitingDrowsySore throat/coryza

0 (0, 6)0 (0, 7)1 (0, 9)1 (0, 11)3.5 (0, 14)4 (0, 14)

FeverMiserable/irritableNausea/vomitingDecreased appetiteDrowsy

0 (0, 3)2 (0, 10)3 (0, 11)3 (0, 12)4 (0, 11)

HeadacheFever

0 (0, 12)3 (0, 12)

HeadacheSore throat/coryza

0 (0, 1.5)0 (0, 10)

DiarrhoeaAbnormal colourRespiratory distressFloppy toneLimb pain

5 (0, 9)5 (0, 18)6 (0, 16)6 (1, 19)7 (1, 19)

5 - 8

RashCold extremities

8 (3.5, 16)8 (1, 20)

Limb/joint painSore throat/coryzaRespiratory distressHeadacheAbnormal colour

5 (0, 12)7 (1, 16)7 (1, 17)7 (1, 22)8.5 (4, 18)

Abnormal colourDecreased appetiteSore throat/coryzaLimb/joint painGeneral aches

5 (0, 22)5.5 (1, 17)7 (0, 15)7 (0, 15)7 (1, 18)

General achesFever

5.5 (0, 19)6 (1, 13)

General achesRashCold extremitiesGeneral achesSeizure

9 (4, 17)9 (6, 16)9 (2, 17)9 (4, 17)9 (1, 18)

9-12

DiarrhoeaPhotophobiaConfusion/delirium

10 (6, 14)10 (6, 26)10.5 (5,17)

DrowsyCold extremitiesMiserable/irritableConfusion/delirium

9 (1, 21)11.5 (6, 21)12 (3, 21.5)12 (8, 24)

Nausea/vomitingDecreased appetiteLimb/joint painDiarrhoea

9 (3, 19)10 (3, 23)11 (3, 22)12 (8, 24)

Rash 14 (8, 21)13-16 Neck stiffnessPhotophobiaUnconsciousBulging fontanelle

13 (3, 22)13 (5, 18)15 (11, 15)16 (4, 22)

FloppyNeck stiffness

13 (8, 19)13 (8, 20)

Neck stiffness 15 (7, 25)

Miserable/irritableNeck stiffnessCold extremitiesDrowsyAbnormal colourRespiratory distress

13 (2, 23)13 (6, 25)14 (6, 27)14 (7, 24)15 (1, 24)15 (13, 16)

Rash 18.5 (12,27)

17-20 Seizure 17 (15, 32) PhotophobiaDiarrhoea

17 (5, 37)20 (20, 25)

21-24 Unconscious 23 (17, 43) Unconscious 21(13.5, 49) PhotophobiaConfusion/deliriumSeizure

21 (8, 38)24 (13, 28)24 (24, 27)

>24 SeizureRespiratory distress

24.5 (8, 66)35 (20, 44)

Unconscious 25 (17, 37)

Treatment

© Imperial College London

Treatment

Management of meningococcal disease 1940–1980s: Penicillin and pray

Recognition of rash

Penicillin

Counsel parents

Hope and prayer

© Imperial College London

Purpura Fulminans

Topical treatments

Fasciotomies

Anti-toxins

Anti- clotting

NOTHING WORKS

After Effects

Cohort study of children aged 3-16 years with MD admitted to 3 PICUs and 22 general paediatric wards in the London area

Parents and children seen 2-5 days following hospital admission, and followed up following discharge at 3 months (postal questionnaire) and 12 months (interview)

Psychiatric risk assessed in children (SDQ), parents (GHQ) and both (IES)

Sample

70/78 (89%) (36 boys; 34 girls) consecutive admissions for meningococcal disease

52 PICU

18 Non-PICU

Median age at follow-up: 6.8 years

(IQR: 4–12 years)

Psychiatric assessment of children 3–16 years admitted with meningococcal disease, London

Summary: 50% of children develop mostly new psychopathology following MD (primarily depressive and anxiety-related disorders). In 25% this persisted at one year.

Outcomes in children and parents, 3 months and 12 months post discharge

Children < 6y Children >6y Parents

3 monthspost discharge

12% had PTSD

Psychological symptoms linked to: PICU admission, illness severity, similar symptoms in parents and pre-morbid psychological symptoms

MD associated with emotional and hyperactivity symptoms

~50% mothers and ~25% fathers had PTSD symptoms

12 monthspost discharge

11% children at risk for PTSD

Psychological symptoms linked to illness-related changes in parenting

23% mothers and 11% fathers at high risk for PTSD

Maternal PTSD linked to paternal PTSD

1 child developed PTSD

22% scored above cut-off for psychiatric disorder

Problems: tantrums, difficult to manage, sleep problems, fears and feeding problems

50% at least one disorder15% major depression10% minor depression7% adjustment disorder10% oppositional defiant disorder5% phobic disorder2% panic disorder2% transient psychotic disorder

Psychological after effects in children and their parents

Garralda ME, et al. Pediatr Crit Care Med. 2009;10(6):675-80; Shears D, et al. J Am Acad Child Adolesc Psychiatry, 2007;46(1):76-82; Shears D, et al. Pediatr Crit Care Med. 2005;6:39-43.

Admission to Paediatric Intensive Care

Major stressful event for child and their family

Families experience overwhelming shock and disbelief, accompanied by feelings of helplessness

Parents faced with worries about outcome of treatment and acute life-threatening illness in their child

PICU experience is intense—sights and sounds in the environment, and seeing other children undergo painful, distressing procedures or even death

PICU admission imposes an immense burden on critically ill children, their siblings, parents and other family members, potentially increasing risk of adverse psychological outcomes

Clinical evidence of neuropsychological effects

Prospective observational case-control study of 88 children aged 5-16y admitted to ICUs between 2007-2010 c.f. 100 healthy controls

Follow-up 3-6 months after PICU admission

Demographic and critical illness details were obtained, and children were assessed using tests of intellectual function, memory, and attention

Questionnaires addressing academic performance were returned by teachers

Measurement tools IQ:

Wechsler Abbreviated Scale of Intelligence (WASI; The Psychological Corporation, 1999) – 6 yrs and older

Wide Range Intelligence Test (WRIT; Glutting et al) – 5 yr olds

Verbal memory and learning: Children’s Memory Scale (CMS; Cohen, 1997)

Visual memory, learning and attention: Cambridge Neuropsychological Test Automated Battery (CANTAB; Cambridge Cognition, 2006)

Psychiatric risk

0

10

20

30

40

50

60

70

% at risk for PTSD

Septic Illness M-Encephalitis

Patient Ctr

PTSD risk

Neuropsychologic function after PICU admission

Cognitive function

Als LC, et al. Crit Care Med. 2013;41(4):1094-1103.

• Summary: Meningoencephalitis and sepsis particularly associated with reduced neuropsychological function

Deteriorating academic performance in school post PICU (Sepsis worst performance)

Number of days off since returning to school 11.50 ME 9.00 Sepsis 6.00 Patient Contr

Als LC, et al. Crit Care Med. 2013;41(4):1094-1103.

Conclusions from this studyAls LC, et al. Crit Care Med. 2013;41(4):1094-1103.

In children with sepsis, meningo-encephalitis and other disorders admitted to PICU:

PICU admission was followed by an increase in child psychopathology persisting at 12 months

Children with more severe illness, those with septic shock and those with impairing pre-morbid emotional and behavioural problems have the highest risk

Changes in parenting and maternal mental health may contribute to the persistence of the psychological morbidities and may be potentially treatable

What is known about the outcomes of meningitis?

CNS infections acquired in childhood lead to impairment in motor and cognitive functions (Carter et al. 2003)

12-year follow-up of children with bacterial meningitis found general performance and executive function impairments in comparison to controls (Anderson et al. 2004)

Academic limitations identified in 32% children 4–10 years following bacterial meningitis (Koomen et al. 2005)

Teenagers from national incidence study of infantile meningitis in England & Wales passed significantly fewer 16+ exams compared with controls (De Louvois et al. 2007)

Long-term outcomesSurvivors of meningococcal septic shock that required PICU treatment

Long-term skin scarring & orthopaedic sequelae

n=170, 4-16 years after discharge

Long-term overall outcome and health-related QoL

n=120, 3-18 years after discharge

Long-term health status

n=120, 10 years after discharge

48% scarring61% (73 of 120) had 1 of 4 major adverse outcome variables

35% one or more neurological impairment

8% amputations26 of 73 had >1 major adverse outcome

3% severe mental retardation

6% lower limb length discrepancy

47 of 73 had 1 major adverse outcome

• 13 major physical• 19 mild neurological• 7 problem behaviour• 8 IQ<85

3% epilepsy

All had higher severity of illness scores

Longer LOS and higher severity score predicted worse outcome

2% hearing loss

6% focal neurology (i.e. paresis)

Buysse CMP, et al. Arch Dis Child 2009;94:381–386.

Buysse CMP, et al. Crit Care 2010;14:R124.

Buysse CMP, et al. Arch Pediatr Adolesc Med 2008;162(11):1036-1041.

245 survivors of group B meningococcal disease (3 years after disease)

Age and sex matched healthy controls 2% profound bilateral SNHL 5% moderate bilateral SNHL 6% any SNHL (control < 1%) 4% speech/communication difficulty IQ, memory and executive function significantly worse Significantly higher risk of mental health disorder

(26% vs 10% in controls)

Lancet Neurol 2012;11:774–783.

Outcomes in adolescents

Outcomes from MD - 2003

Cohort of 101 case-control pairs

Short and long term memory and attention deficits

Deficit in cognitive flexibility Higher rates of depression in MCD sufferers This should be attended to in follow up

18 , 36 month follow up of cohort

57% of survivors had physical disability- much higher than studies with younger children

- Serogroup C disease, septicaemia had worse physical outcome

Adolescents who were younger at time of MD- greater degree of cognitive deficit at follow up

- Development of “social brain” in adolescence

QoL worse than peers

• Mental Health – twice as many survivors had depressive score in clinical range

• Social support – lower social support scores

• Educational outcomes- fewer passes at GCSE, 2x more likely to have failed exam in past year

Wide range of significant sequelae from Invasive Meningococcal Disease

1. Singhi PD, et al. In: Helfaer MA, et al, eds. Rogers’ Handbook of Pediatric Intensive Care. Philadelphia, PA: Lippincott, Williams & Wilkins; 2009:500-519; 2. Brandtzaeg P. In: Frosch M, et al, eds. Handbook of Meningococcal Disease: Infection Biology, Vaccination, Clinical Management. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA; 2006:427-479; 3. Granoff DM, et al. In: Kleigman RM, et al, eds. Nelson Textbook of Pediatrics, 19th ed. Philadelphia, PA: Saunders Elsevier; 2011;929-935; 4. Judge D, et al. Intensive Care Med. 2002;28:648-650; 5. Anderson V, et al. J Pediatr Psychol. 2004;29:67-81; 6. Bedford H, et al. BMJ. 2001;323:533-536.

Subacute and Chronic Sequelae of IMD Hearing loss/deafness Ossification of the inner ear Blindness Brain abscess Seizure disorders/epilepsy Cranial nerve palsies Hemiparesis or quadriparesis Obstructive hydrocephalus Neuropsychiatric disorders

Post-traumatic stress disorder Learning deficits Motor deficits/ataxia Neurodevelopment deficits Cerebral infarction/stroke Cerebral arterial or venous thrombosis Subdural effusion

Limb loss Digit amputation Growth plate damage Skin grafts/scar repair Necrotic skin loss Arthritis Renal impairment Chronic organ damage Adrenal failure Cognitive impairment Nonsuppurative complications—eg,

immune complex disorders, vasculitis, arthritis

Empyema Endocrinopathies

Some sequelae do not become evident until years after the illness, long after routine follow-up has ceased.

In Conclusion

Surviving sepsis and meningitis is difficult business

Patients are very inspiring and capable and able

Education about after effects very important

Thank you