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Ketogenic diet in the management of epilepsy

The ketogenic diet (KD) is a therapeutic diet, which has been shown to improve seizure control in patients with drug resistant epilepsy.

The KD is also used to treat the  metabolic conditions: GLUT1 (glucose transport protein deficiency) and PDH (pyruvate dehydrogenase deficiency).

The treatment of metabolic conditions with the ketogenic diet is not currently provided by the Great Ormond Street Hospital Ketogenic Diet Team.

This diet requires the close supervision of a paediatric neurologist, or a paediatrician with a special interest in epilepsy, and a dietitian trained in the use of diets for epilepsy.

Different forms are currently supported by this service:

  • the classical KD (fat: protein + carbohydrate ratio)
  • the medium chain triglyceride diet  (MCT diet)
  • the Modified Atkins Diet (MAD)
For further information about clinical aspects and anticonvulsant mechanisms see References 2-10 and especially References 4 and 5.

 

Background

Indications and patients eligible for the service

Referrals are generally accepted from consultant paediatricians/paediatric neurologists based at Great Ormond Street Hospital or North London hospitals (patients are resident in North London).

In exceptional circumstances, referrals to the service may be accepted for children who live outside North London when  the KD cannot be provided locally.

Feeding difficulties, dysphagia and significant gastro-oesophageal reflux are relative contraindications and should be appropriately managed prior to starting the diet. These problems  should be addressed before the patient is referred to the ketogenic diet service.

The ketogenic diet is indicated:

  • For those patients whose seizures fail to respond to antiepileptic medication (at least two antiepileptic medications in therapeutic doses).
  • For certain epilepsy syndromes early in their course:
    • Lennox-Gastaut syndrome
    • Myoclonic-astatic epilepsy (Doose syndrome)
    • Dravet syndrome (severe myoclonic epilepsy in infancy)
    • Infantile spasms/West syndrome
    • Symptomatic epilepsies if epilepsy surgery is not indicated, eg tuberous sclerosis, bilateral cortical malformations or diffuse bilateral brain injuries
  • For children with the metabolic disorders:
    • Glucose transporter 1 (GLUT 1) deficiency
    • or pyruvate dehydrogenase (PDH) deficiency
  • For patients who have intolerable and/or severe side effects from antiepileptic medication.
The ketogenic diet is contraindicated, or caution should be exercised for those with:

  • fatty acid oxidation defects
  • organic acidurias
  • diagnosis of diabetes mellitus
  • hypoglycaemia under investigation
  • familial hyperlipidaemia
  • severe gastro oesophageal reflux
  • feeding difficulties or food refusual

Initiating the ketogenic diet

The diet is usually initiated in an outpatient setting with the exception of young children (<1 year old) who may be admitted to the GOSH neurology ward for three to five days to start the day.

The ketogenic diet is initiated by the specialist paediatric dietitian and clinical nurse specialist (appendix 1).
   
The family’s expectations for outcomes of the ketogenic diet are discussed before starting the dietary treatment (appendix 2).

Before the diet is commenced, a three-month commitment to try the ketogenic diet is obtained from the family.

Ideally no medication changes should be made during the diet inititation phase (first three months).

During fine tuning phases of the diet, changes to medications should also be avoided.

Children are not fasted to induce ketosis when the diet is started.

All diets are introduced gradually over time to aid tolerance.

Follow-up and ongoing monitoring of the diet

A multidisciplinary follow-up clinic is held each month and is attended by the neurology consultant (and/or clinical fellow or specialist registrar), specialist dietitian and clinical nurse specialist. Children are reviewed in this clinic three and six months after initiation of the diet, and then six-monthly.

If clinically indicated children may be reviewed in clinic more frequently, such as young children (<1 year), children at nutritional risk, or those having difficulties with the diet.

In between outpatient clinics, ongoing contacts with families by the specialist dietitian and clinical nurse specialist are required to ‘fine tune’ or modify the diet. Where possible these follow-ups are conducted as telephone consults.

Blood monitoring and urinalysis is carried out before the diet is initiated and then six-monthly (or more frequently as clinically indicated)  (see appendix 3: investigation and lab surveillance form).

Growth should also be closely monitored.

Side effects of the ketogenic diet

The following need to be monitored by the medical team. Many side effects can be avoided or alleviated by manipulation of the diet. Discuss with the KD team.

  • elevated serum lipids
  • constipation
  • vomiting
  • diarrhoea
  • exacerbation of gastro-oesophageal reflux
  • renal stones
  • poor growth
  • excess ketosis and acidosis
  • drowsiness
  • increased bruising
  • psychosocial food refusal
  • increased risk of fractures
(Reference 5)

Exacerbation of seizures on the ketogenic diet

In some cases, seizures can change or increase in frequency for a few days after starting the diet whilst the brain is changing to using ketones for energy. The child may present with what appears to be non convulsive status.

  • If the child is unwell with worsening of seizures, check the ketones in the urine.
  • Emergency treatment can be given as normal when on the KD eg rectal diazepam, buccal midazolam.
  • Screen for infections (if appropriate: urine culture, chest X-ray etc)
  • If considering making changes to anti-epileptic drugs, please discuss with the KD team.

Medication and the ketogenic diet

Ideally no medication changes should be made during the first three months when the diet is being initiated. During fine tuning of the diet, changes to medications should also be avoided.

Medications should be as low as possible in carbohydrate.

Extra carbohydrate in medications can interfere with the diet. Formulations of some medications may need to be changed when the diet is initiated.If new medications are added the carbohydrate content should be considered. Discuss this with the ward pharmacist and the dietitian (see appendix 4 for further information on medications and the ketogenic diet).

GOSH inpatients on the ketogenic diet

Medical and nursing staff on the wards may have to care for patients on the ketogenic diet in the following circumstances:

  • Admission for initiation of KD diet under specific circumstances (routine for children under one year).
  • Admission for elective procedures under general anaesthetic (surgery, or other investigations).
  • Emergency admission because of status epilepticus or a relapse of the underlying condition.

Guidelines for management of complications of the ketogenic diet

The following links give guidelines to management of:

Complications:

Excess ketosis

Ketones are measured either by testing urine (acetoacetate) or blood (beta hydroxybutyrate).

The aim is to achieve values in the following ranges:

  • If testing urinary ketones: 8-16mmol/L (tested using Ketostix® (Bayermeasures acetoacetate))
  • If testing blood ketones: 4-6 mmol/L (tested using Optium Xceed® (Abbott) blood glucose meter (also able to test ketones measures beta hydroxybutyrate))
NB: Some children may show signs of excess ketosis with levels lower than those above.

Occasionally ketone levels can become too high. This may occur after starting the diet, if the diet has recently been modified or during illness.

The signs of excess ketosis may include:

  • rapid, panting breath (‘Kaussmaul’ breathing)
  • increased heart rate
  • facial flush
  • irritability
  • vomiting  
  • unexpected lethargy
NB: Excess ketosis may also mimic non convulsive status as the children are often less responsive.

Diagnosis

The above symptoms may be related to excess ketosis if:

  • Urinary ketones (acetoacetate) are 16+ and test strip changes to a deep purple straight away.
  • Blood ketones (beta-hydroxybutyrate)  > 6 mmol/L.

Treatment

The aim is to provide some carbohydrates to stop excess ketosis.

Give 15-30ml of pure fruit juice.

If the symptoms have not improved after 15-20 minutes, this should be repeated. It may be necessary to alter the diet ratio if ketone levels are persistently excessive and the child is symptomatic (liaise with the dietitian).

Fluids (fruit juice) are in most cases sufficient to correct excess ketosis and improve symptoms.

In exceptional cases if children are unwell and do not tolerate oral fluids because of excessive vomiting intravenous fluids as 2.5% or 5% dextrose/saline, given as maintenance fluids, are required.

These children will require:

  • Hospital admission and anurgent clinical medical evaluation. Investigations should include: urea, creatinine, electrolytes, glucose, capillary blood gas and infection screen as appropriate.

Metabolic acidosis

A patient who is taking Topiramate, Zonisamide or Acetozalomide will be more at risk of developing metabolic acidosis, as the pH of their blood may be decerased.

Treatment with bicarbonate is rarely required.

Symptoms

  • increased seizures
  • clamminess and pale skin
  • confusion
In severe forms ‘Kaussmaul’ breathing (increased rate and depth of breathing).

Diagnosis: aim to establish underlying cause

  • excess ketosis
  • effect of antiepileptic medication: Topiramate, Zonisamide, and Acetozolamide
  • infection and dehydration
  • other metabolic causes
Check blood gas (capillary), urea, creatine, electrolytes, bicarbonate, glucose, and ketones (urinary ketones or blood ketones - for measurement and abnormal values  see excess ketosis).

  • If ketones are excessively increased follow management under excess ketosis, diet manipulation (to be initiated by dietitian). Consider increasing daily caloric intake or reducing the ratio of the diet.
  • Treat dehydration adequately with fluids (sugar free squash orally or normal saline (0.9% NaCl) if IV fluids if oral hydration is not tolerated).
  • Investigate for infection/sepsis as in clinically indicated and manage accordingly.
  • Consider other other causes of metabolic acidosis – test lactate – and consider discussion with metabolic team.
  • Consider reduction/withdrawal of the Topiramate, Zonisamide or Acetozalomide. Discuss with the ketogenic diet team.

Emergency management of symptomatic hypoglycaemia or blood glucose (BM) < 2.5 mmol/L

Definition of symptomatic hypoglycaemia: low glucose levels that are associated with abnormal clinical manifestations.

Signs and symptoms

Due to counter regulatory sympathetic response:

  • anxiety
  • perspiration
  • pallor
  • palpitations (tachycardia)
  • tremulousness
  • weakness
  • nausea
  • vomitting
  • hypothermia

Due to cerebral glycopenia:

  • headaches
  • confusion
  • irritability / fussiness
  • behavioural change
  • dysarthria
  • ataxia, incoordination
  • hypotonia (infants),
  • dizziness
  • amnesia
  • somnolence, lethargy
  • apnoea (infants)
  • seizures
  • coma
  • stroke, hemiplegia, aphasia
Adapted from Sperling M A, in Nelson Textbook of Pediatrics, Eds. Behrman RE, Kliegman RM, Lenson HB, Chapter 88, pp439-450, 16th edition, 2000.

B.H. Dekelbab and M.A. Sperling, Hypoglycemia in newborns and infants, Adv Pediatr 53 (2006)

Check blood sample/lab sugar and treat if appropriate as below.

Management of symptomatic hypoglycaemia

Treating hypoglycaemia using rapidly absorbed carbohydrate

  • 100ml of NON DIET Coca Cola®
  • 55ml of Lucozade®, Energy Original
  • 100ml of pure fruit juice
  • 2tsp of sugar, ordinary jam, honey or syrup
  • 10g (two level teaspoons) Dextrose powder in 100ml water (dextrose available from GOSH Pharmacy).
If the response to the above treatment is inadequate, more can be administered after 10-15 minutes.
Treating hypoglycaemia using Glucogel® (formerly known as Hypostop)

Give Glucogel® (BBI Heakthcare) (10g glucose per 25g tube).

Or Dextrogel® M & A Pharmachem) (10g glucose per 25g tube). This can be squeezed into the child’s mouth if the child is uncooperative or not able to take the items suggested above.

(Information for treatment of hypoglycaemia from 2010-2011 British National Formulary for Children).
For patients with reduced consciousness level or/and seizures
Give 5 -10ml/kg 10% dextrose intravenously according to UK Resuscitation Council guidelines (Paediatric Immediate Life Support, revised edition April 2008, Resuscitation Council (UK), ISBN 9781903812181). 

Children established on the ketogenic diet presenting with intercurrent or gastrointestinal illness

  • If child is unwell: clinical medical assessment and urgent bloods to include full blood count (FBC), urea, creatinine, electrolytes, bicarbonate, blood gas, lactate, liver function tests, blood or urinary ketones, infection screen (urine for microbiology, chest X-ray, blood culture etc).
  • Check blood glucose levels two- to four-hourly if children are unwell, especially if nil by mouth (note that if the child is ketotic, blood sugar may be low but still acceptable, ie > 2.5 mmol/L.
  • If the child is asymptomatic see clinical manifestations of hypoglycaemia under symptomatic hypoglycaemia and excess ketosis.

  • Emergency management of symptomatic hypoglycaemia or BMs <2.5mmol/L.

  • Check blood sample lab sugar and give emergency treatment if required (see management guidelines for symptomatic hypoglycaemia for further information).
  • Test urine for ketones every time child passes urine.
  • Rehydrate with low carbohydrate clear fluids if tolerated orally eg water or sugar-free squash. Dioralyte® can also be used if necessary.
  • If IV fluids are required use normal saline (0.9% NaCl)
  • or if BMs < 3mmol/L - 2.5% or 5% dextrose/saline solution to maintain BMs between 3 and 4 mmol/l.
If considering making changes to anti-epileptic medications, please discuss with the KD  team.

  • Where possible avoid sugar and carbohydrate containing drugs. If you are unsure of the carbohydrate content of medications, you should contact the ward pharmacist or GOSH Medicines Information (extension 8608) (see appendix 3 for further information on medications and the ketogenic diet).
  • Consider contacting the KD team if further advice is needed (see appendix 5: contact details for the GOSH Ketogenic Diet team).
  • Reintroducing ketogenic diet after illness. If the ketogenic diet has had to be stopped because of an illness, aim to regrade back onto ketogenic diet as soon as possible (liaise with the KD dietitian for advice).
  • Some children may have a ketogenic meal replacement recipe which may used as an alternative to solid food when a child is unwell. A ketogenic formula feed, Ketocal® is available for use with tube feeds.The amount of Ketocal given needs to be individualised for each child (please liaise with the KD dietitian for advice).
  • If the child has a gastrointestinal illness, consider reducing the fat portion of the diet initially and gradually increasing this back up as tolerated over three to four days.

'Nil by Mouth’ Status (NBM)

[Adapted from: The Charlie Foundation. 2007, Professional’s Guide to the Ketogenic Diet (Reference 2)]

The high fat diet regimen of the ketogenic diet (70-90% of calories) forces the body into a dietary induced ketosis. The acidosis that occurs when the diet is first initiated corrects itself with days and is not sustained.

The literature on ketogenic diet and general anaesthetic is scarce, with very little consensus on management. The most comprehensive study undertaken so far suggests that carbohydrate-free solutions are safe and blood glucose remains stable throughout surgical procedures up to 1.5 hours. The most common effect noted in procedures > three hours was a significant decrease in pH, requiring IV bicarbonate. Current advice suggest therefore monitoring blood pH in procedures > three hours and administering IV bicarbonate where necessary (Reference 9).

Sedation for procedures including general anaesthetic

  • Inform KD team of patient's admission.
  • Test urine for ketones every time child passes urine.
  • Take bloods: full blood count (FBC), urea, creatinine, electrolytes, bicarbonate, liver function tests, urinalysis, blood gas, glucose, lactate.
  • General anaesthetic: Keep NBM for normal recommended time period (food - six hours/clear fluids - two hours).
  • If IV fluids are required give normal saline (0.9% NaCl) or Ringers lactate at appropriate rate.
  • If anaesthetic is > 3 hours monitor blood glucose and blood gas (pH and bicarbonate) one- to two- hourly. Consider IV bicarbonate if increase in acidosis.
  • If fasting beyond 12 hours or blood glucose < 3 mmol/L use dextrose containing solutions (i.e. 2.5% or 5%) to maintain blood glucose between 3 and 4 mmol/l.
  • Continue IV normal saline until oral fluids tolerated.
  • Re-introduce normal (ketogenic) diet as soon as possible. Please contact KD dietitians to discuss a suitable diet, or if nasogastric tube or gastrostomy are required, the type of formula to be given.
Where possible, avoid sugar and carbohydrate containing drugs and IV solutions. Contact ward pharmacist or GOSH Medicines Information (extension 8608) for advice about preparation with lowest carbohydrate content (see also appendix 4).

Children on the ketogenic diet admitted to PICU

  • Inform KD team of patient's admission (see appendix 5 for contact details).
  • Intravenous fluids: use normal saline (0.9% NaCl) or Ringers lactate, unless blood glucose levels are low (< 3 mmol/l).If low then give dextrose / saline solutions (2.5% or 5%), aim to maintain blood glucose between 3 and 4 mmol/l.
  • Monitor for hypoglycaemia and metabolic acidosis: blood glucose levels and blood gas one- to two- hourly as appropriate.
  • Investigations should also include measurement of ketones (urine or blood - see excess ketosis), excessive ketosis and acidosis may require treatment with iv bicarbonate
  • A base excess of -10 indicates significant metabolic acidosis and should be half corrected over four hours with intravenous bicarbonate.
    • If acidosis is explained by excess ketosis, dextrose containing maintenance fluids (2.5% or 5 % dextrose) would be appropriate.
    • If acidosis is not completely explained by excess ketosis ie high blood lactate this could be discussed with the Metabolic team (choice of maintenance fluids (normal saline/saline).
  • Medication: must be in lowest carbohydrate form. Contact pharmacy (GOSH medicines information, extension 8608) to check carbohydrate content of preparations, see appendix 4 for further information on medications and the ketogenic diet.
  • Enteral feeding: please contact KD dietitians to discuss the type of formula to be given by nasogastric tube or gastrostom.

Vitamin D and the ketogenic diet

It is not uncommon for children starting on the ketogenic diet or whilst on the diet to have low 25- Hydroxy VItamin D (25OHD) serum levels. It is recommended to check 25OHD levels at baseline (prior to starting on the diet) and at least six-monthly when on the diet.

Serum total hydroxyvitamin D interpretation (taken from GOSH lab reference ranges, August 2009):

At GOSH normal ranges for 25-hydroxy vitamin D (25OHD) are considered to be 50-120nmol/L.                   

  • deficiency < 12.5 nmol/L
  • vitamin D insufficiency 12.5 - 50 nmol/L
  • vitamin D adequate 50 - 140 nmol/L
Total vitamin D is the sum of the 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.

All patients on the diet should be on a maintenance amount of vitamin D of 200 - 400 IU daily (5-10 micrograms). 

Treatment of low 25-hydroxy vitamin D (25OHD ) levels

Treatment is of low levels is indicated for levels < 50 nmol/l.

Treatment of D deficiency/insufficiency should be with cholecalciferol.

This is best administered as the Martindale solution which contains 3000U/ml given according to doses suggested below for three months following which the 25-hydroxy Vitamin D level should be checked.

Dosages: Dose is age dependent in a broad sense.

  • Infants (<1year) 1500 U daily = 0.5ml/day of 3000U/ml Martindale solution 
  • Children 3000 U daily = 1ml/day of 3000U/ml Martindale solution
  • Older children/adolescents  6000 U daily = 2ml/day of 3000U/ml Martindale solution

Acknowledgement

We thank the ketogenic diet team based at the Evelina Children's Hospital (under the medical lead of Ruth Williams, Consultant Paediatric Neurologist), Guy's and St Thomas NHS Trust, London for allowing us to use their ketogenic diet service guidelines as a starting point to develop these guidelines. We are also grateful to Prof P Clayton (UCL Institute of Child Heath) and Dr Nitish Vora for their helpful comments.

References

Reference 1:
Evelina Children's Hospital (2006/7) The Ketogenic Diet (KD) for Children - Ward and Outpatient Clinic Guidelines. Evelina Children's Hospital

Reference 2:
The Charlie Foundation (2007) Professional's Guide to the Ketogenic Diet. Protocols for initiation and management. The Charlie Foundation.

Reference 3:
Freeman JM, Kossoff EH, Freeman JB, Kelly MT. (2006) The Ketogenic Diet: a treatment for Children and others with Epilepsy. Demos Medical Publishing.

Reference 4:
Bough KJ, Rho JM (2007) Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48 (1): 43-58.

Reference 5:
Hartman A L, Vining E P G. (2007) Clinical Aspects of the Ketogenic Diet. Epilepsia: 48(1): p31-42.

Reference 6:
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH (2008) The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7 (6): 500-6.

Reference 7:
Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH (2009) A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50 (5): 1109-17.

Reference 8:
Neal EG, Chaffe HM, Edwards N, Lawson MS, Schwartz RH, Cross JH (2008) Growth of children on classical and medium-chain triglyceride ketogenic diets. Pediatrics 122 (2): e334-40.

Reference 9:
Valencia I, Pfeifer H, Thiele EA May; (2002 ) General anesthesia and the ketogenic diet: clinical experience in nine patients. Epilepsia. 43(5): 525-9.

Reference 10:
Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP ( 2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 50(2: 304-17.

Document control information

Lead author(s)

Christin Eltze, Consultant Paediatric Neurologist, Neurology

Additional authors
Georgina Fitzsimonns, Senior Dietitian, Dietetics
Marian Sewell, Senior Dietitian, Dietetics
Hannah Chaffe, Clinical Nurse Specialist, Neurology

Document owner
Christin Eltze, Consultant Paediatric Neurologist, Neurology

Approved by
Clinical Practice Committee

First introduced: 13 November 2009
Date approved: 22 February 2012
Review schedule: Two years
Next review: 22 February 2014
Document version: 2
Replaces version: 1

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