Neurological Differential Diagnosis - part 8 pps

378 Chapter 11 3 Albinism ◆ Albinism is a genetically determined abnormality in melanin synthesis that is associated with congenital nystagmus, foveal hypoplasia, and impaired visual acuity. ◆ The ocular fundus can be totally devoid of pigment or have a blond appear- ance. The degree of visual impairment is usually inversely related to the degree of ocular pigmentation. 4 Compressive lesions ◆ Craniopharyngiomas ◆ Optic nerve or chiasmatic gliomas – associated with neurofi bromatosis. 5 Hereditary optic atrophies Nystagmus in infants Features Spasmus nutans Congenital nystagmus Age of onset 4 months–3 years Birth Family history Negative Positive or negative Nystagmus Asymmetric (30% unilateral) Bilateral and symmetric Head movement Usually previous to nystagmus Simultaneous with nystagmus Natural history Disappears in 36 months Usually persists Other Guidelines for the determination of brain death in children • Nystagmus in infants can be diffi cult to detect. Although the onset may be at birth but it can be detected later. • The common forms are spasmus nutans and congenital nystagmus. The common distinguishing features are provided in the table below. • Spasmus nutans is a self-limited disorder of infants, characterized by a slow cephalic tremor associated with pendular horizontal and rarely vertical nystagmus that is often monocular. Abnormal head positions are frequently present. • Optic nerve and chiasmatic gliomas can simulate spasmus nutans. Therefore, neuroimaging should always be obtained in such cases. • The guidelines for determination of brain death in children are similar to adults, although they have some unique features, dealing specifi cally with the age group from full-term newborn to the 5-year-old. Pediatric Neurology 379 1 Coma and apnea must co-exist. 2 Absence of brainstem function 2.1 Pupils unreactive to light (midposition or dilated). 2.2 Absence of spontaneous eye movement, or in response to oculocephalic and oculovestibular testing. 2.3 Absence of movement of bulbar musculature, including facial and oro- pharyngeal muscles (corneal, gag, cough, sucking, and rooting refl exes). 2.4 Respiratory movements are absent with patient off the respirator. 2.5 Apnea testing using ‘standardized methods’ can be performed. 3 Absence of hypotension for age or hypothermia. 4 Flaccid muscle tone, absence of spontaneous movements (excluding spinal re- fl exes). 5 Examination consistent with brain death throughout the period of testing and observation. 6 Observation and testing according to age 6.1 7 days to 2 months: two examinations and EEGs separated by 48 hours. 6.2 2 months to 1 year: two examinations and EEGs separated by 24 hours. 6.3 Older than 1 year: when an irreversible cause exists, laboratory testing is not required and an observation period of at least 12 hours is recom- mended. A more prolonged period of at least 24 hours of observation is recommended if it is diffi cult to assess the extent and reversibility of brain damage (e.g. following an hypoxic-ischemic event). The observation pe- riod may be reduced if an EEG demonstrates electrocerebral silence, or the cerebral radionuclide and angiographic study does not visualize cerebral arteries. (Ref: Guidelines for the determination of brain death in children. Pediatrics 1987; 80: 298–300.) Macrocephaly • These features are mainly focused on longer periods of recommended observation relative to the patient’s age as outlined below. • Macrocephaly means enlargement of the head >2 standard deviations from normal. • Statistically, most enlarged heads in children are due to either non- pathological familial large head size or less commonly, hydrocephalus. • There are certain conditions with a large head without signifi cantly enlarged ventricles that occur in the setting of serious neurological abnormalities. Most neurodegenerative conditions of children cause small heads. 380 Chapter 11 1 Benign familial macrocephaly: large parental head size, child with normal de- velopment 2 Hydrocephalus ◆ Features include frontal protuberance, bossing, sunset sign (a tendency for the eyes to turn down so that the sclera is visible between the upper eyelids and iris), thinning and/or prominence of scalp veins, and separation of cranial sutures. 2.1 Obstructive/noncommunicating hydrocephalus 2.1.1 Congenital malformation: aqueductal stenosis, Dandy-Walker, Klippel-Feil syndrome, Chiari II. 2.1.2 Brain tumors: rare; particularly posterior fossa tumors (medulloblas- toma, cerebellar, or brainstem astrocytoma, ependymoma, choroid plexus papilloma), and pineal region tumors. 2.1.3 Vein of Galen malformation: may present with neonatal heart failure. 2.2 Communicating hydrocephalus ■ Secondary to subarachnoid hemorrhage or meningitis. ■ Meningeal malignancy. 3 Benign enlargement of subarachnoid space: also known as benign subdural effusions, etc. ◆ More often in males, associated with large paternal head size. ◆ Distinguished by soft fontanelle, large head, normal development. ◆ Normal ventricular size on CT scan. 4 Subdural hematoma ◆ Signs include bulging fontanelle, vomiting, altered mental status. ◆ Unusual bruising, retinal hemorrhages, or fractures may point to child abuse. 5 Megalencephaly (large brain size) 5.1 Achondroplasia: AD, most are new mutations. True, often alarming, meg- alencephaly. Usually normal cognitive development. 5.2 Sotos syndrome: variable inheritance, megalencephaly with gigantism. 5.3 Hemimegalencephaly: unilateral cerebral enlargement, associated with poor development and intractable seizures/infantile spasms. 5.4 Neurocutaneous disorders: hypomelanosis of Ito, incontinentia pigmenti, neurofi bromatosis, tuberous sclerosis, epidermal nevus syndrome (see Chapter 12: Neurogenetics – Neurocutaneous syndromes). 5.5 Metabolic megalencephaly 5.5.1 Alexander disease (see Developmental regression in toddlers/chil- dren, p. 366) 5.5.2 Canavan disease (see Developmental regression in infants, p. 363) 5.5.3 Glutaric aciduria type I: normal development with macrocephaly until experiencing an encephalopathic event around age 2–3. After this, spasticity and movement disorders may be prominent, with variable cognition. Pediatric Neurology 381 5.5.4 Storage disorders: gangliosidoses (Tay-Sachs, etc.), Krabbe, maple syrup urine disease, metachromatic leukodystrophy, mucopolysac- charidoses (see Developmental regression, pp. 364 and 366). 6 Hydranencephaly ◆ Means hydrocephalus plus destruction or failure of development of parts of the cerebrum, often associated with enlargement of the skull. ◆ The fl uid-fi lled region of the cranium is seen when transilluminated. 7 Conditions with a thickened skull: include anemia, cleidocranial dysostosis, os- teogenesis imperfecta, osteopetrosis, rickets, etc. Nightmares vs. night terrors Nightmare Night terror Repeated, clinically signifi cant awakening from sleep with a detailed recall of disturbing dreams Abrupt, recurrent, and clinically signifi cant awakening from sleep, accompanied by panic and autonomic arousal Individuals rapidly become alert and oriented after awakening from nightmares Individuals are usually unresponsive to the environment and have subsequent amnesia for the episode Polysomnographic recording shows sudden awakening from REM sleep at the time the individual reports nightmares Polysomnographic recording shows sudden partial awakening from NON-REM sleep Often begins in childhood and resolves quickly Onset is usually middle childhood and resolves during late childhood or early adolescence Reassurance only. No therapy or medications are required Reassurance is helpful. Diazepam or clonidine have been used to treat, but are not necessary • Individuals, especially children, sometimes have isolated episodes of sudden arousal from sleep in a condition of terror and confusion. • Common disorders include nightmare and night terror. The important clues for differentiation are provided below. Other differential diagnoses include sleepwalking disorder, other parasomnias, hypnagogic hallucinations in narcolepsy, substance-induced sleep disorders, and nocturnal seizures. • Normal neurological exam 382 Chapter 12 Neurogenetics When to suspect genetic disease 383 Patterns of inheritance 383 Examples of autosomal dominant disorders 384 Examples of autosomal recessive disorders (many others) 385 Examples of X-linked disorders 385 Examples of chromosomal autosomal disorders 385 Examples of sex chromosome disorders 386 Mitochondrial encephalomyopathies 386 Diseases due to trinucleotide repeat expansions 387 Heritable human prion diseases 389 Clinical syndromes 389 Hereditary/genetic ataxias 389 Hereditary/genetic epilepsy syndromes 390 Alzheimer disease genetics 393 Hereditary/genetic movement disorders 393 Hereditary/genetic myopathies 395 Neurocutaneous syndromes 398 Hereditary/genetic peripheral neuropathies 399 Neurological Differential Diagnosis: A Prioritized Approach Roongroj Bhidayasiri, Michael F. Waters, Christopher C. Giza, Copyright © 2005 Roongroj Bhidayasiri, Michael F. Waters and Christopher C. Giza Neurogenetics 383 When to suspect genetic disease 1 Positive family history. This should be explored in detail, as many patients will initially deny any known history of hereditary disease. 2 Unusual morphologic features, especially: ◆ facial dysmorphology ◆ atypical body habitus 3 Absence of obvious alternative etiologies (such as ischemia, infection, and trauma). 4 Clinical constellation with known neurogenetic association, such as: ◆ ataxia ◆ neuropathy ◆ ophthalmoplegia ◆ muscle weakness ◆ progressive myoclonic seizures ◆ developmental regression in children 5 Neurologic disease with additional organ system involvement, such as: ◆ cardiomyopathy ◆ hepatosplenomegaly ◆ cutaneous manifestations ◆ renal disease Patterns of inheritance Patterns of inheritance Risk to offspring Gender bias Transmission Autosomal dominant 50% Males and females equally affected Multiple affected generations and multiple individuals in one generation: includes father to son transmission. Autosomal recessive 25% Males and females equally affected May ‘skip’ a generation. Carriers may be asymptomatic X-linked recessive 50% risk to males or female carriers Males Multiple affected generations and multiple individuals in one generation: father to son transmission is not seen Mitochondrial All children at risk Males and females equally affected Variable expression and disease severity, maternal transmission only 384 Chapter 12 Patterns of inheritance Examples of autosomal dominant disorders • Autosomal dominant nocturnal frontal lobe epilepsy • Benign familial neonatal seizures • Bethlem myopathy • Central core myopathy • Charcot-Marie-Tooth disease (HMSN I) • Childhood absence epilepsy • Dentatorubro-pallidoluysian atrophy • Dopa-responsive dystonia • Essential tremor • Familial amyloid polyneuropathy • Familial episodic ataxia • Familial hyperkalemic periodic paralysis • Familial hypokalemic periodic paralysis • Familial paroxysmal choreoathetosis • Fascioscapulohumeral dystrophy • Hereditary neuralgic amyotrophy • Hereditary neuropathy with pressure palsies • Huntington disease • Hyperekplexia • Juvenile myoclonic epilepsy • Myotonic dystrophy • Neurofi bromatosis 1 • Spinocerebellar ataxias (many types) • Tuberous sclerosis • Von Hippel Lindau disease Autosomal Dominant Autosomal Recessive X-Linked Mitochondrial Neurogenetics 385 Examples of autosomal recessive disorders (many others) • Ataxia telangiectasia • Canavan disease • Cerebrotendinous xanthomatosis • Dejerine-Sottas disease (HMSN III) • Friedreich ataxia • Galactosemia • Gaucher disease • Homocystinuria • Isovaleric acidemia • Krabbe disease • Maple syrup urine disease • Metachromatic leukodystrophy • Mucopolysaccharidosis type I (Hurler) • Mucopolysaccharidosis type III • Neuronal ceroid lipofuscinosis, infantile • Niemann-Pick disease • Phenylketonuria • Propionic academia • Refsum disease, infantile • Sandhoff disease • Spinal muscular atrophy type I (Werdnig-Hoffman) • Tay-Sachs disease • Most congenital metabolic disorders Examples of X-linked disorders • Adrenoleukodystrophy, juvenile • Becker muscular dystrophy • Duchenne muscular dystrophy • Emery-Dreifuss muscular dystrophy • Fragile X syndrome • Lesch-Nyhan disease • Menkes disease • Mucopolysaccharidosis type II (Hunter, X-linked recessive) • Rett syndrome (X-linked dominant, lethal in males?) • Ornithine transcarbamylase defi ciency • X-linked hydrocephalus Examples of chromosomal autosomal disorders • Angelman syndrome (deletion of part of long arm of maternal 15q) • Cri-du-chat syndrome (deletion of short arm of 5p) • Down syndrome (trisomy 21) 386 Chapter 12 • Prader-Willi syndrome (deletion of part of long arm of paternal 15q) • Trisomy 13 • Trisomy 18 Examples of sex chromosome disorders • Klinefelter syndrome (XXY) • XYY karyotype • Turner syndrome (45,X) Mitochondrial encephalomyopathies Disorder Disease features Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Seizures, developmental delay, growth retardation, headaches, and stroke-like episodes with focal neurologic defi cits Myoclonic epilepsy and ragged red fi bers (MERRF) Myoclonus, ataxia, seizures, myopathy, and peripheral neuropathy Leber hereditary optic neuropathy (LHON) Optic disc swelling with visual fi eld loss progressing to involve central vision Neurogenic weakness, ataxia, and retinitis pigmentosa syndrome (NARP) Developmental delay, seizures, dementia, ataxia, sensory neuropathy, proximal weakness, and retinitis pigmentosa Maternally inherited Leigh syndrome (MILS) Dementia, spasticity, optic atrophy Chronic progressive external ophthalmoplegia (CPEO) Ptosis, extra-occular ophthalmoplegia, proximal limb myopathy Kearns-Sayre syndrome (KSS) A CPEO-plus syndrome which includes the above as well as onset prior to age 20 years, heart block, ataxia, and pigmentary retinopathy • Mitochondrial DNA (mtDNA) is nearly exclusively maternally inherited. • mtDNA is a closed, circular DNA molecule consisting of ~16,000 nucleotides coding for 37 genes. • Every cell contains multiple mitochondria with multiple copies of DNA, a condition known as polyplasmy. • Mitochondrial diseases demonstrate a threshold effect, whereby disease onset and severity are a function of the balance between the proportion of mutant and wild-type mtDNAs. • May involve multiple tissues with high energy requirements – such as brain, retina, muscle, cochlea, etc. Neurogenetics 387 Diseases due to trinucleotide repeat expansions Disorder Gene and locus Protein Repeat sequence and location Disease features Inheritance Fragile X syndrome 1/1,500 males FMR1 Xq27.3 FMRP CGG 5’-UTR Mental retardation, elongated facies, large ears, macroorchidism X-linked Friedreich ataxia 1/50,000 X25 9q13–21.1 Frataxin GAA 1st intron Ataxia, dysarthria, extensor plantar response, arefl exia AR Huntington disease 1/20,000 Caucasians 1/100,000 African Americans IT15 4p16.3 Huntington CAG coding Personality change, motor abnormalities, extrapyramidal signs, dysarthria AlzD Myotonic dystrophy 1/7500 DMPK 19q13.3 Myotonic dystrophy protein kinase CTG 3’-UTR Ptosis, facial atrophy, proximal weakness, cardiac conduction abnormalities AlzD Dentatorubro- pallidoluysian atrophy DRPLA 12p13.31 Atrophin-1 CAG coding Ataxia, personality changes, chorea, tonic-clonic seizures, dementia AlzD Spinobulbar muscular atrophy (Kennedy disease) AR Xq13.21 Androgen receptor CAG coding Lower motor neuron disease, feminization X-linked • Unstable expansion of trinucleotide repeats is the mechanism underlying disorders featuring anticipation, the tendency for subsequent generations to be affected at an earlier age and with increased severity. • The molecular mechanisms of disease are poorly understood as the triplet expansions are known to be located in coding sequences (Huntington disease), non-coding sequences (Friedreich ataxia), 5’-untranslated regions (fragile X syndrome), and 3’-untranslated regions (myotonic dystrophy). • CAG repeat expansions that encode polyglutamines appear to result in protein misfolding, a recuring theme in many of these disorders. • DNA molecular diagnostic tests are available. However, estimating disease onset and severity within an individual is not accurately predicted by absolute repeat number. Therefore, great care must be taken to ensure accurate information is provided when using molecular data in genetic counseling, particularly in asymptomatic individuals. Continued [...]... Individuals who are homozygous and carry two APOE-4 alleles have an increased probability (>90%) of developing AlzD by the age of 85 and do so about 10 years earlier than individuals carrying the -2 or -3 allelic variants Gene Chromosome Age at onset % of AlzD Amyloid precursor protein (APP) Presenilin-1 (PS-1) Presenilin-2 (PS-2) Apolipoprotein E (APOE-4 alleles) 21 14 1 19 45–60 30–60 50–65 60+ . (many others) 385 Examples of X-linked disorders 385 Examples of chromosomal autosomal disorders 385 Examples of sex chromosome disorders 386 Mitochondrial encephalomyopathies 386 Diseases due. (deletion of part of long arm of maternal 15q) • Cri-du-chat syndrome (deletion of short arm of 5p) • Down syndrome (trisomy 21) 386 Chapter 12 • Prader-Willi syndrome (deletion of part of long. 1 Presenilin-1 (PS-1) 14 30–60 1–5 Presenilin-2 (PS-2) 1 50–65 < 1 Apolipoprotein E (APOE-4 alleles) 19 60+ 50–60 Hereditary/genetic movement disorders For hereditary ataxias, see p. 389 and Chapter