Pediatrics

PEDIATRICS

12.1	Acute Cerebellar Ataxia

Case History

A 4-year-old boy presented with gait unsteadiness and increased falls several days after recovering from a flu-like illness.

Diagnosis: Acute Cerebellar Ataxia

Images 12.1A–12.1D: Axial and coronal fluid-attenuated inversion recovery (FLAIR) images demonstrate hyperintensity of the cerebellum, the right more than the left, in a patient with acute cerebellar ataxia.

Introduction

Ataxia is a disturbance in the smooth, accurate coordination of the limbs, eyes, and gait, usually resulting from cerebellar dysfunction. Acute ataxia is defined as unsteadiness of walking or of fine motor movement, of less than 72 hours duration, in a previously well child.

Causes include infection, postinfectious inflammatory conditions, toxins, tumors, trauma, and vascular disorders. Most are benign and self-limiting, though some conditions are potentially life-threatening.

Clinical Presentation

Acute cerebellar ataxia is the most common cause of acute ataxia, representing 30% to 50% of cases. It affects children aged 2 to 5 years, with boys more affected than girls. It is a postinfectious condition, often seen after infection with the varicella or Epstein–Barr virus. It may also be seen after vaccination, though less commonly than with vaccine-preventable diseases.

It presents with an unsteady gait, ranging from a wide-based gait to the complete inability to walk. Examination reveals a wide-based, unsteady gait, characterized by lurching and staggering. Symptoms develop over hours to days.

Other signs of cerebellar dysfunction include dysarthria, abnormal truncal tone with titubation or sporadic jerking movements of the trunk, arm ataxia, nausea and vomiting, and nystagmus. On general examination, patients may exhibit evidence of viral exanthema.

Radiographic Appearance and Diagnosis

In acute cerebellar ataxia, the characteristic finding is hyperintensity of the cerebellum on T2-weighted images (T2WIs), which is often asymmetric. There may be restricted diffusion and mild cortical and meningeal enhancement with the addition of contrast. CT scans are less sensitive, but are appropriate to rule out life-threatening conditions, such as hydrocephalus, trauma, hemorrhage, and mass lesions.

There is no specific test to diagnose acute cerebellar ataxia. Though it is the most common cause of acute ataxia in children, life-threatening etiologies must be ruled out first. Accidental toxic ingestion is a common cause of acute ataxia in children, and should be investigated with a toxicology screen. Basic metabolic panel is important to evaluate for hypoglycemia. In select cases where there is concern for an underlying metabolic disorder, appropriate labs should be ordered.

Cerebrospinal fluid (CSF) analysis may reveal a mild protein elevation or a mild lymphocytic pleocytosis.

Treatment

Acute cerebellar ataxia is generally a self-limiting process, with most patients returning to normal after several weeks. Less than 10% of patients are left with permanent symptoms. In rare cases, cerebellar edema may lead to occlusion of the fourth ventricle and ventricular drainage may be lifesaving.

Some children have recurrent attacks, typically preceded by illness. Such patients are sometimes managed with immunotherapies prophylactically to shorten courses of symptoms.

References

1. Nussinovitch M, Prais D, Volovitz B, Shapiro R, Amir J. Post-infectious acute cerebellar ataxia in children. Clin Pediatr (Phila). September 2003;42(7):581–584.

2. De Bruecker Y, Claus F, Demaerel P, Ballaux F, Sciot R, Lagae L, Buyse G, Wilms G. MRI findings in acute cerebellitis. Eur Radiol. August 2004;14(8):1478–1483.

3. Desai J, Mitchell WG. Acute cerebellar ataxia, acute cerebellitis, and opsoclonus-myoclonus syndrome. J Child Neurol. November 2012;27(11):1482–1488.

12.2	Germinal Matrix Hemorrhage

Case History

A premature child had a routine head ultrasound.

Diagnosis: Germinal Matrix Hemorrhage

Images 12.2A–12.2D: Ultrasound showing blood throughout the ventricles (red arrows) and brain parenchyma (yellow arrows).

Introduction

The germinal matrix is a thick layer of immature neuronal and glial cells under the ependymal lining of the ventricles where glial and neuronal differentiation occurs during embryogenesis. Cells migrate peripherally from there using radial glia to form the cerebral cortex. It is densely vascular, though the walls of the blood vessels are weak and vulnerable to ischemia with subsequent hemorrhage in premature infants. The risk of hemorrhage is directly related to the gestational age. Nearly 80% of infants born before 24 weeks have such hemorrhages, with the risk declining every week thereafter. Other risk factors include prolonged labor and low birthweight. By 35 to 36 weeks gestation the germinal matrix has disappeared and there is no risk of hemorrhage.

Most hemorrhages are thought to occur during delivery or in the first few hours after birth. The bleeding occurs initially between the caudate nucleus and the thalamus, at the floor of the lateral ventricle near the foramen of Monro, an area known as the caudothalamic groove. Larger bleeds may expand into the lateral ventricles leading to an intraventricular hemorrhage (IVH).

Clinical Presentation

The clinical outcome is directly related to the grade of the bleed. Grade I and II hemorrhages have a favorable outcome. There is a 20% to 25% mortality in grade III hemorrhages, and over 90% mortality with grade IV hemorrhages. Survivors are at high risk for cerebral palsy and mental retardation. Over 90% are found within 4 days of birth, and nearly half within 5 hours.

Radiographic Appearance and Diagnosis

Suspected cases are best investigated with ultrasounds. As seen in Images 12.2A–12.2C, germinal matrix hemorrhages are echogenic regions. The choroid plexus is normally located there, but any hemorrhage located anterior to this groove is pathological.

Images Hemorrhages are graded on a four-point scale:

1. Grade I: The bleed remains in the subependymal region.

2. Grade II: The bleed extends into the ventricles, but fills less than half of the volume.

3. Grade III: The blood fills and dilates the ventricles.

4. Grade IV: The blood extends into the brain parenchyma. Examples are shown in Images 12.2A–12.2C.

Images In Images 12.2A–12.2D, a grade IV IVH is shown on the right, and a grade III IVH is shown on the left.

Images Complications of survivors include hydrocephalus.

Images Another complication is periventricular white matter infarction, which is thought to be a venous infarct of the white matter adjacent to the hemorrhage. Other patients may develop porencephalic cysts.

Images 12.2E and 12.2F: Gross pathology of grade 4 IVHs (image credit www.wikidoc.org via Professor Peter Anderson, DVM, PhD, and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology).

Images 12.2G–12.2J: Axial T2-weighted images demonstrate massive hydrocephalus in an infant who suffered a grade IV IVH.

Images 12.2K and 12.2L: Axial T2-weighted and T1-weighted images demonstrate a cyst in the left frontal lobe. This is the same patient whose ultrasound is shown in Images 12.2A–12.2D.

Treatment

Images In grade III and IV hemorrhages, CSF drainage may be attempted to relieve hydrocephalus. Postnatal administration of phenobarbital was found to increase the need for mechanical ventilation.

References

1. Fukui K, Morioka T, Nishio S, et al. Fetal germinal matrix and intraventricular haemorrhage diagnosed by MRI. Neuroradiology. January 2001;43(1):68–72.

2. Woodward LJ, Andeson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006;355:685–694.

3. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res. 2010;67:1–8.

4. Meneguel JF, Guinsburg R, Miyoshi MH, et al. Antenatal treatment with corticosteroids for preterm neonates: impact on the incidence of respiratory distress syndrome and intra-hospital mortality. Sao Paulo Med J. March 2003;121(2):45–52.

5. McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clin Perinatol. December 2008;35(4):777–792.

12.3	Hypoxic-Ischemic Encephalopathy

Case History

A newborn infant was found to have low Apgar scores and was unable to breathe independently after labor was complicated by placental abruption.

Diagnosis: Hypoxic-Ischemic Encephalopathy

Images 12.3A–12.3D: Diffusion-weighted images and apparent diffusion coefficient (ADC) map demonstrate restricted diffusion of the thalami (red arrows).

Introduction

Hypoxic-ischemic encephalopathy (HIE) occurs in a newborn when there is global hypoxic-ischemic brain injury.

Clinical Presentation

Severely affected newborns have low Apgar scores at birth. Within 24 hours, they develop seizures and apnea. Patients with mild injury may make a full recovery, but survivors suffer from a spectrum of cerebral palsy and seizures. It accounts for approximately 25% of neonatal deaths. The prognosis for preterm infants is worse. Mildly affected infants may have no immediate symptoms, but are at risk of spastic weakness, cognitive delay, and vision and hearing impairments.

Radiographic Appearance and Diagnosis

MRI is the modality of choice to image neonates with suspected HIE. There is a variable appearance depending on whether the ischemia is total or partial, whether the infant is preterm or term, and the timing of the imaging after the injury. Though there is some overlap, several main patterns are recognized in HIE. In order of descending frequency, they are:

1. Watershed Injury. The white matter and cortex of the vascular watershed areas are vulnerable to injury. The changes can be unilateral or bilateral and are first visible on diffusion-weighted images.

Necrosis of the periventricular white matter is seen and is referred to as periventricular leukomalacia. This is followed by cyst formation and eventually parenchymal loss and hydrocephalus ex vacuo.

Images 12.3E–12.3J: Diffusion-weighted images and ADC map demonstrate acute infarctions of the bilateral frontal and occipital lobes and deep gray matter in a newborn with HIE.

Images 12.3K–12.3M: Axial T2-weighted images demonstrate extensive periventricular white matter hyperintensities due to periventricular leukomalacia.

2. Basal Ganglia and Thalamic Lesions. This occurs after acute and severe hypoxia in term birth. Mechanisms include a ruptured uterus, placental abruption, or cord prolapse. The earliest and most sensitive finding is restricted diffusion in the thalami, posterior limb of the internal capsule, and/or basal ganglia, as seen in Images 12.3A and 12.3B. Other characteristic findings include hyperintensity on unenhanced T1-weighted images (T1WIs) in the thalami and basal ganglia. The brainstem can also be involved in severe cases.

Images 12.3N and 12.3O: Axial T1-weighted images demonstrate hyperintensity of the basal ganglia, thalamus, and brainstem in an infant with HIE.

In normal, full-term newborns, the posterior limb of the internal capsule is hyperintense on T1WI and hypointense on T2WI. In infants with severe, acute HIE, absence of normal hyperintensity on T1WI is characteristic, and is known as the “absent posterior limb sign.”

3. Multicystic Encephalopathy. Multicystic encephalopathy occurs after infants experience mild signs of hypoxia ischemia, followed by an unexpectedly severe encephalopathy, most commonly after term birth. The presumed mechanism is a protracted, difficult delivery. It presents radiographically with multiple cysts of the white matter and cerebral cortex. The cystic cavities are traversed by a web of delicate glial strands and contain fluid, debris, and macrophages. Ulegyria refers to shrunken deep cortical gyri, usually in the parasagittal region. It is one of the leading causes of epilepsy arising from the posterior cortex.

Images 12.3P and 12.3Q: Axial T2-weighted and T1-weighted images demonstrate hyperintensity of the brainstem, basal ganglia, and thalami. There is hypointensity of the posterior limb of the internal capsule (red arrows). Images 12.3R and 12.3S: Axial T2-weighted and T1-weighted images demonstrate normal hypointensity and hyperintensity of the posterior limb of the internal capsule (yellow arrows).

Over time, severe cases of multicystic encephalopathy may cause necrosis such that the brain essentially vanishes, leaving only the meninges remaining.

Treatment

A number of randomized controlled trials have shown that therapeutic hypothermia is beneficial in term and late preterm newborns with HIE in both reducing mortality and improving neurodevelopment outcomes in both term and preterm infants if started before 6 hours of age.

Images 12.3T–12.3W: Axial T2-weighted and T1-weighted images demonstrate diffuse cortical signal abnormality in a patient and cystic changes in the white matter in a patient with multicystic encephalopathy.

Images 12.3X and 12.3Y: Axial and sagittal T2-weighted images demonstrate complete loss of the brain in a child with severe HIE.

References

1. Heinz ER, Provenzale JM. Imaging findings in neonatal hypoxia: a practical review. AJR Am J Roentgenol. January 2009;192(1):41–47.

2. Cabaj A, Bekiesińska-Figatowska M, Mądzik J. MRI patterns of hypoxic-ischemic brain injury in preterm and full term infants—classical and less common MR findings. Pol J Radiol. July–September 2012;77(3):71–76.

3. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. January 2013:1.

4. de Vries LS, Groenendaal F. Patterns of neonatal hypoxic–ischaemic brain injury. Neuroradiology. June 2010;52(6):555–566.

5. Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. April 2015;169(4):397–403.

12.4	Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

Case History

A 10-year-old boy presented with acute visual loss and headaches. A similar episode happened two years ago. He was found to have a right homonymous hemianopsia on examination.

Diagnosis: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

Images 12.4A–12.4D: Axial FLAIR and diffusion-weighted images demonstrate acute infarction in the left temporal and occipital lobes and older lesions in the right occipital and frontal and bilateral temporal lobes in a patient with MELAS.

Introduction

MELAS is a rare mitochondrial disorder that results from mutations in multiple different genes. As it is a mitochondrial disorder, the condition is inherited only from mothers, though both sexes are equally affected.

Clinical Presentation

It presents in patients under 40 with weakness, myalgias, headaches, loss of appetite, vomiting, and seizures. Patients have “stroke-like” events, which are so named because they often do not conform to specific vascular territories. Clinically, the episodes present with hemiparesis, encephalopathy, deafness, visual field defects, aphasia, and headaches. Though they may be temporary initially, there is permanent damage over time. Generalized and partial seizures can occur. Dementia is common at the end stage of the illness.

Lactic acidosis can lead to muscle pain, weakness, spasms, and fatigue as well as gastrointestinal (GI) disturbances (vomiting, incontinence, and abdominal pain), and dyspnea.

Non-neurological symptoms include endocrinopathies, short stature, renal impairment, and cardiac dysfunction.

Radiographic Appearance and Diagnosis

MRI shows infarctions, primarily in the parietal, occipital, or posterior temporal lobes. They may be symmetric or asymmetric, and acute infarctions will show restricted diffusion.

Basal ganglia calcifications are common in older patients and are best seen on CT.

MR spectroscopy may demonstrate elevated lactate level, even in normal-appearing brain and CSF.

Ragged red fibers are a characteristic finding on muscle biopsy.

Elevated lactic acid can be found in the serum.

Treatment

The disease is progressive and eventually fatal. Though controlled trials are lacking, a number of supplements and antioxidants have shown benefits including CoQ10, L-carnitine, citrulline, arginine, and vitamins K-3 and K-1. MELAS patients have a decreased nitrous oxide dependent vasodilation, and this may represent a future therapeutic target. Management of seizures and other symptoms is paramount.

Image 12.4E: Axial CT image demonstrates bilateral basal ganglia calcifications.

Image 12.4F: Gomori trichrome stain demonstrating ragged red fibers in a patient with MELAS (photo credit Nephron).

References

1. Santa KM. Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Pharmacotherapy. November 2010;30(11):1179–1196.

2. El-Hattab AW, Emrick LT, Chanprasert S, Craigen WJ, Scaglia F. Mitochondria: role of citrulline and arginine supplementation in MELAS syndrome. Int J Biochem Cell Biol. March 2014;48:85–91.

3. El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. September–October 2015;116(1–2):4–12.

4. Koga Y, Povalko N, Nishioka J, Katayama K, Yatsuga S, Matsuishi T. Molecular pathology of MELAS and L-arginine effects. Biochim Biophys Acta. May 2012;1820(5):608–614.

5. El-Hattab AW, Emrick LT, Craigen WJ, Scaglia F. Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. Mol Genet Metab. November 2012;107(3):247–252.

12.5	Septo-Optic Dysplasia

Case History

A 2-year-old child presented with short stature. He had nystagmus as an infant.

Diagnosis: Septo-Optic Dysplasia

Images 12.5A–12.5D: Axial and coronal T2-weighted images demonstrate atrophy of the optic nerves (yellow arrows) and chiasm (red arrow) as well as absence of the septum pellucidum (blue arrow).

Introduction

Septo-optic dysplasia (SOD) is a congenital disorder characterized by:

Absence of septum pellucidum

Hypoplasia of the optic nerves

Hypoplasia of the pituitary gland

Two of these three features are needed for diagnosis, and only one-third of patients have all three.

It is rare, affecting about 1:10,000 newborns.

There is no single cause, but it has been linked to young maternal age, maternal diabetes, substance use during pregnancy, and certain medications. It is sporadic in most cases, but in some families, a genetic cause has been discovered.

Clinical Presentation

There is a highly variable clinical presentation. Patients present with visual dysfunction, which ranges from a mild decrease in visual acuity to total blindness. Nystagmus is common in infants. Similarly, there is a wide range of dysfunction of the pituitary–hypothalamic axis. Deficiency of growth hormone is the most common symptom. Severe cases cause panhypopituitarism, and newborns suffer from neonatal jaundice and hypoglycemia. Some patients suffer seizures, and while most patients have cognitive dysfunction, some have normal intellectual functioning.

Radiographic Appearance and Diagnosis

The findings of SOD are best visualized on MRI. It will show absence of the septum pellucidum as well as hypoplasia of the pituitary stalk and optic nerves/chiasm.

It is associated with schizencephaly in 50% of cases as well as holoprosencephaly and cortical malformations, such as polymicrogyria (PMG) and cortical dysplasia.

Treatment

Replacement of pituitary hormones is the mainstay of treatment along with antiepileptic medications.

References

1. Maurya VK, Ravikumar R, Bhatia M, Rai R. Septo-optic dysplasia: Magnetic Resonance Imaging findings. Med J Armed Forces India. July 2015;71(3):287–289.

2. Shammas NW, Brown JD, Foreman BW, Marutani DR, Maddela D, Tonner D. Septo-optic dysplasia associated with polyendocrine dysfunction. J Med. 1993;24(1):67–74.

3. Campbell CL. Septo-optic dysplasia: a literature review. Optometry. July 2003;74(7):417–426.

12.6	Aicardi Syndrome

Case History

A 4-month-old infant presented with infantile spasms.

Diagnosis: Aicardi Syndrome

Images 12.6A–12.6C: Axial T2-weighted and sagittal postcontrast T1-weighted images demonstrate absence of the corpus callosum (red arrows), dilatation of the occipital horns of the lateral ventricles (yellow arrow), and mild cerebellar hypoplasia. Image 12.6D: Gross pathology demonstrates absence of the corpus callosum.

Introduction

Aicardi syndrome is a rare X-linked genetic developmental disorder. Mostly females are affected as this disorder can be fatal in males except those with 47XXY karyotype (Klinefelter syndrome). All cases are sporadic.

It affects less than 1 in 100,000 newborns.

Clinical Presentation

It presents due to pathology of the eye, brain, and spine. There is a wide spectrum of severity.

Infantile spasms are the common presenting feature and start around 5 months of age. Seizures are often progressive and refractory to medications. Intellectual disability and microcephaly are common.

Image 12.6E: Microphthalmia of the right eye (image credit Etan J. Tal). Image 12.6F: Coloboma (image credit National Eye Institute).

Chorioretinal lacunes are holes in the pigmented layer of the retina adjacent to the optic disc and are consistently found in aqueductal stenosis. Other ocular abnormalities include microphthalmia (small or poorly developed eyes) and a coloboma (a gap or hole in the optic nerve). Blindness is common.

In the spine, scoliosis and spina bifida are common as are dysmorphic facial features.

Many patients have GI disturbances including reflux, constipation, and poor feeding.

Radiographic Appearance and Diagnosis

Agenesis or malformation of the corpus callosum is a characteristic feature. Cerebellar hypoplasia is seen in over 90% of cases. Other findings include microcephaly, polymicrogyria porencephalic cysts, and colpocephaly (enlargement of the occipital horns of the lateral ventricle).

Treatment

There is no direct treatment. Treatment involves controlling of seizures and therapy for developmental delay. Porencephalic cysts may require surgical drainage, and hydrocephalus may require shunting.

References

1. Crow YJ. Aicardi-Goutières syndrome. Handb Clin Neurol. 2013;113:1629–1635.

2. Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol. June 2008;50(6):410–416.

3. Hopkins B, Sutton VR, Lewis RA, Van den Veyver I, Clark G. Neuroimaging aspects of Aicardi syndrome. Am J Med Genet A. November 2008;146A(22):2871–2878.

Unless otherwise stated, all pathology images in this chapter are from the website http://medicine.stonybrookmedicine.edu/pathology/neuropathology and are reproduced with permission of the author, Roberta J. Seidman, MD, Associate Professor. Unauthorized reproduction is prohibited.

12.7	Joubert’s Syndrome

Case History

A 2-year-old child presented with developmental delay and macrocephaly. The child was hypotonic, but with brisk reflexes on exam.

Diagnosis: Joubert’s Syndrome

Images 12.7A and 12.7B: Sagittal T1-weighted and axial T2-weighted images demonstrate atrophy of the cerebellar vermis, creating the “bat-wing” appearance of the fourth ventricle (red arrow) and “molar tooth” sign. The dentate nuclei of the cerebellum are dysplastic (yellow arrow).

Introduction

Joubert’s syndrome is a ciliopathy, a genetic disorder of the cellular cilia, that causes abnormal development of the brainstem and atrophy of the cerebellar vermis.

It affects 1 in 80,000 and 1 in 100,000 newborns. It has an autosomal-recessive pattern of inheritance and at least 20 different genes have been discovered.

Clinical Presentation

Infants present with hypotonia, which evolves into ataxia in early childhood. Additional features include episodes of tachypnea or bradypnea, nystagmus, and poor smooth pursuit.

Distinctive facial features include a broad forehead, arched eyebrows, ptosis, widely spaced eyes, low-set ears, cleft lip or palate, and a triangle-shaped mouth. Some patients have polydactyly and renal or hepatic dysfunction. Nearly half of the cases have retinal dysplasia. Intellectual disability is common and ranges from moderate to severe.

Radiographic Appearance

Atrophy of the cerebellar vermis leads to enlargement of the fourth ventricle, which takes on a “bat-wing” appearance on sagittal images. On axial images, the shape of the brainstem takes on a “molar tooth” appearance. There is often dysplasia or heterotopia of cerebellar and inferior olivary nuclei.

Treatment

There is no direct treatment, and physical, occupational, and speech therapy are the main treatment modalities.

References

1. Kumandas S, Akcakus M, Coskun A, Gumus H. Joubert syndrome: review and report of seven new cases. Eur J Neurol. August 2004;11(8):505–510.

2. Brancati F, Dallapiccola B, Valente EM. Joubert Syndrome and related disorders. Orphanet J Rare Dis. July 2010;5:20.

12.8	Fabry’s Disease

Case History

A 9-year-old boy presented with pain in his legs when playing soccer and pain when eating.

Diagnosis: Fabry’s Disease

Images 12.8A and 12.8B: Axial and sagittal T1-weighted images demonstrate round hyperintensities in the pulvinar nuclei of the thalamus (red arrows).

Introduction

Fabry’s disease is due to a deficiency of the enzyme alpha-galactosidase-A (GLA), which degrades a lipid called globotriaosylceramide. Inadequate breakdown results in harmful lipid accumulation in the blood vessels of the heart, eyes, kidneys, and nervous system.

It is the only X-linked lipid storage disease, affecting 1 in 40,000 to 60,000 males. However, it is unique in that it may cause significant morbidity in females who inherit a single altered copy of the GLA gene, though symptoms are typically milder and begin at a later age.

Clinical Presentation

It manifests in childhood or adolescence. Symptoms include:

Acroparesthesias: a painful, burning sensation in the extremities that may be exacerbated by heat and exercise

Gastrointestinal pain: lipid accumulation in the microvasculature of the GI tract can obstruct blood flow and cause pain

Renal insufficiency

Cardiomyopathy

Anhidrosis: decreased or absent sweating

Images 12.8C and 12.8D: Angiokeratomas (image credit Dominique P. Germain).

Hearing loss and tinnitus

Autonomic dysfunction: Patients have decreased sweating.

Angiokeratomas: Small, dark red or purple papules found on the abdomen, buttocks, thighs, and groin.

Ocular involvement: Clouding of the corneas and corneal verticillata, which are whorl-like golden brown or gray deposits in the inferior interpalpebral portion of the cornea.

Image 12.8E: Cornea verticillata (image credit Alessandro P Burlina, Katherine B Sims, Juan M Politei, Gary J Bennett, Ralf Baron, Claudia Sommer, Anette Torvin Møller, and Max J Hilz: Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. In: BMC Neurology 2011, 11:61).

Radiographic Appearance and Diagnosis

Unenhanced T1-weighted images show hyperintensity of the pulvinar nucleus of the thalamus. This is known as the “pulvinar” sign, and may also be seen in other diseases, such as Creutzfeldt–Jakob disease.

The diagnosis is made by measuring the level of alpha-galactosidase activity in leukocytes.

Treatment

Enzyme replacement therapy with hydroxylase alpha-galactosidase is the mainstay of treatment. Many patients require dialysis or kidney transplants. Life expectancy is decreased by several decades due to strokes, heart attacks, and renal failure.

References

1. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. September 2010;103(9):641–659.

2. Laney DA, Peck DS, Atherton AM, et al. Fabry disease in infancy and early childhood: a systematic literature review. Genet Med. May 2015;17(5):323–330.

3. Schaefer RM, Tylki-Szymańska A, Hilz MJ. Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs. November 2009;69(16):2179–2205.

12.9	Pantothenate Kinase-Associated Neurodegeneration

Case History

A 7-year-old child presented with trouble walking due to leg stiffness.

Diagnosis: Pantothenate Kinase-Associated Neurodegeneration

Image 12.9A: Axial T2-weighted image demonstrates hypointensity in bilateral globus pallidus with a central hyperintensity, the “eye of the tiger” sign.

Introduction

Pantothenate kinase-associated neurodegeneration (formerly Hallervorden–Spatz syndrome) is a rare autosomal-recessive disorder caused by a mutation in the pantothenate kinase gene (PANK2), located on chromosome 20. It is essential to form coenzyme A, and is active in mitochondria.

Deficiency of this enzyme leads to accumulation of N-pantothenoyl-cysteine and pantetheine. This in turn leads to accumulation of iron chelates in the brain, specifically in the globus pallidus and the substantia nigra. It is the most common disease in a family of diseases collectively known as neurodegeneration with brain iron accumulation.

It is a rare disease, affecting 1 to 3 per million people.

Clinical Presentation

The illness begins in childhood, usually before 6 years. Gait disturbances are the usual presenting symptom. Patients develop dystonia and a variety of parkinsonian symptoms (rigidity, tremors), dysphagia, dysarthria, as well as progressive cognitive defects. Retinitis pigmentosa causes nyctalopia (night blindness) in most patients, which eventually progresses to complete blindness. Physical examination often reveals spasticity and upgoing toes.

About 25% of patients have an “atypical form.” They present after 10 years, sometimes as late as 40 years, with speech deficits and psychiatric disturbances. Retinal dysfunction is rare in these patients. Disease progression is slower in these patients.

Radiographic Appearance and Diagnosis

T2WIs demonstrate hypointensity of the globus pallidus and pars reticulata of the substantia nigra. A central hyperintensity within the medial globus pallidus creates the “eye of the tiger” sign. In advanced cases, there may be atrophy of the head of the caudate.

Fundoscopy will reveal optic nerve pallor, pigment deposits in the retina, and thin retinal vessels characteristic of retinitis pigmentosa.

Genetic tests can confirm the diagnosis.

Treatment

There is no direct treatment, and the goal is alleviating symptoms with physical and occupational therapy. Oral dystonia may lead to tongue trauma, severe enough to require dental extraction. It is fatal in early adulthood, usually due to secondary infections.

Image 12.9B: Fundoscopy reveals the characteristic findings of retinitis pigmentosa (image credit Christian Hamel).

References

1. Hayflick SJ. Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name. Curr Opin Pediatr. December 2003;15(6):572–577.

2. Hayflick SJ, Hartman M, Coryell J, Gitschier J, Rowley H. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol. June–July 2006;27(6):1230–1233.

3. Thomas M, Hayflick SJ, Jankovic J. Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration. Mov Disord. January 2004;19(1):36–42.

4. Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1490.

12.10

Polymicrogyria

Case History

A 4-year-old child presented with developmental delay and partial seizures.

Diagnosis: Polymicrogyria

Images 12.10A–12.10C: Axial and sagittal T1-weighted images demonstrate polymicrogyria on the right, around the Sylvian fissure (red arrows). Image 12.10D: Gross image of polymicrogyria.

Source: www.wikidoc.org/index.php/File:Arnold-Chiari_Malformation_0003.jpg

Introduction

Images Polymicrogyria (PMG) is a disorder of cortical neuronal organization and is thought to be due to a postmigrational disorder that occurs after the 20th week of gestation. In PMG, there are multiple small gyri separated by shallow sulci. The cortex has an irregular, serrated, or pebble-like appearance. It can affect small or large areas and can be unilateral or bilateral. In the most severe cases, the entire brain is affected.

Images Classic or idiopathic PMG is typically located in the peri-Sylvian fissures, likely because this area is more susceptible to intrauterine ischemic injuries. It is bilateral in 50% of patients, though often asymmetric. Secondary PMG is typically the result of cytomegalovirus (CMV) infection. It can be mild or severe, in which case it is associated with schizencephaly and microcephaly.

Images It has also been described in association with several genetic syndromes including 22q11.2 deletion syndrome, Aicardi syndrome, oculocerebrocutaneous syndrome, Adams–Oliver syndrome, Joubert’s syndrome, Galloway–Mowat syndrome, and Zellweger syndrome. In these cases, it is typically bilateral and symmetric. A severe form called bilateral frontoparietal PMG is due to a mutation in a gene known as GPR56, which is inherited in an autosomal-recessive pattern.

Clinical Presentation

Images The clinical presentation varies depending on the degree and location of cortical involvement. The most severe cases can have encephalopathy, spastic paresis, cerebellar dysfunction, dysphagia, dysconjugate gaze, mental retardation, and medication-refractory epilepsy.

Images In milder cases of unilateral focal PMG, there may be only a slight language delay or patients can be entirely normal.

Radiographic Appearance and Diagnosis

Images On MRI, the cortex is serrated or thickened, though of normal signal intensity. There is reduced white matter volume and decreased interdigitation between the gray and white matter. White matter hyperintensity on T2-weighted images reflects undermyelination. Additional imaging findings include thin cortical ribbon, aberrant sulcation, shallow or deep sulci, decreased white matter volume, ventriculomegaly, thin interhemispheric commissures, hypoplasia of cerebral peduncles/pons/medullary pyramids, patterns of delayed myelination, and dysplastic vessels.

Images Significant white matter hyperintensity on T2-weighted images, particularly in subcortical and periventricular regions, is highly suggestive of CMV infection. Calcifications are frequently seen in patients with congenital CMV.

Images 45% of patients have an abnormal electroencephalogram (EEG), with the abnormality localized primarily to the frontal and temporal lobes. The severity of the EEG abnormality correlates with the extent of the abnormal cortex. PMG can be associated with electrical status epilepticus of sleep even when seizures are not a predominant feature of the patient’s condition.

Treatment

Images Treatment is symptomatic and primarily is aimed at controlling seizures, though many patients have medication-refractory epilepsy.

References

1. Teixeira KC, Montenegro MA, Cendes F, et al. Clinical and electroencephalographic features of patients with polymicrogyria. J Clin Neurophysiol. June 2007;24(3):244–251.

2. Stutterd CA, Leventer RJ. Polymicrogyria: a common and heterogeneous malformation of cortical development. Am J Med Genet C Semin Med Genet. June 2014;166C(2):227–239.

3. Guerrini R. Polymicrogyria and epilepsy. Epilepsia. February 2010;51(Suppl. 1):10–12.

All pathological images in this chapter are courtesy of Roberta J Seidman, MD, Associate Professor, Stony Brook School of Medicine, Department of Pathology, unless otherwise noted.

12.11

Rhombencephalosynapsis

Case History

A 3-year-old child presented with cognitive dysfunction and dysmorphic facial features.

Diagnosis: Rhombencephalosynapsis

Images 12.11A and 12.11B: Axial T2-weighted images demonstrate a single-lobed cerebellum and with horizontal folia and the absence of a vermis.

Introduction

Rhombencephalosynapsis is a congenital abnormality characterized by absence of the cerebellar vermis and fusion of the cerebellar hemispheres, cerebellar nuclei, and superior cerebellar peduncles.

Clinical Presentation

It may occur in conjunction with two syndromes. VACTERL consists of Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects. It also occurs as part of the Gomez–Lopez–Hernandez syndrome, which includes parietal alopecia, numbness in the distribution of the trigeminal nerve, cognitive impairment, short stature, craniosynostosis, and dysmorphic facial features. It may also occur in isolation, and patients present with dysmorphic cranial features, such as a towering skull and hydrocephalus.

Radiographic Appearance and Diagnosis

There is a spectrum of severity ranging from mild hypoplasia of nodulus and vermis to complete absence of these structures. MRI reveals a single-lobed cerebellum with horizontal folia. The cerebellar vermis is hypoplastic or absent, and the fourth ventricle is enlarged and misshapen.

Additional features may include ventriculomegaly, hypoplasia or absence of the corpus callosum, anterior commissure, septum pellucidum, olfactory bulbs, posterior pituitary gland, and optic nerves/chiasm. In some cases, it is associated with holoprosencephaly.

Treatment

There is no specific treatment, and while most patients die in childhood, others survive into adulthood.

References

1. Ishak GE, Dempsey JC, Shaw DW, et al. Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. Brain. May 2012;135(Pt. 5):1370–1386.

2. Toelle SP, Yalcinkaya C, Kocer N, et al. Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children. Neuropediatrics. August 2002;33(4):209–214.

3. Tan TY, McGillivray G, Goergen SK, White SM. Prenatal magnetic resonance imaging in Gomez-Lopez-Hernandez syndrome and review of the literature. Am J Med Genet A. November 2005;138(4):369–373.

4. Barth PG. Rhombencephalosynapsis: new findings in a larger study. Brain. May 2012;135(Pt. 5):1346–1347.

12.12

Schizencephaly

Case History

A 1-year-old infant presented with seizures and developmental delay. Her head circumference was in the second percentile.

Diagnosis: Schizencephaly

Images 12.12A–12.12D: Axial CT image and axial, sagittal, and coronal T1-weighted images demonstrate bilateral schizencephaly.

Introduction

Schizencephaly is a rare congenital malformation of cortical development that results in a cleft in the brain. The etiology is felt to be due to an in utero insult of the germinal matrix that prevents proper neuronal migration and differentiation. Damage to the radial glia prevents neurons from migrating to the cortex. The exact cause is not known, but it is thought to be secondary to fetal cerebral infarction, infection, or in utero toxic exposure. Mutations in the COL4A1 gene occur in some patients.

Clinical Presentation

About 20% of infants are born prematurely and present with hydrocephalus. Later symptoms include seizures, hypotonia, and spastic hemiparesis or quadriparesis. Seizures can be the presenting symptom and can be intractable with seizure focus lying near the schizencephalic clefts. There is a range of overall severity, with 30% to 50% of patients severely affected, 35% moderately affected, and 17% to 25% mildly affected.

Bilateral schizencephaly is associated with severe mental retardation and spastic cerebral palsy. These patients are often microcephalic with epilepsy. In contrast, patients with unilateral clefts may have near normal intelligence with contralateral hemiparesis.

Radiographic Appearance

Neuroimaging will show clefts that extend from the ventricles to the subarachnoid space of the brain. They can be bilateral or unilateral, symmetric or asymmetric. They involve the posterior frontal or parietal lobes 75% of the time.

In open lip schizencephaly, the cleft walls are separated by a wide CSF connection between the subarachnoid space and ventricles. In closed-lip schizencephaly, the walls are in contact with one another, with a thin thread of CSF connecting the subarachnoid space and ventricles between them. They are lined by dysplastic gray matter, which distinguishes schizencephaly from a destructive process such as porencephaly.

Cortical malformations such as lissencephaly or pachygyria are common as well.

Treatment

Treatment is supportive, generally focusing on anticonvulsant therapy and physical/occupational therapy. Up to one-third of patients, typically infants, will have hydrocephalus requiring shunting.

Images 12.12E and 12.12F: Axial T2-weighted and coronal T1-weighted images demonstrate bilateral closed-lip schizencephaly (red arrows) with associated cortical dysplasia.

Image 12.12G: Gross pathology of bilateral schizencephaly.

References

1. Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. January 2013;73(1):48–57.

2. Abdel Razek AA, Kandell AY, Elsorogy LG, Elmongy A, Basett AA. Disorders of cortical formation: MR imaging features. AJNR Am J Neuroradiol. January 2009;30(1):4–11.

3. Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr. March 2009;98(3):421–433.

All pathology images in this chapter are from the website http://neuropathology-web.org and are reproduced with permission of the author, Dr. Dimitri Agamanolis. Unauthorized reproduction is prohibited.

12.13

Porencephaly

Case History

An 12-month-old presented with seizures, cognitive delay, and weakness and spasticity of her left side.

Diagnosis: Porencephaly

Images 12.13A–12.13D: Axial T2-weighted image and axial, coronal, and sagittal T1-weighted images demonstrate a porencephalic cyst on the right, in the territory of the MCA.

Introduction

Porencephaly refers to a rare, congenital, CSF-filled cyst within a cerebral hemisphere. Though different definitions exist, most radiologists use the term to refer to cysts that are in communication with both the ventricles and subarachnoid space.

They are mostly due to in utero infarctions in the middle cerebral artery (MCA) territory, though they can also be due to prenatal infection, trauma, or hemorrhage.

It is associated with mutations in the COL4A1 gene, which expresses collagen and is crucial for the structural stability of vascular basement membranes. Mutations in this gene lead to fragile blood vessels and cerebral hemorrhages.

Clinical Presentation

There is a wide range of clinical symptoms and severity in patients with porencephalic cysts. Spasticity and seizures are often the presenting symptom and are evident during the first year of life. As patients age, language impairment, cognitive dysfunction, and motor deficits (most commonly, spastic hemiplegia or hypotonia) are also frequently encountered.

Head circumference is variable. It may be normal or small, or alternatively there may be progressive enlargement of the cyst, resulting in hydrocephalus and macrocephaly.

Radiographic Appearance and Diagnosis

The appearance of the cyst is isointense to CSF signal on all imaging modalities. It is most often located in the territory of the MCA and communicates with the ventricles and subarachnoid space. A thin membrane may separate the cavity from the lateral ventricle or the subarachnoid space. Porencephalic cysts are lined mostly by white matter, whereas the cavities of schizencephaly are lined by heterotopic gray matter.

Treatment

Treatment is primarily symptomatic, with antiepileptic therapy and physical and occupational therapies being the mainstays of therapy. Shunting of the ventricular system may be needed if there is hydrocephalus. Surgical fenestration of the cyst has also been used in patients with medication-refractory epilepsy.

References

1. Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. January 2013;73(1):48–57.

2. Verbeek E, Meuwissen ME, Verheijen FW, et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet. August 2012;20(8):844–851.

12.14

Colpocephaly

Case History

A 3-year-old child presented with seizures. His language development was delayed and his head circumference was in the second percentile.

Diagnosis: Colpocephaly

Images 12.14A–12.14D: Axial and coronal T2-weighted and sagittal T1-weighted images demonstrate enlargement of the occipital horns with normal caliber frontal horns.

Introduction

Colpocephaly is a congenital condition marked by dilatation of the occipital horns, but with normal caliber frontal horns. This dilatation is the result of white matter loss, not from increased intraventricular pressure.

It is primarily seen in two conditions:

1. Primary malformation from poorly laminated striate cortex, subcortical heterotopia, or defective ependymal lining of the occipital horns.

2. In association with agenesis of the corpus callosum due to absence of splenium and hypoplasia of white matter. This cluster of findings often occurs as part of Aicardi syndrome.

Acquired from periventricular leukomalacia, with loss of periventricular white matter, particularly in premature infants. The acquired form is most common and colpocephaly is associated with several syndromes and systemic disorders such as Zellweger (cerebrohepatorenal) syndrome, hemimegalencephaly, and several chromosomal disorders.

It can occur in association with agenesis of the posterior fibers of the corpus callosum and thus dilatation of the occipital horns, as a primary developmental malformation, or as a result of intrauterine infection or periventricular leukomalacia.

Clinical Presentation

The clinical picture is nonspecific, with varying degrees of mental retardation, seizures, spastic diplegia, and visual loss. Hypertelorism can be present, but is not indicative of visual function. Microcephaly is common.

Radiographic Appearance and Diagnosis

Neuroimaging demonstrates disproportionately dilated occipital horns with normal caliber frontal horns.

EEG findings range from normal to pseudo-hypsarrhythmia in those with myoclonic epilepsy, commonly with bilateral posterior slowing of low voltage occipital spikes.

Treatment

Treatment is with supportive management of symptoms. In contrast to congenital hydrocephalus, there is no role for surgical intervention.

References

1. Noorani PA, Bodensteiner JB, Barnes PD. Colpocephaly: frequency and associated findings. J Child Neurol. April 1988;3(2):100–104.

2. Landman J, Weitz R, Dulitzki F, et al. Radiological colpocephaly: a congenital malformation or the result of intrauterine and perinatal brain damage. Brain Dev. 1989;11(5):313–316.

12.15

Holoprosencephaly

Case History

An infant with severe facial abnormalities died in the first week of life.

Diagnosis: Holoprosencephaly

Images 12.15A–12.15D: Axial and sagittal T2-weighted images demonstrate the characteristic findings of lobar holoprosencephaly. The thalami are fused (red arrow).

Introduction

Holoprosencephaly is incomplete separation of the cerebral hemispheres due to defective cleavage of the embryonic forebrain. It occurs in 1 per 10,000 to 20,000 term births.

There are three forms depending on the degree of cleavage:

1. Alobar: Complete failure of hemispheric cleavage results in a small brain with a small midline vesicle.

2. Semilobar: The brain’s hemispheres have somewhat divided.

3. Lobar: There is considerable evidence of separate brain hemispheres and the brain may be nearly normal.

Approximately two-thirds of patients have the alobar forms and one-fourth have the semilobar form. The remainder of patients have the lobar form.

Almost 50% of patients have a chromosomal abnormality, though less than 25% have a recognizable syndrome. Abnormalities on chromosome 13 account for the majority of chromosomal abnormalities that cause holoprosencephaly. An autosomal-dominant form of holoprosencephaly with sacral agenesis maps to the chromosome 7p36.2 locus.

Clinical Presentation

The degree of developmental delay and motor abnormalities correlates with the type of holoprosencephaly. Most severely affected children (alobar) are stillborn or die in the early neonatal period. Survivors have severe cognitive, motor, and sensory impairments. Microcephaly, seizures, hypotonia, mental retardation, spasticity, athetoid movements, endocrinological dysfunction (including diabetes insipidus), and apnea are common. This is particularly the case when holoprosencephaly is associated with a chromosomal defect.

Midline craniofacial dysplasia is associated with holoprosencephaly in up to 80% of patients. Craniofacial abnormalities include cyclopia, ocular hypotelorism, flat nose, cleft lip, and cleft palate. The degree of craniofacial abnormalities’ severity predicts brain malformation severity.

Non-neurological abnormalities associated with holoprosencephaly include congenital heart defects, clubbing of hands or feet, polydactyly or syndactyly, hypoplasia of the genitourinary system, accessory spleen and liver, and intestinal malrotation. Holoprosencephaly should be suspected in an infant with midline facial deformities, especially when malformations of other organs are present.

While severely affected infants are stillborn or may only live hours to days to months, mildly affected patients can survive into adolescents and less often, beyond. Alobar patients who are most severely affected develop minimal motor and language skills, while semilobar and lobar patients can have more variable and promising outcomes.

Radiographic Appearance and Diagnosis

Incomplete fusion of the cerebral hemispheres in ventral patterning affects deep structures such as the thalamic nuclei, basal ganglia, mesencephalon, and hypothalamic nuclei.

Images Alobar holoprosencephaly: As seen in Images 12.15A–12.15D, the thalami are fused and there is a single, large posteriorly located ventricle. Midline structures are absent, including the septum pellucidum, olfactory tracts, and corpus callosum. The optic nerves may be fused as well, but also may be normal or absent. The middle cerebral artery (MCA) and anterior cerebral artery (ACA) are malformed and often intertwined with the internal carotid artery (ICA) and posterior cerebral artery (PCA). The anterior cerebral artery is usually a single azygous vessel coursing below the inner table of the skull. The sagittal sinuses are deformed or replaced by a network of large, abnormal veins.

Images Semilobar holoprosencephaly: The basic structure of the cerebral lobes is present, but the lobes are fused most commonly anteriorly and at the thalami, with agenesis or hypoplasia of the corpus callosum. There is a single, massive ventricle posteriorly. The olfactory tracts are absent as is the septum pellucidum.

Images 12.15E and 12.15F: Gross pathology of holoprosencephaly.

Images 12.15G–12.15J: Axial CT images demonstrate the characteristic findings of semilobar holoprosencephaly. The frontal lobes are fused anteriorly as are the thalami. There is a single, large ventricle.

Lobar holoprosencephaly: This is the least affected subtype. Images demonstrate more subtle areas of midline abnormalities such as fusion frontal horns of the lateral ventricle. The thalami may be fused, though incompletely. There may be hypoplasia of the body or complete absence of the corpus callosum. The lobes of the brain are well separated and the interhemispheric fissure and falx cerebri are normal.

Molecular genetic testing is available.

EEG will show multifocal spikes, which can evolve into a hypsarrhythmia pattern.

Treatment

There is no specific treatment. If present, hydrocephalus may require a ventriculoperitoneal shunt. In patients with genetic abnormalities, only 2% survive to 1 year of age whereas 30% to 54% of patients without genetic abnormalities survive to 1 year.

References

1. Kauvar EF Muenke M. Holoprosencephaly: recommendations for diagnosis and management. Curr Opin Pediatr. 2010;22(6):687–695.

2. Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis. 2007;2:8.

Unless otherwise stated, all pathology images in this chapter are from the website http://medicine.stonybrookmedicine.edu/pathology/neuropathology and are reproduced with permission of the author, Roberta J Seidman, MD, Associate Professor. Unauthorized reproduction is prohibited.

12.16

Lissencephaly

Case History

An 18-month-old girl presented with seizures and failure to reach developmental milestones. Her head circumference was in the first percentile.

Diagnosis: Lissencephaly

Images 12.16A–12.6C: Axial and sagittal T1-weighted images demonstrate lissencephaly. Image 12.16D: Gross pathology of lissencephaly.

Introduction

Lissencephaly, meaning smooth brain, refers to the appearance of the cerebral cortex in disorders where incomplete neuronal migration in early brain development results in the absence of gyri causing a smooth cerebral surface. Lissencephaly is due to a migratory defect between 12 and 16 weeks gestation, preventing neurons from reaching their destinations.

The majority of patients have mutation of either the LIS1 gene on chromosome 17p13.3 or the doublecortin gene (DCX or XLIS on the X chromosome). Doublecortin mutations result in anterior greater than posterior dysfunction while LIS1 mutations result in posterior greater than anterior dysfunction.

Classic lissencephaly is likely due to a LIS1 mutation, while patients with subcortical band heterotopia are more likely to have mutations in the DCX gene.

Clinical Presentation

There is a variable clinical presentation with less severely affected patients having mild cognitive impairments and less severe epilepsy, while severely affected patients can have marked mental retardation, intractable epilepsy, and severe cerebral palsy. Fifty percent of patients have microcephaly.

Radiographic Appearance and Diagnosis

On imaging, there is a smooth cortical surface except for rudimentary sulci in the parietal, frontal, or whole brain. The Sylvian fissure is broadened and triangular, the interhemispheric fissure is widened, there are nests of gray matter within the white matter, the ventricles may be enlarged, and corpus callosum can be absent.

Several forms exist:

1. Classic: is associated with mutations in LIS1

2. Cobblestone: progressive hydrocephalus, muscular dystrophy, ocular anterior chamber abnormalities, retinal dysplasias, encephaloceles

3. Miller–Dieker syndrome: microcephaly, micrognathia, high forehead, short nose with anteverted nares, low-set ears, thin upper lip

4. Lissencephaly with cerebellar hypoplasia: microcephaly

It is associated with several other migratory defects such as gray matter heterotopia, macrogyria, PMG, and schizencephaly.

Treatment

While standard seizure treatments provide some benefit, seizures in these patients are usually intractable. Though long-term survival has been reported, death typically occurs during infancy, particularly in Miller–Dieker patients who tend to have more severe lissencephaly.

Images 12.16E and 12.16F: Gross pathology showing cobblestone deformity.

References

1. Ghai S, Fong KW, Toi A, Chitayat D, Pantazi S, Blaser S. Prenatal US and MR imaging findings of lissencephaly: review of fetal cerebral sulcal development. Radiographics. March–April 2006;26(2):389–405.

2. Hsieh DT, Jennesson MM, Thiele EA, Caruso PA, Masiakos PT, Duhaime AC. Brain and spinal manifestations of Miller-Dieker syndrome. Neurol Clin Pract. February 2013;3(1):82–83.

3. Lo Nigro C, Chong CS, Smith AC, Dobyns WB, Carrozzo R, Ledbetter DH. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet. February 1997;6(2):157–164.

12.17

Hydranencephaly

Case History

A 3-week-old baby presented with seizures and failure to thrive. On exam, the child’s head circumference was in the 99th percentile.

Diagnosis: Hydranencephaly

Images 12.17A–12.17D: Axial and sagittal T2-weighted images demonstrate preservation of the medial temporal lobes, occipital poles, cerebellum, thalami, and brainstem in an infant with hydranencephaly.

Introduction

Hydranencephaly is a rare (less than 1:10,000) congenital condition in which the majority of the cerebral hemispheres and basal ganglia are replaced by glial tissue and CSF. The thalami, hypothalamus, and brainstem are unaffected, and primitive corticospinal and corticobulbar tracts exist.

It is either a failure of normal brain development or a destructive intrauterine process. Potential intrauterine mechanisms include intrauterine infection, bilateral ICA infarction, fetal hypoxia, and defective embryogenesis causing schizencephaly and cortical agenesis. It has also been proposed that untreated, severe, progressive hydrocephalus may cause hydranencephaly as ventricular pressure destroys midline structures and cerebral parenchyma.

Clinical Presentation

Babies have mild macrocephaly at birth, but appear healthy as primitive reflexes such as sucking, swallowing, crying, and moving the extremities are preserved. In the second or third postnatal week, head size quickly increases and neurological signs develop. These include hyperreflexia, hypertonia, quadriparesis, decerebration, irritability, infantile spasms, seizures, ocular impairments, failure to thrive, blindness, deafness, and eventually cognitive deficits.

As the child ages, brainstem reflexes will remain intact, but higher cortical functions fail to develop. These patients are very unstable once the aforementioned conditions develop and have many medical emergencies such as seizures, pulmonary infections from aspiration and reflux, and autonomic instability.

Radiographic Appearance and Diagnosis

Any imaging modality will reveal the diagnosis. The thalami and brainstem are intact. The cerebellum can be normal, hypoplastic, or dysplastic. While remnants of the occipital poles may remain, no other cortical tissue is present. Any vascular imaging will show absence of flow in the ICAs.

Head ultrasound should be done on any infant with enlarged head or abnormal head circumference growth. Transillumination, simply shining a bright light at the skull, will reveal absence of the forebrain as the light passes through.

The EEG can initially be normal but eventually evolves to abnormal patterns of diffuse slowing or isoelectricity. Visual-evoked potentials are absent, but brainstem audio-evoked potentials are present.

Many cases are detected with prenatal ultrasound.

Treatment

There is no specific treatment. It carries a very poor prognosis, with few infants surviving beyond 1 year.

References

1. Naidich TP, Griffiths PD, Rosenbloom L. Central nervous system injury in utero: selected entities. Pediatr Radiol. September 2015;45(Suppl. 3):454–462.

2. Cecchetto G, Milanese L, Giordano R, Viero A, Suma V, Manara R. Looking at the missing brain: hydranencephaly case series and literature review. Pediatr Neurol. February 2013;48(2):152–158.

12.18

Aqueductal Stenosis

Case History

A 6-month-old girl presented with a head circumference in the 99th percentile.

Diagnosis: Aqueductal Stenosis

Images 12.18A–12.18D: Axial and sagittal T1-weighted images demonstrate massive dilation of the lateral and third ventricles in a patient with aqueductal stenosis. There is a thin rim of preserved neural tissue, which is not the case in hydranencephaly.

Introduction

The cerebral aqueduct connects the third and fourth ventricles and is lined by ependymal cells. At birth, it has a marked length to width discrepancy that makes the aqueduct vulnerable to a number of potential insults.

In aqueductal stenosis, the aqueduct is smaller in size but histologically normal without gliosis. Stenosis tends to occur at two places: beneath the midline of the superior quadrigeminal bodies and at the intercollicular sulcus.

The incidence is 0.5 to 1 in 1,000 births, and AS is responsible for 20% of hydrocephalus cases.

There are both genetic and acquired causes of acqueductal stenosis. Genetic causes include holoprosencephaly, Chiari II, X-linked hydrocephalus with aqueductal stenosis, and pachygyria, autosomal recessive hydrocephalus with aqueductal stenosis, mutation of dorsalizing gene in vertical axis of neural tube, primary defective ependymal, and choroid plexus epithelia.

Acquired causes of acqueductal stenosis include IVH with a thrombus in the aqueduct, congenital infections (CMV, mumps), ependymitis/ventriculitis with gliosis around and within aqueduct, chronic arachnoiditis, aqueductal membrane across lumen, amnion rupture sequence, aneurysms/venous angiomas/vascular malformations, cystic dilatation of perivascular Virchow–Robin spaces in midbrain, tumors of aqueduct, and tumors compressing midbrain tectum from above. Alternatively, aqueductal gliosis is a postinfectious, noninflammatory process, usually from perinatal infection or hemorrhage, in which the aqueduct is slowly replaced by clusters of ependymal cells, and fibrillary gliosis resulting in progressive occlusion.

Clinical Presentation

In congenital acqueductal stenosis, findings include bossing of the forehead, dilated scalp veins, widened sutures, and tense, widened fontanelles. These are exaggerated with activities that raise intracranial pressure (ICP).

The worsening of symptoms is gradual and can occur at any time in childhood or adulthood. In such instances, a downward deviation of the eyes resulting in sclera seen above iris (the sun-setting sign) and abducens nerve palsies can be appreciated.

Other CNS malformations are seen in 75% of patients and include fusion of the quadrigeminal bodies, fusion of the oculomotor nuclei, and spina bifida cystica or occulta.

Radiographic Appearance and Diagnosis

CT and MRI will show marked dilation of the lateral ventricles, third ventricle, and cephalic end of the cerebral aqueduct. The remainder of cerebral aqueduct and fourth ventricle will not be visualized. A thin band of remaining cortex is seen, helping to differentiate acqueductal stenosis from more destructive processes, such as hydranencephaly.

Image 12.18E: Sagittal T2-weighted image demonstrates hydrocephalus in a fetus.

The ventricles expand at 20 weeks gestation and prenatal diagnosis is common. When macrocephaly is present on an intrauterine ultrasound, alpha-fetoprotein levels should be drawn to detect neural tube defects. Prenatal ultrasound and MRI can show the malformation.

Treatment

Hydrocephalus from congenital AS is severe, and the only option is ventriculoperitoneal shunt placement.

With relief of the hydrocephalus, there is a possibility of normal development, and children tend to have better verbal than nonverbal skills. However, the associated anomalies may cause other neurological sequelae such as seizures and motor deficits. Often, prenatal diagnosis is made and elective termination is considered.

Images 12.18F and 12.18G: Axial T1-weighted and coronal T2-weighted images demonstrate aqueductal stenosis. Images 12.18H and 12.18I: Axial FLAIR images demonstrate expansion of the cortex after placement of a shunt.

References

1. Kahle KT, Kulkarni AV, Limbrick DD Jr, Warf BC. Hydrocephalus in children. Lancet. 2015;387:788–799. pii: S0140-6736(15)60694-8.

2. Cinalli G, Spennato P, Nastro A, et al. Hydrocephalus in aqueductal stenosis. Childs Nerv Syst. 2011;27(10):1621–1642.

3. Geng J, Wu D, Chen X, Zhang M, Xu B, Yu X. Aqueduct stent placement: indications, technique, and clinical experience. World Neurosurg. 2015;84:1347–1353. pii: S1878–8750(15)00779-2.

12.19

Neurenteric Cyst

Case History

A 16-year-old boy presented with neck pain, weakness in his arms and legs, and bladder incontinence.

Diagnosis: Neurenteric Cyst

Images 12.19A and 12.19B: Sagittal and axial T2-weighted images demonstrate a large extraaxial cyst compressing the upper cervical spinal cord.

Introduction

A neurenteric cyst is an uncommon, congenital lesion of the spine thought to result from an abnormal connection between the primitive endoderm and ectoderm. They are composed of heterotopic endodermal tissue. During the third week of embryonic life, the neurenteric canal unites the yolk sac and amniotic cavity as it traverses the primitive notochordal plate. Persistence of the neurenteric canal prevents appropriate separation of endoderm and notochord. This anomalous union manifests as rare congenital cysts of the spine defined by the presence of mucus-secreting epithelium reminiscent of the GI tract.

Approximately 90% are located in the intradural/extramedullary compartment; the remaining 10% are divided between an extradural or intradural/intramedullary location. They are most common in the ventral, cervical cord. Rarely, they may be located intracranially, most commonly in the posterior fossa.

They are rare, accounting for about 1% of spinal tumors, and typically present in teenagers and young adults.

Clinical Presentation

Patients present with progressive focal pain at the level of spine lesion, radicular pain and paresthesias, weakness, and bladder and bowel dysfunction. In contrast to other spinal lesions, the symptoms may fluctuate as the size of the cyst changes due to hemodynamic and osmotic factors.

Neurological examination will reveal spastic paraparesis/quadriparesis and hyperreflexia with clonus and upgoing toes. A sensory level is usually present with loss of sensation below the level of lesion.

Radiographic Appearance and Diagnosis

On MRI, the cysts are isointense to CSF on both T1-weighted images and T2-weighted images. They do not enhance with the administration of contrast. CTs are better for detecting the bony malformations, such as scoliosis and spina bifida, which occur in nearly 50% of patients.

CT myelogram: positive meniscus sign (partial dye obstruction with intradural/extramedullary cysts and complete contrast obstruction with intradural/intramedullary cysts).

Treatment

They are treated surgically with the goal of gross total resection. Partial resections may lead to recurrence and arachnoiditis.

References

1. Savage JJ, Casey JN, McNeill IT, Sherman JH. Neurenteric cysts of the spine. J Craniovertebr Junction Spine. 2010;1(1):58–63.

2. Brooks BS, Duvall ER, el Gammal T, Garcia JH, Gupta KL, Kapila A. Neuroimaging features of neurenteric cysts: analysis of nine cases and review of the literature. AJNR Am J Neuroradiol. 1993;14(3):735–746.

12.20

Diastematomyelia

Case History

A 10-year-old girl developed low back and trouble walking. On exam, she was weak in her legs.

Diagnosis: Diastematomyelia

Images 12.20A and 12.20B: Sagittal and axial T2-weighted images demonstrate a longitudinal bifurcation of the spinal cord and hydromyelia (red arrow).

Introduction

Diastematomyelia is a rare congenital malformation where a part of the spinal cord is split longitudinally. It usually occurs in the upper lumbar or lower thoracic cord. Females are affected more than males.

Two types are recognized.

1. Type 1: There is a duplicated dural sac. Hydromyelia (a fluid-filled dilatation of the central canal of the spinal cord) is present as is a midline bony or cartilaginous spur. Cutaneous and vertebral anomalies, such as spina bifida, butterfly or hemivertebrae, are common. This type is more symptomatic.

2. Type 2: There is a single dural sac and the division of the cord may be incomplete. A hydromyelia and bony abnormalities are often absent and patients are less symptomatic.

Clinical Presentation

It usually presents in children with low pain, urinary incontinence, paraparesis, and scoliosis. Cutaneous manifestations including a dimple, hairy patch, hemangioma, meningocele, or lipoma over the affected area are seen in 50% of the cases. Though rare, in adults it presents with slowly progressive paraparesis, sensory loss, and blower/bladder incontinence.

Radiographic Appearance and Diagnosis

MRI is the preferred imaging modality. On axial imaging the spinal cord will divide into two branches. A hydromyelia, if present, will appear as a cyst within the spinal cord, isodense to CSF on all sequences. CT scans are more sensitive for revealing bony abnormalities. The diagnosis is commonly made on prenatal ultrasound.

Treatment

Symptomatic patients may benefit from surgical decompression of neural elements and removal of any bony or fibrous spur. This also allows for repair of duplicated dural sacs.

References

1. Cheng B, Li FT, Lin L. Diastematomyelia: a retrospective review of 138 patients. J Bone Joint Surg Br. 2012;94(3):365–372.

2. Huang SL, He XJ, Xiang L, Yuan GL, Ning N, Lan BS. CT and MRI features of patients with diastematomyelia. Spinal Cord. 2014;52(9):689–692.

12.21

Chiari I Malformation

Case History

A 39-year-old woman presented with severe headaches whenever she sneezed. She noticed that her hands were weak for the past few months and they were atrophied on physical examination. She also had decreased sensation to pinprick over her upper back, shoulders, and upper arms.

Diagnosis: Chiari I Malformation

Images 12.21A and 12.21B: Sagittal and axial T2-weighted images demonstrate a syringomyelia in the upper cervical spine (red arrow) and “peg-like” tonsils, which herniate into the foramen magnum (yellow arrow). Image 12.21C: Gross specimen demonstrates herniation of the cerebellar tonsils. Image 12.21D: Gross specimen demonstrates a syringomyelia.

Source: Images 12.21C and 12.21D, www.wikidoc.org.

Introduction

Images Chiari malformation type I (CMI) describes the displacement of otherwise normal cerebellar tonsils more than 5 mm below the plane of the foramen magnum, into the cervical canal. Most cases appear to occur spontaneously. CMI is due to a combination of a developmental skull malformation, cerebrovascular physiology, and low spinal CSF pressures. CSF pressure gradients or decreased cerebral compliance from cerebral venous hypertension can push the tonsils downward into the spinal canal.

Images CMI often occurs in conjunction with a syringomyelia, meaning “cavitation of the spinal cord.” Syringomyelia is felt to result from CMI as downward displaced cerebellar tonsils cause pulsating pressure waves into the CSF in the spinal compartment. This pressure drives CSF into the spinal cord and dilates the perivascular spaces (Virchow–Robin spaces), leading to interstitial edema, microcysts, and syrinx. Syringomyelia can also be seen in association with myelomeningocele, trauma, arachnoiditis, and intrinsic spinal cord tumor. Syringobulbia is a cystic cavity in the brainstem, which can cause symptoms of lower cranial nerve dysfunction.

Images The prevalence of asymptomatic CMI in the general population is 1.1 per 1,000.

Clinical Presentation

Images CMI is generally asymptomatic in childhood with symptoms beginning in adolescence and adulthood. The average age of presentation is 41 years with slight female predominance, though symptoms have been reported as early as infancy. Symptoms result from both compression of the cerebellar tonsils and from a syringomyelia if present.

Images Symptoms from cerebellar tonsillar compression are headache (valsalva-induced), neck pain, inconsolable crying, torticollis, dysphagia with resultant failure to thrive, dysphonia, sleep-disordered breathing, downward beating nystagmus, scoliosis, gait disturbance, impairment of the limbs (especially hand movements), vertigo, ataxia, tinnitus, and hoarseness. Twenty percent of symptomatic patients have lower cranial nerve dysfunction.

Images Symptoms of syringomyelia are neck and back pain, paresthesias, numbness, and pain of the limbs or trunk, weakness and atrophy of the limbs (especially in the hands), gait disturbance, scoliosis, bladder incontinence, and sexual dysfunction. Children are more likely than adults to experience scoliosis.

Images Signs on physical exam are ataxia, spastic quadriparesis, downbeating nystagmus, decreased sensation in “cape-like” distribution, and wasting of intrinsic muscles of hands. This pattern is called central cord syndrome. The hand weakness and atrophy are due to involvement of the anterior horn cells that give motor innervation to the upper extremities, while the “cape-like” sensory loss is due to disruption of the fibers of the spinothalamic tract as it decussates in the center of the spinal cord.

Images Craniofacial dysostoses, skeletal dysplasias, hydrocephalus, pseudotumor cerebri, and spontaneous intracranial hypotension can all be related to CMI.

Images 12.21E and 12.21F: Axial and sagittal T2-weighted images demonstrate syringobulbia (red arrows).

Radiographic Appearance and Diagnosis

MRI is the gold standard for diagnosis. It will show “peg-like” cerebellar tonsils, which lie 5 mm or more below the plane of the foramen magnum. As a syringomyelia is fluid-filled, it will be a cavity in the central spinal cord, isodense to CSF on all sequences. If the lesion extends into the brainstem (syringobulbia), there may be tongue atrophy and palatal weakness.

Lack of CSF flow behind the cerebellum can also be useful in making the diagnosis.

Treatment

Posterior fossa decompression is indicated for headaches resistant to pharmacological intervention, syringomyelia in association with neuropathic pain, scoliosis, or neurological dysfunction. The goal is alleviating the compression of brainstem and spinal cord and to restore CSF pulsation across the craniocervical junction. Craniocervical decompression has reduction or complete resolution of syringomyelia in 80% of the cases. Acute and subacute neurological symptoms have an 80% response rate, but chronic neurological symptoms will stabilize with surgery, not improve.

Management of asymptomatic syringomyelia is less certain. Some surgeons will intervene only if there are symptoms or evidence of expansion of the cavity. Others believe that syringomyelia represents spinal tissue destruction and will inevitably result in neurological symptoms that may not be reversible once present, and thus intervene prospectively.

Image 12.21G: Intraoperative picture demonstrating decompression of a Chiari malformation.

References

1. Greitz D. Unraveling the riddle of syringomyelia. Neurosurg Rev. October 2006;29(4):251–263.

2. Koyanagi I, Houkin K. Pathogenesis of syringomyelia associated with Chiari type 1 malformation: review of evidences and proposal of a new hypothesis. Neurosurg Rev. 2010;33(3):271–284; discussion 284–285.

3. Strahle J, Smith BW, Martinez M, et al. The association between Chiari malformation Type I, spinal syrinx, and scoliosis. J Neurosurg Pediatr. 2015;15(6):607–611.

12.22

Chiari II Malformation

Case History

A 2-month-old infant was noted to have head lag, feeding difficulties, and trouble tracking objects with her eyes.

Diagnosis: Chiari II Malformation

Images 12.22A and 12.22B: Postcontrast sagittal and axial T1-weighted images and gross pathology demonstrate the core features of a Chiari malformation type II. (1) Herniation of the medulla and cerebellar vermis and tonsils into the cervical canal. (2) Upward herniation of the cerebellum through the tentorium. (3) Elongation of the pons and fourth ventricle. (4) Tectal “beaking” due to fusion of the colliculi. (5) Supratentorial abnormalities such as partial agenesis of the corpus callosum (the splenium most commonly) and heterotopias are also common. (6) The cerebellar hemispheres envelop the brainstem forming the “banana” sign. Image 12.22C: Gross pathology demonstrates several of the features of a Chiari malformation type II (image credit www.wikidoc.org).

Introduction

Images Chiari malformation type II (CMII) can have any of the features of CMI (downward displacement of the cerebellar tonsils 5 mm or more below the plane of foramen magnum, syringomyelia), along with noncommunicating hydrocephalus and lumbosacral spinal bifida.

Images As a result of the downward displacement of the brainstem, a kink between the medulla and cervical spinal cord, and herniation of the cerebellar vermis, CSF circulation is blocked at the level of the foramen magnum. This results in obstructive hydrocephalus.

Images Along with the obstructive hydrocephalus, there also appears to be a migration defect of cerebral cortical neurons. Possible failure of pontine flexion during embryogenesis has also been proposed to result in elongation of the fourth ventricle. There has also been evidence of brainstem hemorrhage, ischemia, or neuronal agenesis.

Clinical Presentation

Images In the first few weeks of life, infants develop symptoms from lower cranial nerve palsies and impaired brainstem function (vocal cord paralysis, stridor, retrocollis, apnea, feeding difficulties, difficulty with secretions), and head lag, later followed by spastic paresis of the upper extremities and opisthotonus.

Images Symptoms include difficulty swallowing (71%), stridor (59%), arm weakness (53%), apnea (29%), and aspiration (12%).

Images CMII is commonly associated with myelomeningocele, which is exposure of spinal neural tissue in the lumbosacral region in 80% of the cases.

Radiographic Appearance and Diagnosis

Images The core features of CMII are best appreciated on sagittal MRI. These are:

1. Herniation of the medulla and cerebellar vermis and tonsils into the cervical canal

2. Upward herniation of the cerebellum through the tentorium

3. Elongation of the pons and fourth ventricle

Images 12.22D and 12.22E: Sagittal and axial T2-weighted images of the lumbar spine demonstrate a myelomeningocele.

4. Tectal “beaking” due to fusion of the colliculi

5. Supratentorial abnormalities such as partial agenesis of the corpus callosum (the splenium most commonly) and heterotopias are also common

6. The cerebellar tonsils are low-lying and hemispheres envelop the brainstem forming the “banana” sign

As a result of this displacement, the pons and cranial nerves are elongated and compressed, and the foramina of Luschka and Magendie and the basal cisterns can be occluded with resultant hydrocephalus. Additional findings include hypoplasia of the posterior fossa, absence of the septum pellucidum, poorly myelinated cerebellar folia, hypoplasia of the falx cerebri, degeneration of the lower cranial nerve nuclei, and cortical malformations including PMG, heterotopias, and cortical dysgenesis. A myelomeningocele, lying as low at L5, is common as well.

Treatment

Surgical intervention for CMII is indicated for patients with critical neurological signs such as apnea, stridor, dysphagia, and disordered breathing. Surgical decompression and dividing a tight, fibrotic band at the C1 level can result in improvement. Typically, correction of the myelomeningocele and ventriculoperitoneal shunt placement for hydrocephalus occurs first. Despite surgical intervention, outcomes are generally poor, as the baseline brainstem and posterior fossa abnormalities are severe.

References

1. el Gammal T, Mark EK, Brooks BS. MR imaging of Chiari II malformation. AJR Am J Roentgenol. January 1988;150(1):163–170.

2. Wolpert SM, Anderson M, Scott RM, Kwan ES, Runge VM. Chiari II malformation: MR imaging evaluation. AJR Am J Roentgenol. November 1987;149(5):1033–1042.

3. Chiapparini L, Saletti V, Solero CL, Bruzzone MG, Valentini LG. Neuroradiological diagnosis of Chiari malformations. Neurol Sci. December 2011;32(Suppl. 3):S283–S286.

12.23

Dandy–Walker Syndrome

Case History

A 4-day-old infant had an MRI as part of an evaluation for abnormalities found on a prenatal ultrasound. The baby had dysmorphic facial features and a cleft palate.

Diagnosis: Dandy–Walker Syndrome

Images 12.23A–12.23C: Axial FLAIR and coronal and sagittal T1-weighted images demonstrate the characteristic features of Dandy–Walker syndrome. Enlargement of the fourth ventricle (red arrow), partial or complete agenesis of the cerebellar vermis (yellow arrow), and an enlarged cisterna magna (blue arrow). The corpus callosum is seen (pink arrow), and there are multiple cortical heterotopias (green arrows).

Introduction

Dandy–Walker Syndrome (DWS) is a disorder of cerebellar development characterized by the following triad:

1. Complete or partial agenesis of the cerebellar vermis

2. Cystic dilatation of the fourth ventricle

3. Enlarged posterior fossa

The incidence of DWS is 1 per 25,000 to 30,000 births, with a slight female predominance.

The exact embryologic malformation leading to DWS is not known, but is thought to result from a neural tube closure defect at the cerebellar level at approximately 4 weeks gestation. As a result, the roof of the fourth ventricle fails to form properly.

DWS is on a spectrum of developmental anomalies associated with trisomy 9 and mutations on the X chromosome. It is associated with many other clinical conditions, including Klippel–Feil syndrome, Cornelia de Lange syndrome, Rubinstein–Taybi syndrome, and hypertelorism.

Clinical Presentation

Macrocephaly, with bulging of the skull most prominent in the occiput, is the most common presenting sign. It is associated with hydrocephalus in 75% of infants at 3 months of age and 80% of infants at 1 year.

Compression of the structures of the posterior fossa results in recurrent attacks of pallor, ataxia, abnormal respirations, headache, vomiting, seizures, apnea, truncal ataxia, and cranial neuropathies. In older infants with hydrocephalus, symptoms of ICP such as headache and nausea and vomiting are seen. Mental retardation and spastic diplegia are common.

Physical examination may reveal macrocephaly, hypotonia, downwardly displaced eyes (sun-setting), spasticity, hemiparesis, enlarged posterior fossa, facial nerve palsies, ataxia, nystagmus, and lower extremity hyperreflexia. Dysmorphic facial features include cleft palate and low-set ears. Polydactyly (extra fingers or toes) and syndactyly (fusion of fingers or toes) are common. Cardiovascular malformations and polycystic kidneys may occur.

Up to 20% of patients do not present until late childhood or adulthood. Symptoms in these patients include headaches, gait ataxia, muscle spasms, facial paralysis, and cognitive and psychiatric disturbances.

Radiographic Appearance and Diagnosis

MRI is the ideal study because it can better identify other cerebral abnormalities, which may also be present.

It will show:

1. Enlargement of the fourth ventricle.

2. Partial or complete agenesis of the cerebellar vermis. The cerebellar hemispheres are preserved and are connected to a thin membrane at the roof of the fourth ventricle.

3. Enlarged cisterna magna. Over time, growth of the cyst pushes the torcula (the confluence of sinuses) superiorly, above the level of the lambdoid suture.

Image 12.23D: Sagittal T2-weighted image demonstrates the characteristic findings of DWS with the torcula (yellow arrow) above the lambdoid suture (red arrow) (image credit Hellerhoff; https://en.wikipedia.org/wiki/Dandy-Walker_malformation#/media/File:Dandy-Walker-Variante_-_MRT_T2_sagittal.jpg).

Images The vast majority of patients will also have hydrocephalus due to aqueductal stenosis by 3 months. DWS is associated with other malformations in two-thirds of children, the most common of which is agenesis of the corpus callosum. Other cortical malformations include heterotopias, abnormal gyral formation, dysraphisms, holoprosencephaly, schizencephaly, and syringomyelia, congenital tumors, occipital encephalocele, and PMG.

Images 12.23E and 12.23F: Axial and sagittal T1-weighted images demonstrate enlargement of the fourth ventricle (red arrow) and partial agenesis of the cerebellar vermis (yellow arrow). The cisterna magna is only mildly enlarged.

In many cases, the diagnosis can be made by prenatal ultrasound.

There is a Dandy–Walker variant that is similar to DWS, but with minimal or no enlargement of the posterior fossa. This variant is much more common than classic DWS, and accounts for one-third of posterior fossa malformations. The clinical presentation is much milder.

Treatment

Decompression of the fourth ventricular cyst will alleviate symptoms, but hydrocephalus almost always recurs and a ventriculoperitoneal shunt is required in two-thirds of affected children. For patients in whom there is no communication between the Dandy–Walker cyst and the lateral ventricles, a posterior fossa shunt may be required as well.

Even after successful shunting, some children will experience transitory, but sometimes fatal episodes of lethargy, apnea, personality change, and vomiting. The mechanism of this is unknown, but is not related to shunt malfunction.

Approximately 70% of live fetuses die, usually due to non-neurological abnormalities.

Genetic counseling is important for parents considering future pregnancies.

References

1. Phillips JJ, Mahony BS, Siebert JR, Lalani T, Fligner CL, Kapur RP. Dandy-Walker malformation complex: correlation between ultrasonographic diagnosis and postmortem neuropathology. Obstet Gynecol. March 2006;107(3):685–693.

2. Forzano F, Mansour S, Ierullo A, Homfray T, Thilaganathan B. Posterior fossa malformation in fetuses: a report of 56 further cases and a review of the literature. Prenat Diagn. June 2007;27(6):495–501.

12.24

Tethered Cord Syndrome

Case History

A child presented with pain, weakness, and incontinence, which had progressed over several years.

Diagnosis: Tethered Cord Syndrome

Image 12.24A: Sagittal T2-weighted image of the lumbar spine demonstrates a low-lying spinal cord in association with a sacral meningocele.

Introduction

Tethered spinal cord syndrome occurs when a fibrous attachment on the spinal cord causes abnormal stretching of the cord. It is usually secondary to neural tube malformation and occurs at the conus medullaris. It is closely linked to spina bifida. It also may occur after spinal cord trauma.

Clinical Presentation

It usually presents in children with progressive low back pain, numbness and weakness of the legs, and bowel/bladder incontinence. Cutaneous manifestations include hairy patches, dimples, or subcutaneous lipomas on the lower back. Syringomyelias may form in some patients. Spina bifida, scoliosis, and clubbed foot are common. Milder cases may not present until adulthood when it presents with pain, paraplegia, and bowel/bladder abnormalities.

Radiographic Appearance and Diagnosis

MRI is the preferred imaging modality. It can demonstrate the location of the tethering and whether there is a lower than normal position of the conus medullaris. MRI will also detect the presence of any tumor or lipoma. Ultrasounds may be used in young infants.

Treatment

In children, early surgery can prevent further neurological deterioration. Almost all patients have decreased pain, and many have improvement in neurological function. Surgical detethering of the spinal cord is also the treatment of choice in most adults as well.

Reference

1. Lew SM, Kothbauer KF. Tethered cord syndrome: an updated review. Pediatr Neurosurg. 2007;43(3):236–248.

12.25

Vein of Galen Malformation

Case History

A 4-week-old baby presented with feeding difficulties and failure to thrive. On examination, the head circumference was in the 96th percentile and the baby was tachycardic.

Diagnosis: Vein of Galen Malformation

Images 12.25A–12.25C: Sagittal T1-weighted image, magnetic resonance angiography, and axial T2-weighted image demonstrate a vein of Galen malformation (red arrow).

Introduction

The vein of Galen is located under the cerebral hemispheres and drains the anterior and central brain areas of the brain into the sinuses of the posterior cerebral fossa. The median prosencephalic vein of Markowski (MProsV) is the primary venous drainage of the brain from 6 to 11 weeks gestation until the subependymal venous drainage system takes over. At that time, the MProsV should regresses into the vein of Galen.

In vein of Galen malformations (VGMs), the MProsV forms anomalous connections with the choroidal arteries around 8 weeks gestation, resulting in high flow pressure and hemodynamic stress, which prevents the MProsV from regressing. It instead forms an aneurysm that drains into the vein of Galen. There is arteriovenous shunting of blood from the choroidal arteries draining into a dilated, persistent median prosencephalic MProsV.

VGMs are the most commonly seen cranial arteriovenous malformations in neonates, with an incidence of 1 per 25,000 births.

Clinical Presentation

The clinical presentation varies by age. Ninety percent of patients present in the neonatal period, most commonly with refractory high output heart failure. It is the result of high volume venous return to the right side of the heart. The right heart chamber dilates and eventually left-sided heart failure occurs secondary to preload volume overload. It manifests as cardiomegaly, difficulty feeding, failure to thrive, and tachycardia. Larger arteriovenous shunting and dysfunction present earlier and can result in cardiogenic shock. Other features include increasing head circumference, a loud intracranial bruit, and dilated orbital veins.

Infants and young children present with hydrocephalus, cognitive delay, and seizures due to compression of adjacent brain structures with resultant hydrocephalus and parenchymal ischemia. Older children and adults present with headaches and subarachnoid hemorrhage.

Radiographic Appearance and Diagnosis

Up to 30% of VGMs are diagnosed with prenatal ultrasound, as early as the second trimester, though most often during the third trimester. Ultrasound will show an anechoic, posterior, midline cystic lesion with significant flow on Doppler examination.

Prenatal MRI can better the size and anatomy of the malformation and feeder veins. On T2WIs, the dilated MProsV will appear as a flow void. The brain parenchyma may show focal white matter lesions or diffuse brain destruction.

Angiography is the gold standard for evaluating the malformation. It will demonstrate reflux into the choroidal arteries and congested cortical veins. The arterial phase will show persistent flow into the malformation. The venous phase will show progressive thrombosis of the sigmoid sinus and reflux into the subependymal veins. There may also be backflow into the cavernous sinus.

Treatment

Conservative medical management of symptoms is the initial treatment. In neonatal cases of severe cardiac failure or hydrocephalus, partial embolization can be performed as early as 2 weeks of age as a temporizing measure.

Once the cavernous sinus has matured, after 5 to 6 months of age, there are interventional options. These include transarterial embolization, venous embolization, and surgical ligation of the arterial feeders from the PCA and MCA with plication of the aneurysm. On average, patients require 2.5 treatments to correct the malformation. Ventriculoperitoneal shunting can also be done after embolization for hydrocephalus.

In older children and adults, management of the hydrocephalus and hemorrhage is the cornerstone. For the hydrocephalus, one can place a ventriculoperitoneal shunt and third ventriculostomy.

Without treatment, mortality rates from cardiac failure or cerebral dysfunction are extremely high. Neonates and patients with brain parenchymal changes, such as encephalomalacia, atrophy, and calcifications, have worse outcomes. Overall mortality rate, including those with embolization, is 15%. Fifty percent to seventy-five percent of those treated with embolization will have minimal to no developmental delays or permanent disabilities.

References

1. Yan J, Wen J, Gopaul R, Zhang CY, Xiao SW. Outcome and complications of endovascular embolization for vein of Galen malformations: a systematic review and meta-analysis. J Neurosurg. July 2015:1–19.

2. Chow ML, Cooke DL, Fullerton HJ, et al. Radiological and clinical features of vein of Galen malformations. J Neurointerv Surg. June 2015;7(6):443–448.

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Apr 19, 2018 | Posted by admin in NEUROLOGY | Comments Off

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