Metabolic Causes of Epilepsy

Primary Category

Epilepsy

P-Category

Secondary Category

S-Category

Authors

Muhammad Saad Anwar MD,

Muhammad Tayyab Anwar MD,

Junaid Kalia MD

Introduction

Epilepsy is a chronic neurological disorder characterized by repeated aberrant electrical activity in the brain and recurrent spontaneous seizures.

Major causes of epilepsy include:

Genetic Disorders (e.g, Fragile X syndrome, Down syndrome, Angelman syndrome etc)
Structural Aberrations (e.g, Tuberous sclerosis, Sturge-weber syndrome, atriovenous malformations, tumors etc)
Metabolic Disturbances (e.g, GLUT-1 deficiency, MELAS syndrome etc)
Immune Dysfunction (e.g, Rasmussen syndrome, anti-NMDA receptor encephalitis etc)
Infectious Diseases (e.g, meningitis, toxoplasmosis, encephalitis etc)
Unknown causes

Metabolic reasons account for a minor part of epilepsy etiology, with more than 200 metabolic causes of epilepsy discovered thus far.

They are often resistant to standard anti-epileptic therapy, but may respond differently depending on the cause.
Dietary modification and supplementation, either alone or in conjunction with antiepileptic medicines, are used to treat the various kinds of metabolic epilepsy.
Seizures are frequently accompanied by a range of other neurological, systemic, or metabolic symptoms. Presence of such symptoms lowers the threshold for investigating for metabolic etiology.
A favourable long-term prognosis requires prompt diagnosis and management.

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Metabolic abnormalities is the most prevalent cause of seizures in infancy and childhood

Etiology and Pathophysiology

A simple chemical reaction in the neurons is shown below:

Any change in the amounts of substrates, enzymes, cofactors, or ATP can result in reduced levels of neuronal function products. This is the foundation of metabolic causes of epilepsy.

Seizures in metabolic illnesses can have a complex etiology that involves one or more of the following mechanisms:

1. Substrate Deficiency

A lack of a single substrate that creates several products required for appropriate neuronal function may result in impaired neuronal function and, eventually, seizures.

One such example is Serine Deficiency.

Serine Deficiency d/t impaired Serine Biosynthesis → Impaired neuronal function → Seizures

2. Enzyme Deficiency

Enzyme deficiency can lead to metabolic seizures by the following mechanisms:

A. Accumulation of Neurotoxic compounds

Toxic substrates are broken down by enzymes into easily excretable compounds.

Deficiency in such enzymes may result in hazardous chemical buildup in the CSF and brain, resulting in decreased neuronal function and seizures.

Ammonia accumulation is one such example.

Ammonia accumulation → Increased glutamine synthesis → Swelling of astrocytes and brain edema → Seizures

Examples of metabolic disorders in this category include Urea Cycle Disorders and Organic Acidemias.

B. Neurotransmitters and amino acid imbalance

Neurotransmitters regulate the precise balance of inhibition and stimulation of neurons in the brain.

A lack of enzymes, which results in a differential drop in neurotransmitter levels, can upset this balance.

A hyperexcitable condition caused by an increase in excitatory neurotransmitters and/or a reduction in inhibitory neurotransmitters resulting in seizures.

Glycine excess due to decreased hepatic glycine cleavage is one example in this case.

Glycine Excess → NMDA excitation in brain → Hyperexcitability → Seizures

Example of metabolic disorders in this category include Epilepsy due to deficiency of GABA transaminase and defects of GABA metabolism.

C. Brain Malformations

Enzyme deficiency may result in a buildup of substrates that must be broken down.

The buildup of redundant contents in neurons can result in macroscopic brain abnormalities and disorganised neuronal activity in the brain.

Enzyme Deficiency → Substrates accumulation in brain → Neuronal Deformation and Brain Malformation → Uncoordinated neuronal activity → Seizures

Example of metabolic disorder in this category include Zellweger syndrome.

3. Vitamin / Co-factor deficiency

A. Co-factors and Vitamins dependency

Co-factors and vitamins are essential components of the body's chemical reactions.

Neuronal metabolism is also largely reliant on the proper concentration of co-factors and vitamins required for numerous chemical processes.

Any factor that reduces their concentration causes neurotransmitter imbalance and the accumulation of aberrant substrates, resulting in neuronal dysfunction and seizures.

One such example is Pyridoxine Dependent Epilepsy.

Pyridoxal Phosphate Deficiency → Low Pyridoxine generation in neurons → Neurotransmitters Imbalance → Seizures

B. Molecular transport abnormalities

Carrier proteins serve as a means of molecular transport in the body.

Any factor impairing the transport of essential metabolic substrates, products or co-factors can lead to neuronal metabolic imbalances and cause seizures.

One such example is the Menke Disease.

Impairment of copper transport → Dysfunction of several copper-dependent enzymes necessary for maintaining neuronal metabolism → Neuronal Impairment → Seizures

4. ATP Depletion

A. Reduced Energy Supply

Glucose is the main energy source for the brain.

Reduced energy states may arise due to: - Hypoglycemia - Impaired brain glucose transport - Impaired ATP generation in the mitochondria

This state of hypoglycemia leads to seizures by neuronal function impairment.

Decreased ATP production → Neuronal Na/K-ATPase malfunction → unstable membrane potentials → Seizures

Examples of metabolic disorders in this category include hypoglycemia, Glut-1 deficiency, respiratory chain deficiency, mitochondrial disorders.

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A disturbed metabolic state (eg, high fever, hypocalcemia, hyponatremia) can cause acute symptomatic seizures by inducing a transient disruption of cortical neuronal function. These are a separate entity from metabolic seizures, transient and resolve once the trigger is removed.

Classification:

Major Groups	Classification	Diagnostic Test	Confirmatory Test	Treatment
	Serine Deficiency Glycine Encephalopathy Maple Syrup Urine Disease Urea Cycle Disorders Organic Acidemia Sulfite Oxidase Deficiency Phenylketonuria	↓ serine and glycine in plasma and CSF ↑ Glycine in CSF and plasma Newborn screening; and ↑ Alloisoleucine and branched chain amino acids in serum, disturbing the normal isoleucine:leucine:valine ratio of 1:2:3 Newborn screening; ↑ plasma Ammonia levels ↑ 3-hydroxypropionic acid, methylcitric acid, and propionylglycine in propionic acidemia on urine organic acid analysis. ↑ methylmalonic and methylcitric acids in methylmalonic acidemia on urine organic acid analysis. ↑ S-sulfocysteine in plasma and urine Newborn screening (hyperphenylalaninemia), ↑ pterins in urine (atypical PKU)	Mutations in the *PHGDH, PSAT1, and PSPH* genes Mutations in the **GLDC, AMT, and GCSH genes Mutations in the BCKDHA, BCKDHB, and DBT genes Mutation identification in the genes that encode the urea cycle enzymes: NAGS, OTC, CPS1, ASS1, ASL, and ARG1 For propionic acidemia: mutation identification in the PCCA or PCCB** genes For methylmalonic acidemia: mutation identification in the MMUT gene Mutation identification in the *SUOX* gene that encodes sulfite oxidase enzyme Dihydropteridine reductase enzyme activity assessment in erythrocytes, fibroblasts and lymphocytes	Oral L-serine 200–600 mg/kg/day Sodium benzoate, NMDA receptor antagonists (seziure control) Branched-chain aminoacid restricted diet, adjunctive compounds Dietary protein restrictions; adjunctive compounds Dietary restrictions; adjunctive compounds to dispose of toxic metabolites or increase activity of deficient enzymes No specific therapy, low cysteine and methionine diet in some cases Phenylalanine restriction, BH4, L-Dopa, 5-hydroxytryptophan, and folinic acid supplementation
	Mitochondrial diseases Glucose transporter type 1 deficiency Guanidinoacetate methyltransferase deficiency Fatty acid oxidation defects	Lactic acidemia, hypoglycemia, elevated TCA (tricarboxylic acid cycle) intermediates in urine organic acids, and elevated alanine in plasma amino acids. ↓ CSF glucose, ↓ CSF-to-blood glucose ratio (<0.46) ↑ guanidinoacetate in blood and urine Newborn Screening and acylcarnitine profile	Mutation identification in mtDNA or nDNA genes Mutation identification in the *SLC2A1* gene Mutation identification in the *GAMT* gene DNA testing is confirmatory.	Adjunctive compounds Ketogenic diet Creatine monohydrate 350–500 mg/kg/day, dietary arginine restriction, ornithine supplementation
	Pyridoxine-dependent epilepsy Pyridoxal phosphate-responsive epilepsy Early-onset vitamin B6-dependent epilepsy Cerebral folate deficiency Methylenetetrahydrofolate reductase deficiency Molybdenum cofactor deficiency Biotinidase deficiency Holocarboxylase synthetase deficiency Menke’s Disease	↑ 𝜶AASA levels in urine, plasma, and CSF, ↑ P6C in urine ↓ pyridoxal phosphate in CSF ↑ glycine and threonine in CSF and plasma ↑ 3-methoxytyrosine in CSF ↓ 5-hydroxyindolacetic acid and homovanillic acid in CSF. ↑ lactate, metabolic acidosis, ↑ glycine in plasma and CSF ↓ MTHF level in CSF with normal plasma folate levels ↑ total plasma homocysteine, ↓ methionine, ↓ CSF MTHF, ↓ blood folate level ↑ S-sulfocysteine in plasma and urine, ↑ total homocysteine and cystine in plasma ↓ serum uric acid level, ↑ urinary xanthine and hypoxanthine levels Metabolic acidosis, lactic acidosis, and hyperammonemia ↑ 3-methylcrotonylglycine, 3-hydroxyisovalerate, methylcitrate, propionylglycine, and hydroxypropionate in urine Metabolic acidosis, lactic acidosis, and hyperammonemia ↑ 3-methylcrotonylglycine, 3-hydroxyisovalerate, methylcitrate, propionylglycine, and hydroxypropionate in urine ↓ serum copper and cerulopasmin and ↑ urine homovanillic acid : vanillylmandelic acid.	Mutation identification in the *ALDH7A1* gene Mutation identification in the *PNPO* gene Mutation identification in the *PLPBP* gene Mutation identification in the *FOLR1* gene Mutation identification in the MTHFR gene Mutation identification in the *MOCS1, MOCS2, or GPHN* genes Mutation identification in the *BTD* gene Mutation identification in the *HLCS* gene Mutation identification in ATP7B gene	100 mg IV pyridoxine → oral 5–15 mg/kg/day in two divided doses Oral PLP 10 and 30 mg/kg/day Pyridoxine, pyridoxal phosphate, or a combination of both treatments Folinic acid supplementation, milk-free diet (debatable) Oral betaine supplementation IV cPMP for type A, No specific therapy for other types Oral biotin 5 to 10 mg/day Oral biotin Subcutaneous injections of copper histidine
	Lesch-Nyhan syndrome Adenylosuccinate Iyase deficiency Dihydropyrimidine dehydrogenase deficiency Dihydropyrimidinase deficiency	↑ uric acid levels in urine and blood ↑ succinylaminoimidazole carboxamide riboside and succinyladenosine in urine, CSF, and plasma ↑ uracil and thiamine levels in urine, plasma and CSF ↑ dihydrouracil and dihydrothymine in urine Moderate elevations of uracil and thiamine in urine also seen.	Mutation identification in the HGPRT1 gene Mutation identification in the *ADSL* gene Mutation identification in the *DPYD* gene Mutation identification in the *DPYS* gene	Xanthine Oxidase inhibitors, symptomatic treatment No effective treatment Symptomatic treatment Symptomatic treatment
disorders	Zellweger spectrum disorder Gaucher disease type 2 and 3 Niemann-Pick type C Metachromatic leukodystrophy	↑ phytanic acid and VLCFA, ↓ plasmalogens Glucocerebroside deposits in liver, bones, kidneys, CNS, spleen Sphingomyelin accumulation in organs Sulfatide compounds accumulation in neural and nonneural tissue (kidneys and gallbladder)	Mutation identification in the PEX genes Mutation identification in the *GBA* gene Mutation identification in *NPC1* or *NPC2* genes Mutation identification in the *ARSA* gene	Dietary restrictions, adjunctive compounds No specific therapy Glycosphingolipid synthesis inhibitor No specific therapy
	Congenital Disorders of Glycosylation	ㅤ	Mutation identification in the CAD gene	Uridine supplementation

Clinical Approach

First level investigations:

complete blood count
arterial blood gases and electrolytes
blood glucose
liver functions tests
plasma ammonia
serum uric acid
thyroid functions tests

Second level investigations:

Newborns or infants with epilepsy and developmental delay

Therapeutic trials with pyridoxine, pyridoxal 5 phospate or folinic acid;

In patients with response to therapeutic trials:

urinary vanillactic acid
serum pipecolic acid
SF pipecolic acid
CSF alpha aminoadipic semialdehyde
CF biogenic amine
CF aminoacid;

In patients without response to therapeutic trials:

aminoacids
copper and ceruloplasmin in plasma
CF aminoacids

Patients with epilepsy and movement disorders

Lactate, pyruvate, lactate/pyruvate ratio and guanidoacetate in blood

Urinary creatine/creatinine ratio and pterins

Lactate, pterins, biogenic amine and glycorrachia/glycemia ratio in CSF

Patients with multiorgan involvement

Lactate, pyruvate, lactate/pyruvate ratio, acylcarnitines, aminoacids, folic acids, homocysteine, sialotransferrin isoelectring focusing in plasma

Ketones, organic acids, orotic acid, purine and pyrimidine in urine

Third level investigations:

Biopsy: skin (lysosomal storage disease) or muscle (mitochondrial diseases)
Oriented molecular genetics investigations

Figure 1. Clinical approach to metabolic causes of epilepsy

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It is vital to understand that the seizure itself may cause a rise in lactate levels; however, this increase is transitory, and lactate is swiftly eliminated when the seizure has ended. As a result, finding a sustained increase in lactate 1 or 2 hours after a seizure enhances the possibility of metabolic illnesses such as mitochondrial abnormalities and organic acidemias.

Management:

Seizures that are refractory to conventional therapy, have involved more than one organ system, present with characteristic deformities and/or severity increasing with time, need a prompt metabolic workup.

A correct diagnosis may not only impact therapy, but it may also allow for family counselling, which is an essential aim even if there are no direct therapeutic consequences.

Once a diagnosis is reached, the possibility of a specific treatment is explored, which often improves epilepsy and also other symptoms.

After initial stabilization of these patients, a comprehensive metabolic analysis as shown in the clinical approach section, is pursued.

Pyridoxine and Pyridoxal Phosphate should be given as therapeutic trial to the patients.

If seizures are refractory to anti-epileptic drugs, a trial of folinic acid is also recommended.

Treatment with antiepileptic drugs often needs to be continued nevertheless.

If no particular therapy is available, antiepileptic medication should be administered based on seizure phenotype and epilepsy syndrome.

In the long-run, These errors of metabolism are treated with "sick–day" management, medical diets, cofactor/vitamin supplements, substrate inhibition, stem cell transplant, and gene therapy.

Clinically and on EEG, therapeutic results range from full control to improvement or avoidance of epilepsy.

Secondary outcomes include improved or stable psychomotor/cognitive development, behavioral/psychiatric disorders, seizures, and neurologic and systemic symptoms.

Care must be taken in diagnosing the condition and once diagnosed, working up on the associated co-morbidities.

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Valproic acid should NOT be used for seizure control in mitochondrial disorders and urea cycle disorders, and used with caution in many other inborn errors of metabolism.

Bibliography

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Metabolic Causes of Epilepsy - An Introduction

Introduction