section name header

Information

Nervous System Disorders

= autosomal dominant inherited disorder, probably of neural crest origin affecting all 3 germ cell layers, capable of involving any organ system

Path: frequently combination of

  1. pure neurofibromas (= tumor of nerve sheath with involvement of nerve, nerve fibers run through mass)
    1. localized neurofibroma (most common, 90%)
    2. diffuse neurofibroma mostly solitary + not associated with NF1
    3. plexiform neurofibroma (PATHOGNOMONIC of NF1)
      • Often precedes development of cutaneous neurofibromas!
  2. neurilemmomas (= nerve fibers diverge and course over the surface of the tumor mass)

Histo: proliferation of fibroblasts + Schwann cells

◊More frequent involvement of deep large nerves (sciatic nerve, brachial plexus) in NF1 in contradistinction to isolated neurofibromas without NF1!

Peripheral Neurofibromatosis (90%)!!navigator!!

= NEUROFIBROMATOSIS TYPE 1 = NF1 = VON RECKLINGHAUSEN DISEASE

[Friedrich von Recklinghausen (1833–1910), pathologist in Königsberg, Würzburg and Strasbourg]

= fully penetrant autosomal-dominant disorder with variable expressivity characterized by dysplasia of mesodermal + neuroectodermal tissue with potential for diffuse systemic involvement

Genetics: NF1 gene = tumor suppressor gene localized in the pericentromeric region of chromosome 17 produces neurofibromin that functions as a negative regulator of Ras signaling proteins; 50% represent new spontaneous mutations

mnemonic: ‘von Recklinghausen' has 17 letters

Incidence: 1÷3,000; M÷F = 1÷1; all races

  • One of the most common genetic diseases and phakomatoses!

Predisposing factor: advanced paternal age >35 years (2-fold increase in new mutations)

Diagnostic clinical criteria (at least two must be present):

  1. ≥6 “coast-of-California” café-au-lait spots
    • >5 mm in diameter in prepubertal individuals
    • >15 mm in diameter in postpubertal individuals
  2. ≥2 neurofibromas of any type / ≥1 plexiform neurofibroma
  3. Intertriginous freckling (Crowe sign) in axilla / inguina
  4. Optic pathway glioma
  5. ≥2 Lisch nodules = pigmented iris hamartomas
  6. Characteristic skeletal lesion
    • sphenoid bone dysplasia
    • dysplasia + thinning of long bone cortex
  7. 1st-degree relative (parent, sibling, child) with NF1

CLASSIC TRIAD:

  1. Cutaneous lesions
  2. Skeletal deformity
    • Musculoskeletal abnormalities predominate in NF1!
  3. Mental deficiency

May be associated with:

  1. MEA IIb (pheochromocytoma + medullary carcinoma of thyroid + multiple neuromas)
  2. CHD (10 fold increase): pulmonary valve stenosis, ASD, VSD, IHSS

Cx: malignant transformation to malignant neurofibroma + malignant schwannoma (2–5–29%), glioma, xanthomatous leukemia

Rapid episodes of growth of neurofibromas:

puberty, pregnancy, malignancy

CNS Manifestations of NF1

  • Intracranial
    1. Optic pathway glioma
    2. Cerebral glioma astrocytomas of tectum, brainstem, gliomatosis cerebri (= unusual confluence of astrocytomas)
    3. Hydrocephalus obstruction usually at aqueduct of Sylvius
      Cause: benign aqueductal stenosis, glioma of tectum / tegmentum of mesencephalon
    4. Vascular dysplasia
      = occlusion / stenosis of distal internal carotid artery, proximal middle / anterior cerebral artery
      • moyamoya phenomenon (60–70%)
    5. Neurofibroma of cranial nerves III–XII (most commonly V + VIII)
      • 30% of patients with solitary neurofibromas have NF1
      • Virtually all patients with multiple neurofibromas have NF1
    6. Craniofacial plexiform neurofibroma
      = locally aggressive congenital lesion composed of tortuous cords of Schwann cells, neurons and collagen with progression along nerve of origin (usually small unidentified nerves)
      Location: commonly orbital apex, superior orbital fissure
      • Plexiform neurofibromas are PATHOGNOMONIC for NF1
    7. CNS hamartoma (up to 75–90%)
      = probably dysmyelinating lesion (may resolve)
      Location: pons, basal ganglia (most commonly in globus pallidus), thalamus, cerebellar white matter
      • multiple foci of isointensity on T1WI + hyperintensity on T2WI without mass effect (= “unidentified bright objects”)
    8. Vacuolar / spongiotic myelinopathy (in 66%)
      Location: basal ganglia (esp. in globus pallidus), cerebellum, internal capsule, brainstem
      • nonenhancing hyperintense foci on T2WI
  • Spinal cord
    1. Cord neurofibroma
      • smooth round / tubular masses of varying sizes at nearly every level throughout spinal canal
      • spinal cord displaced to contralateral side
      • enlargement of neural foramen ← “dumbbell” neurofibroma of spinal nerves (in 30%)
      • smooth fusiform / spherical mass:
        • hypoattenuating mass (20–30 HU) in up to 73% ← cystic degeneration, xanthomatous features, confluent areas of hypocellularity, lipid-rich Schwann cells
        • areas of higher attenuation ← densely cellular components / collagen-rich regions
        • slightly hyperintense to muscle on T1WI, hyper-intense periphery + hypointense core on T2WI
        • hypoechoic heterogeneous well-circumscribed cylindrical lesion with variable through transmission
    2. Paraspinal / presacral plexiform neurofibroma
      = regional enlargement of nerve root trunk (plexus / multiple fascicles of medium to large nerve); exclusive to NF1
      Localized and plexiform neurofibromas of the paraspinal and sacral region are the most common abdominal neoplasm in NF1.
      Location: retroperitoneal along lumbosacral plexus adjacent to psoas muscle at single / multiple vertebral body levels
      Form: ropelike = involving non-branching nerves; “bag of worms” = in branching nerves
      • heterogeneous echotexture with variable through transmission
      • smooth round / tubular symmetric / asymmetric paraspinal masses within / adjacent to psoas m.:
        • homogeneously hypoattenuating (20–25 HU) in up to 73% ← myxoid + mucinous stroma
        • focal areas of higher attenuation ← excessive collagen
        • homo- / heterogeneous enhancement to 30–50 HU on CECT in 50%
      • enlargement of adjacent neural foramen in 30%

      Cx: malignant degeneration
    3. Lateral / anterior intrathoracic meningocele
      = diverticula of thecal sac extending through widened neural foramina / defects in vertebra
      Cause: dysplasia of meninges focally stretched by CSF pulsations ← pressure differences between thoracic + subarachnoid space superimposed on osseous vertebral defect
      • erosion of bony elements with marked posterior scalloping
      • widening of neural foramina ← protrusion of spinal meninges

      DDx: mediastinal / lung abscess

Skeletal Manifestations of NF1 (in 25–40%)

= skeletal dysplasias + pseudarthroses

Age: during first year of life

  • Orbit
    • Harlequin appearance to orbit = sphenoid wing dysplasia = partial absence of greater and lesser wing of sphenoid bone + orbital plate of frontal bone ← failure of development of membranous bone
    • hypoplasia + elevation of lesser wing of sphenoid
    • defect in sphenoid bone ± extension of middle cranial fossa structures into orbit
    • concentric enlargement of optic foramen ← optic glioma
    • enlargement of orbital margins + superior orbital fissure ← plexiform neurofibroma of peripheral and sympathetic nerves within orbit / optic nerve glioma
    • sclerosis in the vicinity of optic foramen ← optic nerve sheath meningioma
    • deformity + decreased size of ipsilateral ethmoid and maxillary sinuses
  • Skull
    • macrocranium + macroencephaly
    • left-sided calvarial defect adjacent to lambdoid suture = parietal mastoid (rare)
  • Spine
    • dwarfism caused by scoliosis
    • sharply angled focal kyphoscoliosis (50%) in lower thoracic + lumbar spine; kyphosis predominates over scoliosis; incidence increases with age
      Cause: abnormal development of vertebral bodies
    • hypoplasia of pedicles + transverse + spinous processes
    • posterior scalloping of vertebral bodies ← dural ectasia← weakened meninges allowing transmission of normal CSF pulsations
    • dumbbell-shaped enlargement of neural foramina
  • Appendicular skeleton
    • anterolateral bowing of lower half of tibia (most common) / fibula (frequent) / upper extremity (uncommon) secondary to deossification → thinning → pathologic fracture
    • pseudarthrosis / nonunion after bowing fracture in 1st year of life
      Location: tibia, fibula
    • atrophic thinned / absent fibula
    • periosteal dysplasia = traumatic subperiosteal hemorrhage with abnormally easy stripping of periosteum from bone
    • subendosteal sclerosis
    • bone erosion from periosteal / soft-tissue neurofibroma
    • intramedullary longitudinal streaks of increased density
    • multiple nonossifying fibromas / fibroxanthomas
    • single / multiple cystic lesions within bone ← deossification / nonossifying fibroma
    • focal gigantism = unilateral overgrowth of a limb bone ← overgrowth of ossification center
      Site: marked enlargement of a digit in a hand / foot

Pulmonary Manifestations of NF1

  • Lung
    • exertional dyspnea
    • intrathoracic lateral + anterior meningoceles
    • peripheral pulmonary nodule = pedunculated intercostal neurofibroma
    • progressive pulmonary interstitial fibrosis with lower lung field predominance (in up to 20%)
    • large thin-walled bullae with asymmetric upper lobe predominance
  • Mediastinum
    • Neurogenic tumors account for 9% of primary mediastinal masses in adults + 30% in children
    • mediastinal mass:
      • well-marginated smooth round / elliptic mass
      • extensive fusiform / infiltrating mass
    • paravertebral neurofibroma
  • Chest wall
    • numerous small well-defined subcutaneous neurofibromas
    • twisted “ribbonlike” ribs in upper thoracic segments ← bone dysplasia / multiple neurofibromas of intercostal nerves:
      • localized cortical notches / depression of inferior margins of ribs (DDx: aortic coarctation)
    • chest wall mass invading / eroding / destroying adjacent rib

Abdominal Tumors in NF1

  1. NEUROGENIC TUMORS IN NF1
    1. Neurofibroma
    2. Plexiform neurofibroma
    3. Malignant peripheral nerve sheath tumor
    4. Ganglioneuroma
    5. Ganglioneuromatosis
  2. NEUROENDOCRINE TUMORS IN NF1
    1. Periampullary carcinoid
    2. Pheochromocytoma in adults
      Location: solitary + unilateral (84%); bilateral (10%); extraadrenal (6%)
    3. Paraganglioma
  3. OTHER TUMORS ASSOCIATED WITH NF1
    1. GIST
    2. Embryonal tumor
    3. Adenocarcinoma
    4. Parathyroid adenoma
      • hyperparathyroidism

Vascular Lesions in NF1

= Schwann cell proliferation within vessel wall

Age: common in childhood

  1. Cranial artery stenosis
  2. Renal artery stenosis: very proximal, funnel-shaped
    • Renal artery stenosis in NF1 is one of the most common causes of hypertension in childhood!
  3. Renal artery aneurysm
  4. Thoracic / abdominal aortic coarctation

GI Tract Manifestations in NF1 (10–25%)

Neurofibromas appear as well-defined masses but frequently infiltrate into adjacent fat, muscle, or viscera → local recurrence after resection is common.

  1. Neurofibroma
    • most clinically occult
    • intestinal bleeding (hematemesis, melena, hematochezia) with mucosal involvement
    • obstruction with nausea, vomiting, abdominal distension (intussusception, volvulus, simulating Hirschsprüng disease with plexiform neurofibromas of colon)

    Location: jejunum >stomach >ileum >duodenum
    Site: myenteric >mesenteric / subserosal plexus
    Associated with: increased prevalence of carcinoid tumors + GI stromal tumors
    1. single / solitary neurofibroma, neuroma, ganglioneuroma, schwannoma
      • subserosal / submucosal filling defect (“mucosal ganglioneurofibromatosis”)
      • displacement of intestine
      • external mass effect on serosal surface
      • infiltrating submucosal / mucosal polypoid masses
      • lobular mural thickening of soft-tissue attenuation with variable amount of luminal narrowing ← infiltration through intestinal wall
    2. mesenteric plexiform neurofibroma
      Location: common in perirectal space
      Site: from root of mesentery to wall of intestine
      • mass effect on adjacent barium-filled loops
      • multiple eccentric polypoid filling defects involving mesenteric side of small bowel
      • mesenteric fat trapped within entangled network (15–30 HU) CHARACTERISTIC
      • multiple leiomyomas ± mucosal ulcers

    Cx: intussusception
  2. Malignant peripheral nerve sheath tumor
    • Most common malignant abdominal tumor in NF1
  3. Ganglioneuroma
  4. Carcinoid
    • more common in NF1 than in general population

    Location: near ampulla of Vater
    Histo: psammomatous somatostatinoma
  5. Gastrointestinal stromal tumor

Genitourinary Manifestations of NF1 (rare)

  1. Renal artery stenosis
    • plexiform neurofibroma with vascular narrowing
  2. Urinary bladder neurofibroma
    Origin: vesicoprostatic (male) / urethrovaginal neural plexus (female)
    • symptoms of urinary tract obstruction: frequency, urgency, incontinence, hematuria, abdominal pain
    • solitary hypoechoic bladder wall mass
    • diffuse bladder wall thickening; mass may surround uterus, vagina, sigmoid colon
    • scalloped contour of urinary bladder

    Cx: hydronephrosis

Ocular Manifestations in NF1 (6%)

  • pulsatile exophthalmos / unilateral proptosis (herniation of subarachnoid space + temporal lobe into orbit)
  • buphthalmos
  1. Plexiform neurofibroma (most common)
  2. Lisch nodules
    = PATHOGNOMONIC asymptomatic melanocytic iris hamartomas <2 mm in size
    • yellow / brown pigmented nodular elevations projecting from surface of iris; mostly bilateral
    • asymptomatic

    Age: 5–10 years; >20 years of age in >90%
  3. Optic glioma (in 12% of patients, in 4% bilateral)
    Age: 75% in 1st decade
    • extension into optic chiasm (up to 25%), optic tracts, optic radiation
    • increased intensity on T2WI if chiasm and visual pathway involved
  4. Perioptic meningioma
  5. Choroidal hamartoma: in 50% of patients

Skin Manifestations in NF1

  1. Café-au-lait spots
    = tan / light brown pigmented often ovoid cutaneous macules + patches with irregular borders ≥6 in number >5 mm in greatest diameter prior to puberty >15 mm in postpubertal individuals
    • randomly distributed
    • “coast of California” type (= smooth outline)
      DDx: “coast-of-Maine” spots of McCune-Albright syndrome (with more jagged borders)

    Age: usually present at birth, increase in number over first 1–2 years of life
    • One of the earliest manifestations of NF1

    Histo: increased melanin pigment in basal epidermal layer
    DDx: tuberous sclerosis, fibrous dysplasia
    Extent: often parallels disease severity
  2. Intertriginous freckling (= Crowe sign)
    = pigmented cutaneous macules <5 mm in size
    Age: 3–5 years
    Location: intertriginous skin of axilla (in 66%), groin, submammary fold, neck
  3. Dermal (cutaneous) neurofibroma

Histo: benign mixture of Schwann cells + fibroblasts + perineural cells + mast cells

Age: begins to appear around early childhood / puberty subsequent to detection of café-au-lait spots

  1. localized = fibroma molluscum = string of pearls along peripheral nerve
    • firm well-circumscribed movable tumor
    • soft compressible fleshy nodule of cutis
    • firm rubbery nodule of subcutis
      Cx:NO malignant degeneration!
  2. plexiform neurofibroma = multilobulated tortuous entanglement / interdigitating network of tumor along a nerve and its branches
    • Exclusively seen in NF1 (in 30%)

    Age: noticeable by 4–5 years
    • soft gritty often hyperpigmented tumor feeling like a “bag of worms / braided ropes”
    • may become very large hanging in a pendulous fashion associated with massive disfiguring enlargement of an extremity (= elephantiasis neuromatosa)
    • ± osseous hypertrophy ← chronic hyperemia
      Cx: may transform to malignant peripheral nerve sheath tumor (MPNST = neurofibrosarcoma) in 10%!
      Dx: new onset of pain / neurologic deficit / rapid growth associated with preexisting plexiform neurofibroma → FDG-PET
  3. diffuse neurofibroma
    Location: most common in subcutaneous tissue

Neurofibromatosis with Bilateral Acoustic Neuromas!!navigator!!

= NEUROFIBROMATOSIS TYPE 2 = NF 2 = CENTRAL NEUROFIBROMATOSIS

= rare autosomal dominant syndrome characterized by propensity for developing multiple schwannomas, meningiomas, and gliomas of ependymal derivation

mnemonic: MISME

  • Multiple Inherited Schwannomas
  • Meningiomas
  • Ependymomas

Incidence: 1÷50,000 births

Etiology: deletion on the long arm of chromosome 22; in 50% new spontaneous mutation

mnemonic: Neurofibromatosis 2 is located on chromosome 22!

Symptomatic age: during 2nd / 3rd decade of life

Diagnostic criteria:

  1. bilateral 8th cranial nerve masses
  2. first-degree relative with unilateral 8th nerve mass, neurofibroma, meningioma, glioma (spinal ependymoma), schwannoma, juvenile posterior subcapsular lenticular opacity
  • NO Lisch nodules, skeletal dysplasia, optic pathway glioma, vascular dysplasia, learning disability
  • café-au-lait spots (<50%): pale and <5 in number
  • cutaneous neurofibroma: minimal in size + number / absent
  • Intracranial
    1. Bilateral acoustic schwannomas (SINE QUA NON)
      Site: superior / inferior division of vestibular nerve
      • usually asymmetric in size
    2. Schwannoma of other cranial nerves
      Frequency: trigeminal nerve >facial nerve
      • Nerves without Schwann cells are excluded: olfactory nerve, optic nerve
    3. Multiple meningiomas: intraventricular in choroid plexus of trigone, parasagittal, sphenoid ridge, olfactory groove, along intracranial nerves
    4. Meningiomatosis = dura studded with innumerable small meningiomas
    5. Glioma of ependymal derivation
  • Spinal
    • symptoms of cord compression
    1. Extramedullary
      1. Multiple paraspinal neurofibromas
      2. Meningioma of spinal cord (esp. in thoracic region)
    2. Intramedullary
      1. Spinal cord ependymomas

Outline