• Carbohydrate consumption is limited to deplete carbohydrate stores
• Fats are subsequently metabolised instead of carbohydrates
• Mitochondrial beta-oxidation transforms fatty acids into ketone bodies
• Ketone bodies (acetone, acetoacetate, and beta-hydroxybutyrate) accumulate in the blood, urine, and CSF
• This process affects seizure onset and propagation, and in many cases, leads to reduction or cessation of seizures

• Tegretol is an enzyme inducer and therefore can lower valproate and phenytoin levels.
• It will also reduce the efficacy of the oral contraceptive pill.
• Avoid macrolides – particularly erythromycin – as it can alter carbamazepine levels and cause toxicity, including hyponatremia.
• Research has shown an increased risk of SJS in people of Han Chinese ethnicity with the HLA-B1502 allele. Care should be taken when considering carbamazepine in this population and HLA-B1502 testing is recommended before starting the drug in particular ethnic populations (Han Chinese, Filipinos, Malaysians, South Asians Indians, and Thai). 

The HLA testing in New South Wales can be done via a blood test using the Immunogenetics Request Form.

The choice of the type of Ketogenic Diet prescribed for each individual patient depends on multiple factors including the underlying condition, the age of the patient, their capacity for oral intake and their food preferences.

• The Classical Ketogenic Diet uses fixed ratios of fat to carbohydrate/protein. A 4:1 ratio, for example, uses four grams of long-chain fat to each gram of carbohydrate and protein combined.
• The Medium Chain Triglyceride Diet uses medium-chain triglycerides such as MCT oil, Liquigen, or Coconut Oil.
• The Modified Atkins Diet has somewhat greater flexibility than the Classical Ketogenic Diet and allows greater amounts of protein.
• The Low Glycaemic Index Diet attempts to achieve stable blood glucose levels.
• All of these diets require close monitoring and need to be carried out under medical and dietary supervision.

>70% seizure reduction in at least three publications from at least two KD centres:

• Angelman syndrome
• Complex 1 mitochondrial disorders
• Dravet syndrome
• Epilepsy with myoclonic–atonic seizures (Doose syndrome)
• Glucose transporter protein 1 (Glut-1) deficiency syndrome
• Febrile infection-related epilepsy syndrome (FIRES)
• Infantile spasms
• Ohtahara syndrome
• Pyruvate dehydrogenase deficiency (PDHD)
• Super-refractory status epilepticus
• Tuberous sclerosis complex

50% seizure reduction or limited single centre evidence:

• Adenylosuccinate lyase deficiency
• CDKL5 encephalopathy
• Childhood absence epilepsy
• Cortical malformations
• Epilepsy of infancy with migrating focal seizures
• Epileptic encephalopathy with continuous spike-and-wave during sleep
• Glycogenosis type V
• Juvenile myoclonic epilepsy
• Lafora body disease
• Landau-Kleffner syndrome
• Lennox-Gastaut syndrome
• Phosphofructokinase deficiency
• Rett syndrome
• Subacute sclerosing panencephalitis (SSPE)

The efficacy of the KD depends upon the underlying condition - average efficacies are listed below:

• Up to 10% of the patients may become seizure-free.
• Reduces seizure frequency by more than 50% in half of all patients who try it.
• Reduces seizure frequency by more than 90% in one-third of patients.

• Carnitine deficiency (primary)
• Carnitine palmitoyltransferase (CPT I or II) deficiency
• Carnitine translocase deficiency
• β-oxidation defects
• Medium-chain acyl dehydrogenase deficiency (MCAD)
• Long-chain acyl dehydrogenase deficiency (LCAD)
• Short-chain acyl dehydrogenase deficiency (SCAD)
• Long-chain 3-hydroxyacyl-CoA deficiency
• Medium-chain 3-hydroxyacyl-CoA deficiency.
• Pyruvate carboxylase deficiency
• Porphyria

Most of these conditions can be excluded on a routine urine metabolic screen and blood carnitine profile.

• Inability to maintain adequate nutrition
• Surgical focus identified by neuroimaging and video EEG monitoring
• Parent or caregiver hesitance re: fussy eating and potential non-compliance with diet
• Bulbar dysfunction or Gastroesophageal disease - aspiration risk

Most patients will require a risk assessment of aspiration as fat-aspiration can lead to severe complications, such as fat-aspiration pneumonia, and can be lethal.

• Presence of kidney stones
• Dyslipidaemia
• Liver disease
• Failure to thrive
• Gastroesophageal reflux
• Poor oral intake
• Constipation
• Cardiomyopathy
• Chronic metabolic acidosis
• High carbohydrate content of current medications

• Full blood count with platelets (looking for: anaemia; thrombocytopenia; evidence of iron, folate, or vitamin B deficiency)
• Electrolytes and renal function (looking for low HCO3, low Ca, and low Mg)
• Serum liver function tests, including albumin, AST, ALT, blood urea, nitrogen, (looking for evidence of transaminitis and low albumin)
• Fasting glucose (looking for hypoglycaemia)
• Fasting lipid profile (looking for elevated triglycerides and cholesterol)
• Selenium, Zinc, 25 OH vitamin D, vitamin B12, Folate, Iron (looking for deficiencies of these as the KD is very low in these micronutrients)
• Serum β-hydroxybutyrate (if the level is already high the KD may be contraindicated)
• Anticonvulsant levels (if applicable)
• Total and free carnitine, serum acylcarnitine profile (screen for inborn errors of metabolism or carnitine deficiency), and plasma amino acids (looking for protein deficiency). Before ordering these metabolic tests, please note that they are very expensive if ordered externally (i.e. outside of the hospital setting). Where possible, they should be conducted within the hospital setting to avoid prohibitive costs for the family.

The Ketogenic Diet places patients at risk of renal stones and elevated calcium secretion. Initial and ongoing urine monitoring should include:

• Urinalysis (to check for proteinuria and elevated ketonuria)
• Urine Ca/Cr ratio, Urine Citrate/Cr ratio (looking for nephrocalcinosis)
• For guidance on minimising Calculi risk, refer to a renal physician.

• It will be necessary to liaise regularly with the Dietitian regarding diet and growth parameters.
• The Dietitian will conduct a full nutrition assessment at every clinic review (including diet record analysis, appropriateness of diet, growth review, micronutrient bloods, supplementation requirements, compliance with diet, knowledge of diet and provision of education).
• Fine-tuning or modification of the diet is possible to increase ketosis.
• The Dietitian needs to be notified when there is a change of medication, as the carbohydrate content needs to be factored into the diet.

Medications and vitamin and mineral supplementation:

• It is essential that any newly prescribed medications or vitamin and mineral supplements are sugar-free (or contain minimal carbohydrate content).
• Sudden introduction of carbohydrates while on the diet in any form may induce seizures.
• This applies to all medications including pain relief and antibiotics (e.g. syrups may need to be changed to sugar-free syrups or to crushable tablets).

• Height
• Weight
• BMI

When a child starts on the Ketogenic Diet, they may feel lethargic and lack energy for several weeks. During the initiation period on the diet, they may also experience the following easily treatable, but potentially serious side effects:

• Dehydration
• Hypoglycaemia
• Low-grade acidosis
• Constipation
• Hunger
• Diarrhoea
• Vomiting
• Abdominal pain
• Changes in taste

If a child remains on the diet over a longer period of time, as with any medical therapy, they may experience adverse effects. Some of these include:

• Kidney stones
• Constipation
• Dehydration
• High blood cholesterol and triglyceride levels
• Slowed growth or weight gain
• Bone fractures
• Vitamin deficiencies (e.g. selenium, vitamin D, zinc etc.)

All of the above possible side effects should be monitored in patients on the Ketogenic Diet.

Typically, children come off the Ketogenic Diet after around two years. However, if there is no improvement after three months, the ketogenic diet is often ceased. The treating neurologist will determine when the diet will be discontinued and the method for gradual discontinuation.

Refer to the patient’s Emergency Letter (if available) and consider the following recommendations specific to Ketogenic Diet patients:

Resuscitation:

• Resuscitate as per usual protocols
• Administer normal saline bolus (as per child’s age and requirements)

Investigations specific to being on the diet:

• Unwell KD patients require close and regular monitoring
• Avoid hypoglycaemia, particularly if vomiting or diarrhoea present (at least 4-hourly bedside checks of blood glucose required).
• Avoid high ketone levels  (at least 4-hourly urine samples to check ketone levels).  If the urine ketone levels are high, perform blood ketones (beta-hydroxybutyrate). Avoid blood ketone level of > 7 mmol/L.
• Venous gas (to check for metabolic and lactic acidosis)
• Electrolytes (look for hypernatraemia, hyper/hypokalaemia)
• Lactate (looking for elevated lactate)

Hydration:

• Where hydration is required, aim to use fluids containing the lowest possible dextrose level, while maintaining blood sugar levels in the normal range.
• Oral hydration: offer clear fluids low in carbohydrate (e.g. hydrolyte, gastrolyte, diet cordial).
• IV hydration: Normal saline as IV fluid in most cases but if there are concerns re: hypoglycaemia or prolonged IV use, consider adding low dextrose fluids to IV (e.g.  2.5% dextrose) in conjunction with the Normal Saline.
• NG hydration: consider using gastrolyte as this contains no more than 3% glucose
• Regular ongoing monitoring of glucose (as per the Hypoglycaemia Protocol) and ketones is required, and medical staff should chart dextrose, glucagon or polyjoule as necessary (see hypoglycaemia protocol for dosages). 

Medications:

• It is essential that any newly prescribed medications are sugar-free (or contain minimal carbohydrate content). This applies to all medication including cough syrups, pain relief and antibiotics (e.g. syrups may need to be changed to sugar-free liquids or to crushable tablets). Compounding can be discussed with the patient’s local Pharmacy.
• Consider placing an alert to avoid sugar and carbohydrates in the Allergies section of the medication chart for patients on the ketogenic diet.

If additional advice or support is required, contact the patient’s treating Ketogenic team or the relevant Neurology Fellow on-call directly.

If a patient on the Ketogenic Diet requires a routine surgical or medical procedure, it is important to be aware of the following:

Fasting and BSLs

• Fasting poses a significant risk for Ketogenic Diet patients
• Try to avoid unnecessary fasting prior to procedures
• Regular routine monitoring of BSLs required
• If BSL’s drop while fasting, consider using IV normal saline + 2.5% dextrose to achieve normal sugar levels 

Operative lists

• Ketogenic Diet patients should be treated as you would treat a diabetic patient i.e. they should be placed FIRST or early on the operative list
• The anaesthetist should be informed regarding regular monitoring of BSL’s intra-operatively – It is recommended that BSL's are performed every 30-60 minutes.

IV Fluids:

• Normal saline is the preferred fluid (except where hypoglycaemia present, see above)

Following the procedure/cessation of fasting period:

• Reinstitute the Ketogenic Diet once fasting/procedure is over
• Consider using the KetoCal formula NG at 4:1 or 3:1 if the patient cannot yet resume their usual ketogenic diet (e.g. Ortho. and ENT procedures).

Medications:

It is essential that any newly prescribed medications are sugar-free (or contain minimal carbohydrate content). This applies to all medications including pain relief and antibiotics (e.g. syrups may need to be changed to sugar-free liquid or use crushable tablets).