Neurology Flashcards
What is SCNA1 associated with?
- The sodium channel, voltage-gated, type I, alpha subunit (SCN1A) gene
- on chromosome 2q24.3
- important in controlling sodium transport into neurons
- Over 150 mutations have been linked to epilepsy
- include genetic epilepsy with febrile seizures plus and DRAVET syndrome
- Specific mutations in SCN1A have also been associated with epilepsy of infancy with migrating focal seizures and familial hemiplegic migraine
- DO NOT use sodium channel blocking anti-seizure medications.
What is Dravet syndrome? (AKA severe myoclonic epilepsy of infancy)
- Associated with SCNA1 gene mutation
- Severe end of GEFS+
- Normally presents first year of life (approx. 6/12)
- Prolonged, febrile and afebrile, focal (usually hemiclonic) and generalized tonic-clonic seizures
- Other seizure types including myoclonic and atypical absence seizures appear between the age of 1 and 4 years
- Same in both sexes
- Onset usually about 6/12 and usually associated with fever (60%)
- Immunisation may trigger earlier onset
- Associated with epileptic encephalopathy
- Head size and neurological examination are usually normal initially, over time ataxia and pyramidal signs may develop. Development is typically normal in the first year of life, with plateauing or regression in later years.
What is Rett syndrome?
- Abnormality of the MEPC2 gene on chromosome on the X chromosome
- other gene implicated is CDKL5
- affects only girls (1 in 8500) (similar defect causes severe encephalopathy in boys)
- Usually de novo
- syndrome involving developmental delay, loss of language skills, and repeated hand wringing movements),
What gene abnormality can associated with atypical Rett syndrome?
- One of the proteins affected by CDKL5 is MECP2 protein
- The cyclin-dependent kinase-like 5 (CDKL5) gene, located on chromosome Xp22, encodes a CDKL5 protein that acts as a kinase (changing activity of other proteins).
What is fragile X syndrome and how is it associated with seizures?
- Usually caused by a trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene, located on chromosome Xq27.3.
- most frequent cause of familial intellectual impairment - second most common cause of intellectual impairment after Down syndrome.
- elongated face, large or protruding ears, and large testes
- Patients typically have autistic features
- Epilepsy in up to 40% of patients. Seizures and EEG features are similar to those seen in childhood epilepsy with centrotemporal spikes
- Seizures typically improve with age.
- Diagnosis : analysis of the number of trinucleotide repeats using PCR and methylation status using Southern blot analysis.
What is Ohtahara syndrome and what gene abnormality is it associated with? (AKA early infantile epileptic encephalopathy)
- frequent intractable seizures and severe early encephalopathy
- normally tonic seizures
- has onset in the first month of life (range 1-3 months)
- Equal in both sexes
- Head size normal at first
- abnormal neuro and development exam
- Severe GDD with or w/o regression
- May evolve to have West or Lennox Gastaut syndrome.
What is an epileptic spasm?
- sudden flexion, extension or mixed flexion-extension of proximal and truncal muscles, lasting 1-2 seconds i.e. longer than a myoclonic jerk (which lasts milliseconds) but not as long as a tonic seizure (which lasts > 2 seconds).
- Spasms typically occur in a series, usually on wakening
- Spasms may be bilaterally symmetric, asymmetric, or unilateral, depending on whether they are generalised onset or focal onset.
- Epileptic spasms usually occur in a series (several in a cluster) right arrow if singular, consider other seizure types.
What is West syndrome?
- West syndrome is characterized by the onset of epileptic spasms, between 3-12 months of age. Global developmental impairment (with or without regression) is typically seen.
- Ohtahara syndrome or other early onset epilepsies (typically with focal seizures) may evolve to have clinical and EEG features of West syndrome after 3-4 months of age.
- M>F
- May have normal or abnormal neuro exam and normal head
- GDD typically seen at age of onset
What is the difference between self-limited neonatal seizures and self-limiting familial neonatal epilepsy?
-Similar presentation and electrical features
- Familial has a strong Fhx where SLNS
are de novo mutations
-Present day 4-7 of life (term, and term corrected)
-If onset is later (1st 2/12 of life) it is called SL FNE
- Focal and hemi-clonic in nature. May alternate side to side; tonic features, vocalisations, automatisms, focal to bilateral tonic clonic.
-Can occur in clusters, minutes
-Usually remit by 6/12 (usually around 4-6 weeks)
-May develop seizures later on in life
-Normal development
-Some neonates with KCNQ2 (K voltage gated channelopathy) mutations may have myokymia (continuous muscle activity causing stiffness and subtle twitching)
What are the typical EEG features of Self-limited neonatal seizures and self-limiting familial neonatal epilepsy?
- May be normal
- May have theta pointu alternant pattern (seen in half patients) interictal (in-between seizures). NOTE not specific to this type of epilepsy
- Rhythmic spikes or slow waves are seen with ictal events. These may be focal (mainly seen in the centro-temporal regions, although other focal areas may be affected) or generalized
- Abnormal EEG may be enhanced in sleep
What is CDKL5 gene and how is it involved in epilepsy?
- The cyclin-dependent kinase-like 5 , located on chromosome Xp22,
- CDKL5 protein that acts as a kinase (changing activity of other proteins).
- One of the proteins affected by CDKL5 is MECP2 protein.
- Identified in girls with atypical (early onset seizure variant) Rett syndrome. Includes features of classic Rett syndrome (including developmental delay, loss of language skills, and repeated hand wringing movements), but also causes recurrent seizures beginning in infancy.
- Mutations in CDKL5 are also reported in X-linked epileptic spasms with intellectual impairment, seen more commonly in females.
- Mutations in CDKL5 are also reported in Ohtahara syndrome
What is Lennox Gastaut syndrome?
- Multiple types of intractable seizures - tonic seizures in sleep, atonic and atypical absence seizures also occur, focal, spasms, non-convulsive status
- Onset of seizures age 1-7 years old
- Often previous abnormal underlying brain structures
- Cognitive and behavioral impairments
- Diffuse slow spike-and-wave and paroxysms of fast activity on EEG.
- DDX include Dravet syndrome, atypical childhood epilepsy with centrotemporal spikes
- 10-30% have PROGRESSED to this syndrome (i.e WEST or OHTAHARA syndrome)
What is febrile seizures plus ? (or genetic febrile seizures plus)
Syndrome characterised by persisting febrile seizures past normal age and/or accompanied by general seizures ( T/C, atonic, Myoclonic, absence)
- NORMAL development
- Distinguish between the two based on presence of Fhx
- Onset between the age of 6/12 and 6 years.
- Usually self-terminate. Usually resolve by puberty
- Dominant inheritance with incomplete penetrance.
- SCN1A, SCN1B, GABRG2 and PCDH19.
- Background EEG normal
- Ictal EEG depends on kind of seizure type occurring
What is Child absence epilepsy?
- Multiple daily absence seizures, brief (<10 secs)
- V. occasionally may have GTC in adolescents
- Absences >45 secs and post ictal SHOULD NOT happen
- NORMAL development (+ Hx and neuro)
- Genetic/idiopathic in an otherwise normal child
- Onset 2-12 years (peak 5-6 years)
- DDx between 8-12 years is JAE. CAE is FAR MORE frequent
- Provoked by hyperventilation
- SELF-LIMITING
- May have associated ADHD or learning difficulty
- BG EEG normal. 1/3 have occipital intermittent rhythmic delta activity (OIRDA)
- Ictal EEG approx. 3 Hz generalised spike and wave
What is Childhood occipital epilepsy (Gastaut type)?
-Rapid onset and brief (usually <3 minutes) focal visual and sensory seizures. Frequent w/o Rx
-Usually small multi-coloured circles which increase in size and move horizontally. May get deviation or head turning to affected side
-Other sx include ictal blindness, complex hallucinations, eye pain, repetitive eyelid closure/fluttering, headache, N+V
-Post ictal headache in 50%, N+V in 10%
-4% Impaired awareness, 43% hemi-clonic seizure
-Absence seizures post occipital seizure is common
-Onset between 15m and 19 yrs (peak 8-9 yrs)
-Remission in 50-80% in 2-4 years if treated
- NORMAL development and exam
-Epileptic encephalopathy with continuous spike-and-wave during sleep can occur as a co-morbid disorder- Do EEG if cognitive decline
EEG- At ictal onset, there is decr in the usual BG occipital spike or spike-and-wave with sudden appearance of occipital faster rhythms with spikes of low amplitude.
What is childhood epilepsy with centrotemporal spikes? (AKA Rolandic epilepsy)
- Infrequent, brief, hemifacial (lips, tongue, mouth) aka frontoparietal operculum seizures that may evolve to a focal to bilateral tonic-clonic seizure IF they occur nocturnally (not during the day)
- Can get Todd’s paresis
- Seizures >30mins VERY rare
- Onset between 3-14 years (peak 8-9 yrs)
- Self-limiting- usually resolve by age 13 years
- Normal development + exam. Can get abnormal behavioural and neurophysiological deficits if not treated
- Hx of febrile seizures in 5-15%
- Note: consider Fragile X if male with ID
- Inter-ictal EEG shows high voltage centro-temporal spikes activated during sleep and drowsiness
- Ictal EEG – rare to capture. Little literature on it
What is Doose syndrome? (AKA myoclonic/atonic seizures)
- Myoclonic jerks (may be subtle) followed by atonia resulting in a fall (drop attack)
- 2/3 have febrile seizures or GTC PRIOR to onset of m/a seizures
- Onset 6 months - 6 years (peak 2-4 years)
- Epileptic encephalopathy
- M>F 2:1
- Normal Bhx, HC and neuro exam
- Normal development initially may become impaired due to EE
- MUST exclude Glucose transporter defects
- BG EEG- GENERALISED slowing, bi-parietal theta
- Ictal- generalized spike or polyspike with myoclonus. Aftergoing high voltage slow wave with atonia.
What is Landau Kleffnar syndrome?
- Subacute onset of progressive acquired aphasia (from acquired verbal auditory agnosia) on BG of PREVIOUS NORMAL development
- 20-30% DO NOT have seizures (if do they are focal, atypical absence or atonic.
- 40% present with progressive aphasia; seizures or both. Behavioural, psychiatric and cognitive disturbances are common
- Seizures are very infrequent, nocturnal and brief
- Self-limiting BUT often residual significant language impairment (>80%) and can be severe
- Epileptic encephalopathy
- Similar EEG features to other epilepsies with Centrotemporal spikes. Can result as a progression of these
- Onset between 2-8 years (peak 5-7 yrs), remission common by 10yrs old
- Interictal-High amplitude spike and wave is seen in the temporal-parietal regions
What is Juvenile absence epilepsy?
- INFREQUENT absence seizures
- GTC occurs in 80% (usually within 30min of waking)
- Distinguished between CHILD HOOD ABSENCE EPILEPSY have very frequent absence seizures
- Age onset 8-20 years (peak 9-13yrs). Lifelong
- Normal Bhx, HC and neuro exam. NORMAL development
- ADHD and learning difficulties may occur
- May have partially or fully impaired awareness. In impaired awareness can follow simple commands
- Interictal may be generalized spike-and-wave, fragments of generalized spike-and-wave or polyspike-and-wave
- Ictal- Regular 3-6 Hz generalized spike-and-wave or polyspike-and-wave
What can provoke absence seizures?
Hyperventilation well for three minutes. Expect to see on EEG generalized spike-and-wave is seen.
What is Juvenile myoclonic epilepsy?
- Most common genetic/generalised epilepsy
- Myoclonic and GTC (>90%)
- Myoclonic usually distal and within 30m to 1hr of waking
- May get infrequent absence (< daily), very brief, mild impaired awareness (can do simple commands)
- NORMAL development, Hx and exam
- Onset 8-25 years old
- May have Fhx
- Some genes involved. 15q13.3 microdeletion is associated with it
- The EEG shows generalized spike-and-wave and polyspike-and-wave. Photosensitivity is common
What is epilepsy with GTC alone?
- Common genetic/generalised idiopathic epilepsy
- GTC only. Usually within 1-2 hours of waking
- Provoked by sleep deprivation, alcohol and fatigue
- Onset 5-40 yo (peak 11-23 years)
- Lifelong treatment
- NORMAL development, Hx and exam
- Interictal- Generalized spike-and-wave or polyspike-and-wave is seen in the interictal EEG. Half of patients have these abnormalities only in sleep
- Ictal- usually obscured by artefact. Generalized fast rhythmic spikes are seen in the tonic stage. Bursts of spikes and after-coming slow waves are synchronous with clonic jerks
How does Carbamazepine work?
- Iminodibenzyl derative
- Related to TCA’s
- Inhibits voltage gates sodium channels + L-type calcium channels
- Metabolised into active form Carbamazepine-epoxide more so in infants and children = increased risk of toxicity
- Increases metabolism of oral anticoagulants, beta-blockers, haloperidol, felodipine and theophylline
- Interaction with erythromycin can cause carbamazepine toxicity
- Dose range 15-25mg/kg/day
- Adverse reactions: Hypersensitivity rash, ataxia, sedation, nausea, leukopenia, thrombocytopenia
Some of the more common side effects include diplopia and ataxia. It can also cause Stevens Johnson syndrome.
What kind of seizures are treated with Carbamazepine?
Focal seizures
GTC
SE: hypersensitivity rash, ataxia, low plts, low WCC, sedation
What kind of seizures are treated with Sodium Valproate?
All seizure types
SE: N+V, abdo pain, tremor, hair loss, low plt, deranged LFTS
TERATOGENIC (also increased risk of spina bifida)
What kind of seizures are treated with Lamotrigine?
All seizure types including absence/focal
Reduced dosing to 1/3 (5mg/kg/day) if concurrently using sodium valproate
SE: Rash
What kind of seizures are treated with Vigabatrin?
Focal seizures
Infantile spasms
West syndrome
50-150mg/kg/day
SE: Sedation, visual field constriction
What kind of seizures are treated with Ethosuximide?
Absence seizures
20-50mg/kg/day
SE:GI disturbance, rash
What kind of seizures are treated with Topiramate?
All seizure types
6-9mg/kg/day
SE: Anorexia, weight loss, sedation, parasthesiae
What kind of seizures are treated with Clobazam?
All seizure types
2mg/kg/day
SE: Sedation
What kind of seizures are treated with Phenytoin?
All seizure types
5mg/kg/day
SE: N+V, diarrhoea, rash, peripheral neuropathy
MUST monitor levels
What kind of seizures are treated with Phenobarbitone?
All seizure types
5-8mg/kg/day
Not for use as montherapy <16 yo
SE: sedation
What kind of seizures are treated with Levetiracetam?
Focal seizures +/- secondary generalised
Adjunct for myoclonic and GTC
Status loading
No drug interactions
SE: sedation, asthenia, dizziness
How does Levetiracetam work?
Unclear
Can act prophylactically to prevent seizure progression
Rapidly and almost completely absorbed as active form
Not protein bound
Enzymatically hydrolysed in the blood to inactive form and excreted within 24 hours
1/2 life 5-7 hours
Peak plasma approx. 1 hr
How does Clobazam work?
Enhance the effect of GABAa receptors by increasing channel opening FREQUENCY = Increase in calcium ion influx
Rapidly and completely absorbed oral
Peak levels 1-4 hours
Highly protein bound
Metabolised by the liver to active products
Half life elimination is 10-50hrs
How does Ethosuximide work?
Blocks T-type calcium channels in thalamacortical and dorsal root ganglions. Allows normal thalamic activity.
Rapidly absorbed. Almost 100% bioavailability. Active.
Peak levels 3-7 hours
Not protein bound.
Hepatic metabolism into inert substance (20% excreted unchanged in urine)
How does Phenobarbitone work?
Enhances effect of GABAs receptors by increasing channel opening DURATION
90% bioavailability (much lower in neonates due to poor absorption)
Peak levels 1-6 hours (9hrs in neonates)
45% protein bound
Metabolized in liver to inactive substances
Elimination slower in Neonates
Multiple interactions with other meds
Hepatic enzyme INDUCER (CYP450)
- Increases the metabolism of many AEDs such as phenytoin, carbamazepine, valproic acid, lamotrigine and Topiramate
-Some of the more common side effects include nystagmus, gum hypertrophy, hirsuitism, ammonia, liver, rash (associated with Stevens Johnson syndrome), folic acid depletion, decreased bone density.
How does Phenytoin work?
Hydantoin derivate
Inhibits VG sodium channels by reducing frequency of excitability.
Also inhibits calcium channels
Absorbed in the small intestine (more alkaline)
Absorption increased with co-feeding in small children
Bioavailability approx. 95%
Peak levels 2-12 hours
90% protein bound
Metabolized in liver into inert substances
Excreted by the kidneys
Metabolism is saturable at therapeutic levels so beware of toxicity. Lots of variability between patients
Interacts with valproate (binding sites displaced by valproate)
NEED to monitor levels
How does Sodium Valproate work?
Valproate is a short chain fatty acid
Precise mechanism uncertain
Some kind of effect on Voltage gated Na channels
Complete oral absorption and 100% bioavailability
Peak levels 1-2 hours (slower absorption in neonates)
90% bound to protein
Lots of interpatient variability
Metabolised into active substance by liver
1/2 life 6-15hr in kids (10-70hrs neonates)
Inhibits metabolism of many AEDs
Need higher doses of sodium valproate if using with other AEDs
Some of the more common side effects include increased appetite, weight gain, insulin resistance, metabolic syndrome, hair loss, easy bruising (can cause thrombocytopenia and other coagulation abnormalities). It has also been linked to polycystic ovarian syndrome.
How does Lamotrigine work?
Inhibition of use depending voltage sensitive sodium channels
+ undefined mechanisms
Absorbed easily, unaffected by food intake
Bioavailability 95%
Peak levels 1-3 h
55% protein bound
Metabolised by liver into inactive substance
Phenytoin(most effect), phenobarbitone and carbamazepine decrease plasma concentrations
Sodium Valproate reduces the rate of clearance and doubles the half life (CYP inhibitor)
Carbamazepine reduces the half life (CYP inducer)
SE: diplopia and ataxia
What is Tuberous sclerosis?
- autosomal dominant (2/3 sporadic)
- variable penetrance
- defect in protein tuberin (TSC2) or harmatin (TSC1)
- 2 major genes TSC1 (9q34) and TSC2 (16p13)
- tuberin and harmatin regulate protein synthesis and cell size (act like tumour supressor genes)
Involves multiple organs:
- head –> subependymomas, cortical tubers, SEGAs, seizures, cognitive impairment
- heart –> rhabdomyomas (50%), arrythmias
- kidneys –>angiomyolipomas, cysts
- eyes –> retinal harmatomas
- skin –> Shargreen patches, facial angiofibromas, ungal/periungal fibromas (nails), hypomelanotic macules
Seizures may present early with infantile spasms +/- hypsarrthymia on EEG. Later in childhood can be myoclonic
How is TS diagnosed?
At least 2 major criteria OR 1 major + 2 minor
Major criteria:
-head –> subependymomas, cortical tubers, SEGA
-heart –> rhabdomyomas
- kidneys –>angiomyolipomas
- eyes –> retinal harmatomas
- skin –> Shargreen patches(90%) (at least 3), facial angiofibromas(>75%), ungal/periungal fibromas (nails, occur in adolescence), hypomelanotic macules (>3)
Lung- pulmonary lymphangioleioyomatosis
What are classic signs in the early past history suggestive of Dravet syndrome?
Prolonged febrile convulsion Hemiclonic seziures Convulsions post vaccinations Family history of epilepsy May not yet have regression in milestones!
What typical EEG changes do you see in absence epilepsy?
3 Hz spike and wave throughout
frontally dominant
last 2-35 secs
What typical EEG changes do you see in Rolandic epilepsy?
Spike and waves centrotemporal regions
What typical EEG changes do you see in JME?
4 cycles(s) spike and wave and polywave spike and burst
What typical EEG changes do you see in lennox gaustaut syndrome?
Slow spike-wave discharges at 1.5-2.5Hz cycles(s)
What typical EEG changes do you see in West syndrome, infantile spasms?
Hypsarrythmia
Diffuse giant waves with chaotic background of irregular, sharp multiple spikes and and sharp waves with little synchrony between hemispheres.
During the spasm there is marked suppression of the background
What is the typical triad of West syndrome?
Infantile spasms
Developmental delay
Hypsarrthymia on EEG
What is CMT disease?
Charcot marie tooth - Type 1 most common
CMT1A most common gene, found on 17p11, encodes PMP22 which is a component of myelin = demyelinating disease
- DUPLICATION of PMP22
-AD in family
Progressivedisease
Features more prominent in teens
-Distal symmetric polyneuropathy (glove and stocking)
- Loss of DTR
- Intrinsic muscle wasting
- DISTAL weakness
- Sensory loss (proprioception and vibration, followed by motor loss
- Nerve conduction studies show a decreased velocity to <50% (latency is long) and affects sensory first and may be absent
What is different about CMT type 2 disease?
Less common than type 1
It’s an axonal neuropathy rather than demyelinating.
Therefore get loss of number of muscle fibres
So NCS show a DECREASED amplitude affecting sensory first. Also has increase latency (decreased velocity) due to loss of fast conducting fibres
what is myasthenia gravis
NMJ defect
- can be autoimmune (antibodies)
- can be congenital
Often have thymoma
ptosis (uni/bilat)
Decreased DTRs
IgG antibody to nictonic Ach receptors
- serological testing includes measurement of IgM and IgG antibodies that bind to AchRs
50% +ve in children
Nerve conduction studies –> sensory preserved
motor velocities and latencies are normal. BUT slow repetitive stimulation of muscle will show a DECREMENTAL response.
Dx made based on 2 positive tests- 1x serological and 1x electrodiagnostic
What are the differences between dystrophy and myopathy?
Dystrophy–> destructive, high ++ CK, degenerative loss and destruction of normal architecture, uniform changes with atrophy on biopsy
Myopathy –> functional, minimally raised CK, abnormal architecture, patchy fasicular changes, inflammatory changes if dermatomyositis
Where is the gene located that causes DMD?
Xp21.2-p21.1
Not all are located here. There can be less common mutations and point mutations so be aware testing can initially be negative
What is SMA?
Spinal muscular atrophy Destruction of anterior horn Type 1--> die Type 2 --> sit, don't walk Type 3 --> walk Recessive Most common after CF 1 in 40 to 1 in 60 carriers 1/10,000 born with SMA Homozygous deletion of SMN gene on 5q12.2-q13 Bell shaped chest Can smile, body not moving Tongue fasciculations Hand tremor
Ix: Gene panel
EMG- tests health of muscle. Examines individual muscle units
–> in SMA produce fibrillating potentials in early disease
Apart from SMA, what other disease can you diagnose using EMG?
Myotonic dystrophy
“dive bomber” sound produced by a myotonic discharge. ◦This discharge can be triggered mechanically, by needle insertion. ◦It consists of high frequency discharges that vary consistently in amplitude and frequency, ranging from 150/second down to 20/second.
What characteristic EEG findings found with Ohtahara syndrome?
Burst Suppression
What characteristic EEG findings found with Infantile spasms?
-Hypsarhythmia with burst suppression events
What characteristic EEG findings found with CAE?
3Hz spike and wave
What characteristic EEG findings found with benign focal epilepsy (Rolandic)
centro-temporal spike and wave or occipital spike and wave
What characteristic EEG findings found with continuous slow wave sleep epilepsy?
continuous spike and wave in slow wave sleep
What characteristic EEG findings found with Landau Kleffner syndrome?
Continuous temporal spike and wave
What 3 electroclinical epilepsy syndromes that have typical onset in the neonatal period?
Benign familial neonatal epilepsy (BFNE)
Ohtahara syndrome
Early myoclonic encephalopathy (EME)
What electroclinical epilepsy syndromes that have typical onset in the infancy period?
Febrile seizures plus (FS+)
Benign familial infantile epilepsy (BFIE)
West syndrome
Dravet syndrome
Myoclonic epilepsy of early infancy (MEI)
Epilepsy of infancy with migrating focal seizures
What electroclinical epilepsy syndromes have typical onset in the childhood period?
Febrile seizures plus (FS+)
Early onset childhood occipital epilepsy (Panayiotopuolos syndrome)
Epilepsy with myoclonic atonic seizures
Childhood absence epilepsy
Benign epilepsy with centrotemporal spikes (BECTS)
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
Late onset childhood occipital epilepsy (Gastaut type) Epilepsy with myoclonic absences
Lennox Gastaut syndrome (LGS)
Epileptic encephalopathy with continuous spike wave during sleep (CSWS)
Landau-Kleffner syndrome (LKS)
What electroclinical epilepsy syndromes have typical onset in the adolescence period?
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Epilepsy with generalised tonic clonic seizures alone Autosomal dominant epilepsy with auditory features (ADEAF)
Other familial temporal lobe epilepsies
What is the AED of choice based on seizure type?
Generalised
GTC-epilim over 3y ( under 3y clobazam/ levetiracetam/ lamotrigine)
Myoclonic-epilim/clobazam
Tonic /atonic-epilim/clobazam
Focal Carbamazepine*/Lamotrigine
*HLA-B 1502 ++ risk of SJS with Carbamazepine (Asian popn)
What is the AED of choice based on seizure syndrome?
Childhood absence epilepsy
- First: ethosuximide
- Second: valproicacid, lamotrigine
- Third: levetiracetam, clobazam, acetazolamide
Juvenile myoclonic epilepsy
- First: Valproicacid
- Second: lamotrigine, levetiracetam,topiramate
Self-limited childhood epilepsy with centrotemporal spikes
- First: carbamazepine, lamotrigine
- Second:, levetiracetam, valproicacid
What is the AED of choice based on seizure syndrome? (continued)
Infantile Spasms
- First: ACTH/prednisolone –2 weeks, then taper
- First (tuberous sclerosis): vigabatrin
- Second: vigabatrin, ketogenic diet
Dravet syndrome
- First: valproic acid + clobazam
- Second: levetiracetam, ketogenic diet, stiripentol
Lennox Gastaut syndrome
- First: Valproicacid + clobazam
- Second: rufinamide, felbamate, ketogenic diet
What % seizure free?
1st drug monotherapy 47%
2nd drug monotherapy 13%
3rd drug monotherapy 1% Combination 4%
Cumulative % 65%
What are the prognostic factors for remission of seizures?
- age of onset < 12 years,
- normal intelligence,
- lack of preceding neonatal seizures, and
- < 21 seizures before diagnosis.
If all of these factors were present, then by 10 years after diagnosis, the chance of remission was about 80%. If any one factor was absent, remission was anticipated in only 40%
what is the risk of reoccurrence of seizures once weaned AED (after 2 years seizure free)?
Risk of recurrence approx 30-40% over a 5 year period following discontinuation
Predictors include
-Syndrome, e.g. JME vs Absence
-Family history of seizure (RR 3-4)
-Abnormal EEG (slowing) on therapy RR=2
-Severe mental retardation (IQ < 50, RR= 3)
What typical dysmorphic features are associated with fetal valproate syndrome?
Tall forehead Thin vermillion border Long upper lip Shallow philtrum Broad nasal root Flat nasal bridge Medial eyebrows
If have to use Epilim in pregnancy what dose is recommended?
Higher risk and dose dependent >800mg/day
Increased risk of learning difficulties and cardiac, orofacial clefts, hyposapadias, club foot, intestinal atresia, fetal valproate syndrome, developmental delay.
Recommend <330mg/day
Adrenoleukodystrophy
x-linked
Congenital demyelinating condition
Accumulation of very long chain fatty acids
- Patients usually become symptomatic between 5 and 15 years of age with evidence of academic deterioration, behavioral disturbances, and gait abnormalities. Generalized seizures are common in the early stages. Upper motor neuron signs include spastic quadriparesis and contractures, ataxia, and marked swallowing disturbances secondary to pseudobulbar palsy. These dominate the terminal stages of the illness.
- Hypoadrenalism is present in ≈50% of cases.
- Brown gums and brown mucosa
- MRI tends to show symmetrical cerebral white matter signal change (increased signal T1 = increased fat), but it usually involves the posterior periventricular white matter.
Treatment is with bone marrow transplant
Metachromatic leukodystrophy
- AR
- white matter disease caused by a deficiency of arylsulfatase A (ASA), which is required for the hydrolysis of sulfated glycosphingolipid
- Lysosomal storage disorder
- Low serum and urine arylsulphatase A
- The clinical manifestations of the late infantile form of MLD, which is most common, usually present between 12 and 18 months of age as irritability, inability to walk, and hyperextension of the knee, causing genu recurvatum
- Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state
- MRI characterised by bilateral symmetrical confluent areas of signal change in periventricular white matter with sparing of subcortical U fibres
- Can look similar to adrenoleukodystrophy but does not have brown gums and mri changes more diffuse
- The clinical progression of the disease relates to the pathological involvement of both central and peripheral nervous system, giving a mixture of upper and lower motor neuron and cognitive and psychiatric signs.
- Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state. As the disease progresses, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear, with death in the first decade of life.
Treatment is bone marrow transplant
Krabbe disease- Globoid cell leukodystrophy
Lysosomal storage disease of galactocerebrosidase deficiency (responsible for the liposomal hydrolysis of galactolipids formed during white matter myelination)
Usually infant onset but have slower onset forms which present in childhood (and are thlisserefore less severe)
- rare, often fatal, autosomal recessive, degenerative disorder that affects the myelin sheath of the nervous system.
- The build-up of unmetabolised lipids affects the growth of the nerve’s protective myelin sheath and causes severe degeneration of MOTOR skills
Sx: irritability , fevers, hypertonia, seizures, developmental delay
MRI- demonstrates symmetric high-signal-intensity areas in the deep white matter. The internal and external capsules are also involved
Leigh’s disease
Mitochondrial disorder (mitochondrial encephalopathy) Neurodegenerative disorder which usually presents before the age of 2 years
This is also known as subacute necrotizing encephalomyelopathy, and is a rare neurometabolic disorder
Sx: Developmental delay or regression, dystonia, ataxia, cranial nerve palsies, seizures, weakness, ptosis, external ophthalmoplegia, psychomotor regression, hearing loss, movement disorders
- can present in infancy with poor feeding, poor swallow and FTT
- IIntermittent respirations with associated sighing or sobbing are characteristic and suggest brainstem dysfunction. Some patients have external ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and decreased visual acuity.
Ix- high csf lactate
MRI- In decreasing order of severity, the affected areas are the basal ganglia, brainstem cerebellum, and cerebral cortex. Abnormal results on CT or MRI scan consist of bilaterally symmetric areas of low attenuation in the basal ganglia and brainstem as well as elevated lactic acid on MR spectroscopy.
Rx: none. Prognosis poor, usually death in early childhood
Lissencephaly
disorder of neuronal migration
‘smooth brain’
absence of gyri (agyria)
Thickened cortex (pachygyria)
2 genes
LISI (most severe posteriorly)
DCX (most severe anteriorly)
MOTHERS of lissencephalic boys- those who have the DCX gene often have band heterotopia
Band heterotopia
band of white matter (all the way round) of grey matter between white matter
often asymptomatic
60% are DCX females (mothers of lissencephalic boys)
Septo-opto-dysplasia
abnormality of ventral induction (5-10weeks gestation)
associated with midline defects
i.e absent septum pellucidum or corpus collosum
under development of optic nerve
pituitary gland dysfunction
possible causes:
sodium valproate (maternal)
rare familial cause
Cocaine use
stages of neural development
- dorsal induction
- ventral induction
- neuronal proliferation
- neuronal migration
- cortical organisation
- myelination
disorders of dorsal induction
spina bifida, anencephaly, caudal regression
disorders of ventral induction
absent septum pellucidum
septo-opto-dysplasia
lobar holoprosencephaly ( mild form grey matter crossing, i.e fusing of frontal lobe)
Malformations of cortical development
Lissencephaly Polymicrogyria schizencephaly heterotopia focal cortical dysplasia
can be genetic –> chromosomal, or individual geners
can be due to trauma, infection, teratogens, hypoxia
polymicrogyria
many small gyri
schizencephaly
full thickness cleft through hemisphere
‘cleft brain’
cleft filled with csf
cleft lined by polymicrogyria
heterotopia
abnormal position of grey matter
can be single - i.e subependymal nodular heterotopia
focal cortical dysplasia
subtle focal dysplastic cortex
lissencephaly
smooth brain with increased cortical thickness
subependymal heterotopia
can be single (asymptomatic)
or multiple lining tall the ventricles –> can be x-linked (boys die in utero) presents with seizures, GI dysmotility, aortic root dilatation
Friedriechs ataxia
- AR
- involving the spinocerebellar tracts, dorsal columns in the spinal cord, the pyramidal tracts, and the cerebellum and medulla.
-Freidrich’s ataxia is caused, in most cases, by a loss of function mutation in the frataxin gene. Frataxin is a mitochondrial protein. The hypothesis is that there is mitochondrial accumulation of iron.
- The onset of ataxia is somewhat later than in ataxia-telangiectasia but usually occurs before age 10 years.
- The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities.
-As it doesn’t affect anterior horn cells specifically, fasciculations are not a particular feature
- Patients develop a characteristic explosive, dysarthric speech, and nystagmus is present in most children.
- Typically noted is a marked loss of vibration and position sense caused by degeneration of the posterior columns and indistinct sensory changes in the distal extremities.
- extensor plantar responses with absent lower limb deep tendon reflexes
-Friedreich ataxia is also characterised by skeletal abnormalities, including high-arched feet (pes cavus) and hammertoes, as well as progressive kyphoscoliosis
Telangectasia ataxia
ADD - see Immunology
Raised AFP
Oculomotor apraxia and telangiectasia
Spinocerebellar ataxia
A group of inherited progressive disorders affecting incoordination of gait and often associated with poor coordination of hands, speech, and eye movements (nystagmus, abnormal saccade movements)
RARE cf Friederichs
- AD, AR and X-linked (heaps of types
- In children SCA types 1-3 and AD
- All child types are triplet repeats
- Type 2 and 3 can present from age of 1
- Ataxin gene 1-3 affected
- other non-cerebellar sx: parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures
- often have cerebellar atrophy
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
- These children present with developmental delay, weakness and headache, as well as focal signs that suggest a stroke.
- Brain imaging indicates that injury does not fit within the usual vascular territories.
- Children with MELAS may be normal for the first several years, but they gradually display delayed motor and cognitive development and short stature.
The clinical syndrome is characterised by:
- recurrent stroke-like episodes of hemiparesis or other focal neurologic signs
- lactic acidosis, ragged red fibers (RRF), or both
- and at least two of - focal or generalised seizures, dementia, recurrent migraine headaches, and vomiting.
- CSF protein is often increased.
- Neuropathology may show cortical atrophy with infarct-like lesions in both cortical and subcortical structures, basal ganglia calcifications, and ventricular dilatation.
Batten disease
-Juvenile type of neuronal ceroid lipofuscinoses (NCLs)
which is a group of inherited, neurodegenerative, lysosomal storage disorders
-most common form of NCL
- characterised by visual loss, progressive dementia, seizures, motor deterioration, and early death.
- Children affected with JNCL tend to develop normally for the 1st 5 yrs of life.
- Their initial symptom is usually progressive visual loss and their retinal pigmentary changes often results in an initial diagnosis of retinitis pigmentosa.
Topiramate AEDs
Some of the more common side effects include slow thinking, weight loss, paraesthesia. Topiramate also inhibits renal carbonic anhydrase and so can cause proximal and distal acidifcation defects. A metabolic acidosis is common. Calcium phosphate nephrolithiasis can occur.
Dienchephalic syndrome
Diencephalic syndrome is a rare cause of failure to thrive associated with hypothalamic/optic chiasm region tumours.
Patients present with severe emaciation despite normal caloric intake, normal linear growth, normal intellectual development, abnormal eye movement such as nystagmus and sometimes blindness which may be from optic atrophy. Symptoms of increased intracranial pressure may also be present. Some case series have reported hyperactivity, hyperalertness, euphoria and vomiting.
The most common tumour type associated with diencephalic syndrome is pilocytic astrocytoma.
Other gliomas that have been associated with diencephalic syndrome include pilomyxoid astroctyoma, ganglion cell tumours, pleomorphic xanthoastrocytoma, astroblastoma, dysembryoplastic neuroeithelial tumours and choroid plexus tumours.
Usually both the hypothalamus and the optic chiasm are involved. The tumour may be solid or cystic, may compress the frontal lobes and may extend into the third ventricle
Horner syndrome
Horner syndrome presents with homolateral miosis, mild ptosis, and apparent enophthalmos (smaller/sunken appearance) with slight elevation of the lower lid.
Patients may also have decreased facial sweating, increased amplitude of accommodation, and transient decrease in intraocular pressure.
If occurring before two years of age, heterochromia iridis with hypopigmentation may occur on the affected side.
May occur due to:
◾Birth trauma with shoulder dystocia - brachial plexus injury. Klumpke palsy (C8, T1) - “claw hand” where the forearm is supinated and the wrist and fingers are hyperextended. Horner’s secondary to injury of stellate ganglion. Anisocoria (unequal pupils) may sometimes pass undetected for years.
◾Lesions in midbrain, brainstem, upper spinal cord, neck, midline fossa or orbit
◾Post thoracic surgery, e.g. CHD
It can sometimes be the presenting symptom of tumours such as NBL in the cervical or mediastinal regions
Myotonic dystrophy
Caused by a triplet repeat in the DMPK gene.
- decreased fetal movements
- polyhydramnios
-Newborns present with generalised weakness and hypotonia. Facial weakness is a feature and it is not infrequent that the newborn will require ventilatory support
Lysosomal disorders and neuro
White cell lysosomal diseases presenting older (i.e at 8 years of age) would include ◾GM2 gangliosidosis( juvenile Tay Sachs) ◾Gaucher’s type 3, ◾late onset Krabbe’s disease, ◾mannosidosis type 2 ◾metachromatic leukodystrophy-late onset ◾MPS 2 and 7 ◾Niemann Pick type C
A lysosomal storage disease might cause neurological symptoms, but probably not the gum discolouration. Usually the child would have dysmorphism, and more of a developmental delay rather than loss of previously acquired skills.
Lead encephalopathy
Lead intoxication
Blue line in gums
Behavioural changes
Hardly produces any significant changes on CT scan with chronic exposure. But very rarely we do get atrophy and white matter changes on the CT
Syringomyelia
Syringomyelia is where a cyst/syrinx forms within the spinal cord. As the syrinx widens it causes compression of adjacent nerves. Where it affects the anterior horn cells it causes fasciculations. Syringomeyelia is associated with an Arnold Chiari malformation and with other spinal cord abnormalities such as spina bifida or a tethered cord
- may present with long standing clumsiness and mild motor development delay
Fasciculations
Fasciculations occur with anterior horn cell damage. They arise as a result of spontaneous depolarisation of a lower motor neurone leading to the synchronous contraction of all the skeletal muscle fibres within a single motor unit. Fasciculations most often occur in cases of anterior horn cell damage. The anterior/ventral horn is the portion of the spinal cord that contains the motor neurones which innervate skeletal muscle
- SMA
- Syringomyelia
- Other LMN disease
Segawa disease
- Dopa responsive dystonia
- Hereditary progressive dystonia
- AD and AR types
- sx start from about age 4-5 years old
- Progressive dystonia results in unilateral club foot and toe walking
- diurnal variation of toe walking (worse as the day goes on)
- Unilateral equinovarus
- Responds to Rx with L- Dopa
Porencephaly/ Porencephalic cyst
- Porencephaly is the presence of cysts or cavities within the brain that result from developmental defects or acquired lesions, including infarction of tissue or in-utero parenchymal haemorrhage
- True porencephalic cysts are most commonly located in the region of the Sylvian fissure and typically communicate with the subarachnoid space, the ventricular system or both
- They can represent developmental abnormalities of cell migration and are often associated with other malformations of the brain, including microcephaly, abnormal patterns of adjacent gyri and encephalocele
- Several risk factors of porencephalic cyst formation have been identified including: haemorrhagic venous infarctions, carious thrombophilias such as protein C deficiency and factor V Leiden mutations, perinatal alloimmune thrombocytopenia, von Willebrand’s disease, maternal warfarin use, maternal cocaine use, congenital infections, trauma such as amniocentesis and maternal abdominal trauma
- Risk factor is also Congenital heart disease resulting in an in utero insult –> Porencephalic cysts –> Encephalomalacia –> results in motor deficits
Predominant pattern of brain injury in children with congenital heart disease
- predominant pattern of brain injury is focal white matter injury and apparent brain immaturity (similar to preterm infants).
- Can also get porencephalic cysts from in utero insults
-Risk factors include peri-operative hypoxaemia, hypotension and diminished regional cerebral oxygen saturation.
ADEM
- acute disseminated encephalomyelitis
- rapid demyelinating disease
- usually preceded by viral illness
- encephalopathy is a required feature in ADEM
- can get Optic neuritis and transverse myelitis, or other neurological signs like palsies, hemiparesis
- can get seizures
- usually <10 years old
CSF- Mild pleocytosis (<50 wcc), not usually +ve for oligoclonal bands
MRI- multifocal T2 hyperintense lesions in deep and subcortical white matter (relative sparing periventricular areas); involves thalami and basal ganglia commonly
- NOTE cannot tell diff between acute viral encephalitis and ADEM so have to treat with antibiotics/acyclovir until dx ADEM made
RX: Methylpred 5-7 days
Plasmapheresis if non responsive
Recovery quick in 1-6 months
Relapse 10%
Neuromyelitis optica
-Optic neuritis in combination with the transverse myelitis make neuromyelitis optica (NMO) the first diagnostic consideration. Most cases will be aquaporin-4 positive.
MS
- Can get transverse myelitis sx and eye sx
- usually oligoclonal band positive
NMDA encephalitis
- anti- NMDA receptors
- onset usually <12 years
- F>M
- can occur as a result of underlying ovarian teratoma
- present with behaviour change, then abnormal movements (hyperkinetic phase), then unresponsive phase
- seizures
- autonomic instability
- risk of relapse (12% in 2 years)
CSF: NMDA antibody positive
Rx: IV methylpred, IVIG, +/- plasma exchange; rituximab
- recovery is slow up to 3 years
- most have some form of deficit
- Better outcomes if rx early with ritux
Viral labrynthitis vs viral cerebellitis
- both present as unsteady and can have nystagmus
- viral cerebellitis MORE common
- viral labrynthitis often have vomiting and neuro findings can be assymetrical
- both can occur post viral illness
