PaedNeurology Flashcards
At the end of a cranial nerve examination, what should you tell your examiner you would like to do to complete it?
If relevant/not done: assess pupillary responses to light and accommodation, examine patient’s glasses, formally assess acuity, look at fundi/retinal photographs.
Origin of cranial nerves III-IV?
Mid brain
Origin of cranial nerves V-VIII?
Pons
Origin of cranial nerves IX, X, XI, XII?
Medulla or bulb
What is Dravet syndrome?
Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge. Development remains on track initially, with plateaus and a progressive decline typically beginning in the second year of life. Individuals with Dravet syndrome face a higher incidence of SUDEP (sudden unexplained death in epilepsy) and have associated conditions, which also need to be properly treated and managed. These conditions include:
- behavioral and developmental delays
- movement and balance issues
- orthopedic conditions
- delayed language and speech issues
- growth and nutrition issues
- sleeping difficulties
- chronic infections
- sensory integration disorders
- disruptions of the autonomic nervous system (which regulates things such as body temperature and sweating)
SCN1A-Related Seizure Disorders
- Name four of the seizure disorders included in the group.
- Diagnosis?
- Management? Which AEDs should be avoided?
CLINICAL FEATURES.
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.
DIAGNOSIS/TESTING
The diagnosis of SCN1A-related seizure disorders relies on detection of a heterozygous pathogenic variant in SCN1A. The proportion of probands with a pathogenic SCN1A variant is much higher with sequence analysis than with deletion/duplication analysis.
MANAGEMENT
Treatment of manifestations: Antiepileptic drugs (AEDs) include benzodiazepines (diazepam and clonazepam), stiripentol (used in Europe; not currently FDA approved for use in the US), topiramate, and valproic acid. Clobazam can be used for the treatment of seizures in Lennox-Gastaus syndrome. Phenobarbital is effective but poorly tolerated because of its effects on cognition. Use of the ketogenic diet to decrease seizure frequency has been beneficial in some affected individuals.
Prevention of secondary complications: Use of protective helmets by individuals with atonic seizures or myoclonic-astatic epilepsy.
Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration; EEG monitoring for new or different seizure types.
Agents/circumstances to avoid: AEDs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis. Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing, swimming, driving, or working/playing at heights).
Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of the use of antiepileptic drugs during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4000 µg daily; the effects of pregnancy on anticonvulsant metabolism; and the effect of pregnancy on maternal seizure control.
Other: The AEDs clobazam and stiripentol, used in treatment of SMEI, are not FDA-approved for this use in the US. Sleep deprivation and illness can exacerbate seizures. Persons with epilepsy should be made aware of motor vehicle driving laws.
Genetic counseling.
SCN1A-related seizure disorders are inherited in an autosomal dominant manner. A proband with anSCN1A-related seizure disorder may have an inherited or de novo mutation. The proportion of cases caused by de novomutation varies by phenotype: the percentage of probands with an SCN1A-related seizure disorder and an affectedparent decreases as the severity of the phenotype in the proband increases; thus, most SCN1A-related SMEI and ICE-GTC are the result of de novo mutation. Each child of an individual with an SCN1A-related seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.
Differential diagnosis for acute encephalopathy in the neonate
Sub-categories of metabolic disorders that you would consider?
How do organic acidaemias present?
How do amino acidemias and urea cycle defects present?
Give two examples of peroxisomal disorders. How do they present?
NEJM Case 28-2008
An 8-Day-Old Infant with Congenital Deafness, Lethargy, and Hypothermia
This is a difficult clinical situation because of the urgency with which treatable disorders must be identified from a broad list of potential causes. The initial differential diagnosis includes disorders related to
- trauma
- infection
- epilepsy
- toxins
- hypoxia–ischemia
- metabolic
Potential clues in this case included an unwitnessed fall shortly after birth, sensorineural deafness, and hypothermia without other signs of shock. Remember to ask about fetal movements, any trauma, hearing screen, feeding, etc.
- TRAUMA
Trauma is an important consideration in an afebrile infant presenting with acute changes in mental status, particularly in light of the history of an unwitnessed fall. The increase in head circumference from 33 to 35.5 cm in the 8 days before admission and the tense anterior fontanelle could be the consequence of traumatic intracranial bleeding. Retinal hemorrhage is strongly associated with traumatic brain injury and at this age is unlikely to be related to delivery.1 The cerebrospinal fluid was bloody and did not clear, and the xanthochromia indicates bleeding at least several hours before the lumbar puncture.2 Although basilar skull fractures can cause hearing loss, trauma is not a likely cause of this infant’s bilateral sensory deafness.3
Radiologic examinations are the best means to evaluate closed head injuries associated with reduced levels of consciousness.
- INFECTIONS
Infections are important treatable causes of acute encephalopathy in infancy. Although this infant was afebrile, hypothermia is frequent in overwhelming infections in infancy. However, hypothermia due to infection is usually associated with shock,5 and there were few such signs in this infant. Other vital signs were normal, no suggestive findings were reported from the initial physical examination, and the initial laboratory evaluations did not reveal evidence of multisystem involvement.
Bacterial meningitis in this age group is most frequently due to group B streptococci, Escherichia coli, or Listeria monocytogenes.6 Although there was no nuchal rigidity on the initial physical examination, its absence does not exclude meningeal irritation in very young infants. The cell counts in the blood and cerebrospinal fluid are not suggestive of bacterial infection, particularly an advanced infection causing this degree of encephalopathy. The MRI findings of symmetric injury to deep nuclei and brain-stem structures are not suggestive of meningitis, in which the cerebral cortex is most frequently compromised, presumably due to its greater proximity to the inflamed meninges.7 Although perforating arteries supplying deep brain structures are occasionally compromised in meningitis, the extent and symmetry of the lesions in this patient do not suggest such a cause.
Congenital infections present in the perinatal period, and two of these, rubella and cytomegalic virus, are associated with congenital sensorineural deafness. This infant did not have microcephaly, systemic involvement, intracranial calcifications, or retinopathy, making congenital infection unlikely, and polymerase-chain-reaction (PCR) assay and maternal antibody testing ruled out these diagnoses. Acquired enteroviral8 and herpes simplex viral infections can present with isolated central nervous system disease in this age group, although enteroviral infections in the absence of systemic disease are not associated with such severe hemorrhagic complications, and the negative PCR results on the cerebrospinal fluid analysis substantially reduce the probability of a herpes simplex infection.
3-5: SEIZURES, TOXIN AND CVAs
Seizures are a common cause of acute alterations in consciousness. The tonic eye deviation and posturing observed in this infant raise the possibility of seizures, although the infant responded more clearly to ventricular drainage than to anticonvulsant therapy. The cerebrospinal fluid, imaging studies, and electroencephalography indicate that epilepsy is not the primary problem in this case. Toxic causes of acute encephalopathy are an important initial consideration, although ingestion of a central nervous system depressant as a cause is unlikely in light of the evidence of hemorrhage, and ingestion of an anticoagulant is unlikely in the absence of systemic bleeding and with normal coagulation studies.
Strokes are relatively common in the perinatal period and frequently present with an isolated decline in mental status, although they generally present in the immediate perinatal period and rarely cause this degree of encephalopathy.9 Although hemorrhage and edema are common acute sequelae of strokes, the distribution of injuries observed in this infant are not consistent with arterial compromise, and there was no evidence of venous thrombosis on magnetic resonance venography. A global hypoxic–ischemic injury can present with encephalopathy and symmetric hemorrhagic injury to the basal ganglia, thalamus, and brain stem.10 An unwitnessed asphyxial event or arrhythmia could lead to such a presentation but is much less likely in the absence of evidence of injury to other organ systems.
METABOLIC DISORDERS
Metabolic causes of acute encephalopathy in infancy include disordered metabolism of
- organic acids
- amino acids
- ammonia
- glucose
- peroxisomal disorders
- mitochondrial disorders
- Organic acidemias present with vomiting and systemic acidosis and can thus be ruled out in this patient.
- Amino acidemias and urea-cycle defects can present acutely with seizures and encephalopathy in the case of a catabolic stress that increases protein breakdown, such as an intercurrent infection. However, the brain injuries shown on CT and MRI are not consistent with these causes.
- Defects of gluconeogenesis, such as galactosemia, could present with hypoglycemia and secondary encephalopathy and brain injury. However, galactosemia presents with vomiting, acidosis, and jaundice, and the newborn screening for this disease was negative.
- Peroxisomal disorders, such as Zellweger’s syndrome and infantile adrenoleukodystrophy, which are due to mutations in genes required for metabolism of fatty acids and result in an accumulation of lipids in the nervous system, can present with encephalopathy, but this condition is manifested at the time of birth; in addition, dysmorphic features and hepatomegaly are common, and these disorders are not associated with cerebral hemorrhage.
Mitochondrial Disorders
Mitochondrial disorders often present with acute decompensation with overwhelming lactic acidosis and shock or with encephalopathy alone in the neonatal period and early infancy.11 The elevated lactate levels in the cerebrospinal fluid but not in the blood in this patient suggest a mitochondrial disorder expressed predominantly in the brain. In contrast to the other disorders considered thus far, the MRI findings are strongly suggestive of a mitochondrial disorder. Leigh’s syndrome, also known as subacute necrotizing encephalopathy, presents in infancy with symmetrical injuries to the basal ganglia and thalamus, deep white matter, brain stem, cerebellum, and spinal cord, with relative sparing of the cerebral cortex,12,13 precisely the distribution of injury in this case. Although this infant’s presentation is hardly subacute, in early infancy Leigh’s syndrome frequently presents as an acute encephalopathy. Furthermore, the disease process probably began before admission; the observed increase in head circumference would not occur immediately after an acute hemorrhage. An increase in head circumference has been reported in early infantile presentations of Leigh’s syndrome14,15 and indicates that the subacute descriptor is appropriate. The sudden onset of this infant’s symptoms may have been due to cumulative damage to brain-stem structures or to an acute increase in intracranial pressure because of bleeding.
Cerebral hemorrhage, which was prominent in this infant even before the platelet count fell, is uncommon in Leigh’s syndrome16 but is common in a related disorder, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke). However, there was no systemic lactic acidosis; the symmetry and exclusively subcortical location of the injury would be unusual for MELAS, and that disorder almost always presents in older children and young adults. Hemorrhages in the thalamus, midbrain, and retina are common in Wernicke’s encephalopathy, which is due to a thiamine-responsive reduction in the activity of enzymes such as pyruvate dehydrogenase that are necessary for carbohydrate oxidation; congenital deficiency of pyruvate dehydrogenase is a frequent cause of Leigh’s syndrome. Wernicke’s encephalopathy and the mitochondrial encephalopathies of infancy may present with hypothermia without other evidence of shock, presumably due to hypothalamic injury. This infant had hearing loss, which is common in mitochondrial cytopathies. Although such hearing loss is not typically congenital, its presence in an infant with encephalopathy may be an important clue to the diagnosis of a mitochondrial cytopathy. NB: They started thiamine empirically in this infant during work-up.
The MRS in this case suggests increased brain lactate, but this could not be definitively demonstrated. Although elevated lactate in the cerebrospinal fluid strongly suggest a disorder of oxidative phosphorylation, the clinical response to a ventricular tap suggests that this patient probably had reduced cerebral perfusion at some time, and it is also possible that the elevated lactate on MRS and in the cerebrospinal fluid reflected compromised tissue perfusion or mitochondrial dysfunction associated with hemorrhage rather than a primary mitochondrial disorder.
In summary, it is likely that this infant with acute encephalopathy and hypothermia, increasing head circumference, extensive symmetric injury to deep gray-matter structures, elevated lactate in the cerebrospinal fluid, and sensorineural hearing loss had a mitochondrial encephalopathy. The distribution of injuries is strongly suggestive of Leigh’s syndrome, although the amount of hemorrhage is unusual. When lesions have atypical characteristics, the term “Leigh-like syndrome” is used, and that diagnosis seems most appropriate in this case.
Leigh’s syndrome is a phenotype defined by the presence of hemorrhagic necrosis in the deep gray-matter structures of the brain, brain stem, and spinal cord, as seen in this patient. The disease is caused by abnormalities in mitochondrial energy metabolism that affect the vascular endothelium, presumably resulting in ischemia; mutations in genes that are associated with these pathways are found in some patients. As with most mitochondrial cytopathies, the reason for the specific distribution of the lesions is not known. Even in a family with the same mitochondrial genetic defect, one sibling can have Leigh’s syndrome while another has a different neurodegenerative disease.
The mitochondrion has both mitochondrial and nuclear genetic input into its structure and function, and defects in both have been associated with Leigh’s syndrome. The disease is most commonly associated with defects in complex IV (cytochrome oxidase), complex I, or the pyruvate dehydrogenase pathway. The muscle biopsy was tested for abnormalities in the electron transport chain. There was decreased citrate synthase activity, suggesting a decreased number of mitochondria, and deficiencies were found in multiple electron-transport-chain enzymes: complexes I, II, and IV. An elevation in the levels of long-chain acetylcarnitines was present, suggesting secondary dysfunction in fatty acid oxidation in the context of oxidative–phosphorylation abnormalities. Pyruvate dehydrogenase deficiency was ruled out by the normal pyruvate level in the cerebrospinal fluid and the presence of multiple deficiencies in the electron transport chain.
The finding in this case of a deficiency of complex II in addition to complexes I and IV is unusual. Complex II has four structural subunits, none of which are encoded in the mitochondrial DNA (mtDNA). The presence of multiple deficiencies in the electron transport chain, including complex II, together with the lack of a family history supporting maternal inheritance, would make a primary mtDNA-encoded defect unlikely.
To better characterize this disorder and to offer genetic risk assessment for the family, molecular diagnostic studies were pursued. No mutations in mtDNA, including those associated with lactic acidosis and stroke (MELAS; mtDNA 3243, tRNALeu), mitochondrial encephalopathy with ragged red fibers (MERRF; mtDNA 8344, tRNALys), and neuropathy, ataxia, and retinitis pigmentosa (NARP; mtDNA 8993, ATPase 6), were found on full mtDNA screening by microarray analysis. Analysis for mtDNA deletion and duplication in muscle was normal. Testing for mtDNA depletion in muscle was not performed, since nuclear factors that underlie the stability of mtDNA may cause multiple complex deficiencies in the electron transport chain, but complex II would not be expected to be deficient, as it was in this patient.
Genes encoding nuclear DNA (nDNA) that are associated with structural complex defects in the electron transport chain have been identified, but all result in dysfunction in a single complex. Nonstructural nDNA genes that are important in a variety of mitochondrial functions have been described, some of which have been associated with Leigh’s syndrome. Testing for these abnormalities is not widely available and was not pursued. Testing was negative for abnormalities in SLC26A4 (Pendred’s syndrome), mitochondrial hearing loss gene GJB6 (connexin 30), GJB2 (connexin 26), and hearing loss–associated mtDNA mutations at nucleotide positions 8296, 8344, 8356, and 8363 (tRNALys) and 7445, 7472, 7510, 7511, and 7512 (tRNASer).
In summary, the diagnosis of Leigh’s syndrome is supported by the clinical and neuroimaging abnormalities, the gross and microscopic pathological findings, and the presence of multiple deficiencies in the electron transport chain in muscle. No specific molecular diagnosis was made, as is the case in 20 to 50% of cases of Leigh’s syndrome, since the majority of nDNA-encoded proteins that are important in mitochondrial function, structure, replication, segregation, and stability have not been identified. Since no mtDNA mutation was identified, the abnormality is presumed to be in nDNA, so that the genetic risk of having an affected infant is substantially less than 100% for subsequent pregnancies in this mother. However, we do not know whether a sporadic mutation occurred in the patient or whether it is an inherited disorder, and thus we cannot further predict the genetic risk for future pregnancies.
