Arnold-Chiari malformation

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Arnold-Chiari malformation was first described by Cleland in 1883 in a child with spina bifida. Hans Chiari, an Austrian pathologist was the first person who described type 2 Arnold-Chiari malformation. Hans Chiari also described different classification of Arnold-Chiari malformation into 4 groups.

Arnold chiari malformation may be classified according to herniation content into 4 subtypes. Type 1 has herniation of cerebellar tonsils. Type 2 has herniation of cerebellar tonsils and vermis. Type 3 has herniation of cerebellar tonsil and vermis and lower brain stem. Type 4 has cerebellar hypoplasia with brain stem in posterior fossa.

The exact pathogenesis of Arnol-Chiari malformation is not fully understood but It is thought that Arnol-Chiari malformation is the result of bone developmental abnormalities or mesodermal growth and differentiation abnormalities. Genes involved in the pathogenesis of Arnold-Chiari malformation include PAX1, PAX2, PAX3, PAX6, FGF2, TBX6, HOX gene, Noggin gene, and EFNB1. Conditions associated with Arnold-Chiari malformation include hydrocephalus, syringomyelias,Tethered spinal cord syndrome, neurofibromatosis type 1, Noonan syndrome, Pierre Robin sequence, Klippel-Feil syndrome, Albright hereditary osteodystrophy, x-linked aqueductal stenosis, Goldenhar syndrome, Williams syndrome, Shprintzen- goldberg syndrome, achondroplasia, familial osteosclerosis, velocardiofacial syndrome, and connective tissue disorders.

The cause of Arnold Chiari malformation include craniosynostosis, osteopetrosis, vitamin D deficiency and genetic mutations.

On the basis of seizure, visual disturbance, and constitutional symptoms, Arnold-Chiari malformation must be differentiated from astrocytoma, oligodendroglioma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

The prevalence of Arnold Chiari malformation is unknown since most of the cases are accidentally found. The mortality rate of Arnold Chiari malformation depends on the subtype but type 3 has the highest mortality rate as a result of respiratory failure in infancy. Arnold Chiari malformation commonly affects adolescence and adulthood, but also has been seen in younger children. There is no racial predilection to Arnold Chiari malformation.

Common risk factors in the development of Arnold-Chiari malformation include lumbar-peritoneal shunt and multiple lumbar puncture.

There is insufficient evidence to recommend routine screening for Arnold-Chiari malformation.

MRI is the gold standard test for the diagnosis of Arnold Chiari malformation. Cerebellar tonsillar herniation, wedge shaped tonsils, syringohydromyelia, small posterior fossa, obstructive hydrocephalus, and brainstem anomalies.

Patients with Arnold-Chiari malformation may have a positive history of lumbar puncture, lumbar-peritoneal shunt, hydrocephalus, syringomyelias,Tethered spinal cord syndrome, neurofibromatosis type 1, Noonan syndrome, Pierre Robin sequence, Klippel-Feil syndrome, Albright hereditary osteodystrophy, x-linked aqueductal stenosis, Goldenhar syndrome, Williams syndrome, Shprintzen- goldberg syndrome, achondroplasia, familial osteosclerosis, velocardiofacial syndrome, and connective tissue disorders. The most common symptoms of Arnold-Chiari malformation is headache, arm pain and weakness, neck pain, nausea and vomiting, balance problem, dizziness and ear ringing.

Patients with Arnold Chiari malformation usually appear normal. Physical examination of patients with Arnold Chiari malformation is usually remarkable for impaired coordination, sensory/ motor deficit, abnormal gait, nystagmus, scoliosis, and autonomic dysfunction.

There are no diagnostic laboratory findings associated with Arnold Chiari malformation.

There are no ECG findings associated with Arnold Chiari malformation.

There are no ultrasound findings associated with Arnold-Chiari malformation.

CT scan may be helpful in the diagnosis of Arnold Chiari malformation. Findings on CT scan diagnostic of Arnold Chiari malformation depends on the subtype and include herniation of cerebellar tonsils, vermis, and lower brain stem, underdeveloped cerebellum and crowded foramen magnum.

MRI may be helpful in the diagnosis of Arnold-Chiari malformation. Findings on MRI diagnostic of Arnold-Chiari malformation include cerebellar tonsillar herniation, wedge shaped tonsils, syringohydromyelia, small posterior fossa, obstructive hydrocephalus, and brainstem anomalies.

There are no other imaging findings associated with Arnold-Chiari malformation.

There are no other diagnostic studies associated with Arnold-Chiari malformation.

There are no established measures for the primary prevention of Arnold-Chiari malformation.

There are no established measures for the secondary prevention of Arnold-Chiari malformation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Arnold-Chiari malformation was first described by Cleland in 1883 in a child with spina bifida. Hans Chiari, an Austrian pathologist was the first person who described type 2 Arnold-Chiari malformation. Hans Chiari also described different classification of Arnold-Chiari malformation into 4 groups.

• Arnold-Chiari malformation was first discribed by Cleland in 1883 in a child with spina bifida.^[1]
• Hans Chiari, an Austrian pathologist and Julius Arnold (1835-1915), professor of anatomy at Heidelberg first described Arnold-Chiari malformation.
• Hans Chiari also described different classification of Arnold-Chiari malformation into 4 groups.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Arnold chiari malformation may be classified according to herniation content into 4 subtypes. Type 1 has herniation of cerebellar tonsils. Type 2 has herniation of cerebellar tonsils and vermis. Type 3 has herniation of cerebellar tonsil and vermis and lower brain stem. Type 4 has cerebellar hypoplasia with brain stem in posterior fossa.

Arnold chiari malformation may be classified according to herniation content into 4 subtypes:^[1]

Subtypes	Explanation	Association
Type1	Herniation parts: Cerebellar tonsils	Syringomyelia
Type 2	Herniation parts: Cerebellar tonsils and vermis	Lumbosacral myelomeningocele
Type 3	Herniation parts: Cerebellar tonsil and vermis, lower brain stem	Occipital encephalocele
Type 4	Herniation parts: Brain stem located in posterior fossa, underdeveloped cerebellum	A variation of cerebellar hypoplasia

File:Neck MRI 130850-dichromatic t1-t2-t2.png

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The exact pathogenesis of Arnol-Chiari malformation is not fully understood but It is thought that Arnol-Chiari malformation is the result of bone developmental abnormalities or mesodermal growth and differentiation abnormalities. Genes involved in the pathogenesis of Arnold-Chiari malformation include PAX1, PAX2, PAX3, PAX6, FGF2, TBX6, HOX gene, Noggin gene, and EFNB1. Conditions associated with Arnold-Chiari malformation include hydrocephalus, syringomyelias,Tethered spinal cord syndrome, neurofibromatosis type 1, Noonan syndrome, Pierre Robin sequence, Klippel-Feil syndrome, Albright hereditary osteodystrophy, x-linked aqueductal stenosis, Goldenhar syndrome, Williams syndrome, Shprintzen- goldberg syndrome, achondroplasia, familial osteosclerosis, velocardiofacial syndrome, and connective tissue disorders.

• The exact pathogenesis of Arnol-Chiari malformation is not fully understood but It is thought that Arnol-Chiari malformation is the result of cascade of anomalies that lead to:
  • Bone developmental abnormalities
  • Mesodermal growth and differentiation abnormalities
• These anomalies can be congenital as a result of developmental error or acquired.
• All the potential causes of Chiari malformation will lead to posterior cranial fossa abnormalities and subsequently herniation of cerebellar and/or other structures from foramen magnum.

• Genes involved in the pathogenesis of Arnold-Chiari malformation include:^[1]
  • PAX1
  • PAX2
  • PAX3
  • PAX6
  • FGF2
  • TBX6
  • HOX gene
  • Noggin gene
  • EFNB1
• There are many findings emphasizing on genetic basic of Chiari malformation including:
  • Many studies described higher prevalence of Chiari malformation among mono zygote twins or between family members.
  • There are some evidence showing autosomal dominant/ recessive transmission.
  • There are many genetic conditions that have association with Chiari malformation.

Conditions associated with Arnold-Chiari malformation include:^{[2][3][4][5][6][7]}

• Hydrocephalus
• Syringomyelias
• Tethered spinal cord syndrome
• Neurofibromatosis type 1
• Noonan syndrome
• Pierre Robin sequence
• Klippel-Feil syndrome
• Albright hereditary osteodystrophy
• X-linked aqueductal stenosis
• Goldenhar syndrome
• Williams syndrome
• Shprintzen- goldberg syndrome
• Achondroplasia
• Familial osteosclerosis
• Velocardiofacial syndrome
• Connective tissue disorders such as:
  • Ehlers-Danlos syndrome
  • Marfan Syndrome.

On gross pathology, there is no characteristic finding of Chiari malfromation.

On microscopic pathology, there is enlaged, dysplastic / reactive fibrous tissue and choroid plexus in a Chiari II malformation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The cause of Arnold Chiari malformation include craniosynostosis, osteopetrosis, vitamin D deficiency and genetic mutations.

Common causes of Arnold Chiari malformation may include:^[1][2][3]

• Craniosynostosis
• Osteopetrosis

Less common causes of Arnold Chiari malformation include:

• Vitamin D-resistant rickets

Arnold Chiari malformation is caused by a mutation in following genes:^[4]

• PAX1
• PAX2
• PAX3
• PAX6
• FGF2
• TBX6
• HOX gene
• Noggin gene
• EFNB1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

On the basis of seizure, visual disturbance, and constitutional symptoms, Arnold-Chiari malformation must be differentiated from astrocytoma, oligodendroglioma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

On the basis of seizure, visual disturbance, and constitutional symptoms, Arnold-Chiari malformation must be differentiated from astrocytoma, oligodendroglioma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

Diseases	Clinical manifestations					Para-clinical findings			Gold standard	Additional findings
	Symptoms				Physical examination
						Lab Findings	MRI	Immunohistopathology
	Head- ache	Seizure	Visual disturbance	Constitutional	Focal neurological deficit
Other
Arnold-Chiari malformation [1][2][3]	+	+	+	−	+	−	Cerebellar tonsillar herniation Wedge shaped tonsils Syringohydromyelia Small posterior fossa Obstructive hydrocephalus Brainstem anomalies	We do not perform biopsy for Arnold-Chiari malformation	MRI	It is associated with some syndromes including: Neurofibromatosis type 1 Noonan syndrome Pierre Robin sequence Klippel-Feil syndrome Albright hereditary osteodystrophy
Brain metastasis [4][5]	+	+/−	+/−	+	+	−	Multiple lesions Vasogenic edema	Based on the primary cancer type we may have different immunohistopathology findings.	History/ imaging	Most common primary tumors that metastasis to brain: Lung cancer Renal cell carcinoma Breast cancer Melanoma Gastrointestinal tract If there is any uncertainty about etiology, biopsy should be performed
Adult primary brain tumors
Glioblastoma multiforme [6][7][5]	+	+/−	+/−	−	+	−	Supratentorial Irregular ring-nodular enhancing lesions Central necrosis Surrounding vasogenic edema Cross corpus callosum (butterfly glioma)	Astrocyte origin Pleomorphic cell Pseudopalisading appearance GFAP + Necrosis + Hemorrhage + Vascular prolifration +	Biopsy	Highest incidence in fifth and sixth decades of life Most of the time, focal neurological deficit is the presenting sign.
Oligodendroglioma [8][9][10]	+	+	+/−	−	+	−	Almost always in cerebral hemisphers (frontal lobes) Hypointense on T1 Hyperintense on T2 Calcification Chicken wire capillary pattern	Oligodendrocyte origin Calcification + Fried egg cell appearance	Biopsy	Highest incidence is between 40 and 50 years of age. Most of the time, epileptic seizure is the presenting sign.
Meningioma [11][12][13]	+	+/−	+/−	−	+	−	Well circumscribed Extra-axial mass Dural attachment CSF vascular cleft sign Sunburst appearance of the vessels	Arachnoid origin Psammoma bodies Whorled spindle cell pattern	Biopsy	Highest incidence is between 40 and 50 years of age. Most of the time, focal neurological deficit and epileptic seizure are the presenting signs. May be associated with NF-2
Hemangioblastoma [14][15][16][17]	+	+/−	+/−	−	+	−	Infratentorial Cystic lesion with a solid enhancing mural nodule	Blood vessel origin Capillaries with thin walls	Biopsy	Might secret erythropoietin and cause polycythemia May be associated with von hippel-lindau syndrome
Pituitary adenoma [18][19][5]	−	−	+ Bitemporal hemianopia	−	−	Endocrine abnormalities as a result of functional adenomas or pressure effect of non-functional adenomas	Isointense to normal pituitary gland in T1	Endocrine cell hyperplasia	Biopsy	It is associated with MEN1 disease. Initialy presents with upper bitemporal quadrantanopsia followed by bitemporal hemianopsia (pressure on optic chiasma from below)
Schwannoma [20][21][22][23]	−	−	−	−	+	−	Split-fat sign Fascicular sign Often have areas of hemosiderin	Schwann cell origin S100+	Biopsy	It causes hearing loss and tinnitus May be associated with NF-2 (bilateral schwannomas)
Primary CNS lymphoma [24][25]	+	+/−	+/−	−	+	−	Usually deep in the white matter Single mass with ring enhancement	B cell origin Similar to non hodgkin lymphoma (diffuse large B cell)	Biopsy	Usually in young immunocompromised patients (HIV) or old immunocompetent person.
Childhood primary brain tumors
Pilocytic astrocytoma [26][27][28]	+	+/−	+/−	−	+	−	Infratentorial Solid and cystic component Mostly in posterior fossa Usually in cerebellar hemisphers and vermis	Glial cell origin Solid and cystic component GFAP +	Biopsy	Most of the time, cerebellar dysfunction is the presenting signs.
Medulloblastoma [29][30][31]	+	+/−	+/−	−	+	−	Infratentorial Mostly in cerebellum Non communicating hydrocephalus	Neuroectoderm origin Homer wright rosettes	Biopsy	Drop metastasis (metastasis through CSF)
Ependymoma [32][5]	+	+/−	+/−	−	+	−	Infratentorial Usually found in 4th ventricle Mixed cystic/solid lesion Hydrocephalus	Ependymal cell origin Perivascular pseudorosette	Biopsy	Causes an unusually persistent, continuous headache in children.
Craniopharyngioma [33][34][35][5]	+	+/−	+ Bitemporal hemianopia	−	+	Hypopituitarism as a result of pressure effect on pituitary gland	Calcification Lobulated contour Motor-oil like fluid within tumor	Ectodermal origin (Rathkes pouch) Calcification +	Biopsy	Initialy presents with lower bitemporal quadrantanopsia followed by bitemporal hemianopsia (pressure on optic chiasma from above)
Pinealoma [36][37][38]	+	+/−	+/−	−	+ vertical gaze palsy	B-hCG rise leads to precocious puberty in males	Hydrocephalus (compression of cerebral aqueduct)	Similar to testicular seminoma	Biopsy	May cause prinaud syndrome (vertical gaze palsy, pupillary light-near dissociation, lid retraction and convergence-retraction nystagmus
Vascular
AV malformation [39][40][5]	+	+	+/−	−	+/−	−	Supratentorial: ~85% Flow voids on T2 weighted images	We do not perform biopsy for AVM	Angiography	We may see bag of worms appearance in CT angiography
Brain aneurysm [41][42][43][44][45]	+	+/−	+/−	−	+/−	−	In magnetic resonance angiography, we may see aneurysm mostly in anterior circulation (~85%)	We do not perform biopsy for brain aneurysm	MRA and CTA	It is associated with autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome, pseudoxanthoma elasticum and Bicuspid aortic valve (Angiography is reserved for patients who have negative MRA and CTA)
Infectious
Bacterial brain abscess [46][47]	+	+/−	+/−	+	+	Leukocytosis Elevated ESR Blood culture may be positive for underlying organism	Central hypodense signal and surrounding ring-enhancement in T1 Central hyperintense area surrounded by a well-defined hypointense capsule with surrounding edema in T2	We do not perform biopsy for brain abscess	History/ imaging	The most common causes of brain abscess are Streptococcus and Staphylococcus.
Tuberculosis [48][5][49]	+	+/−	+/−	+	+	Positive acid-fast bacilli (AFB) smear in CSF specimen Positive CSF nucleic acid amplification testing Hyponatremia (inappropriate secretion of antidiuretic hormone) Mild anemia Leukocytosis	Hydrocephalus combined with marked basilar meningeal enhancement	We do not perform biopsy for brain tuberculosis	Lab data/ Imaging	It is associated with HIV infection
Toxoplasmosis [50][51]	+	+/−	+/−	−	+	Normal CSF	Multifocal masses with ring enhancement Mostly in basal ganglia, thalami, and corticomedullary junction.	We do not perform biopsy for brain toxoplasmosis	History/ imaging	It is associated with HIV infection
Hydatid cyst [52][5]	+	+/−	+/−	+/−	+	Positive serology (Antibody detection for E. granulosus)	Honeycomb appearance Necrotic area	We do not perform biopsy for hydatid cysts	Imaging	Brain, eye, and splenic cysts may not produce detectable amount of antibodies
CNS cryptococcosis [53]	+	+/−	+/−	+	+	Positive CSF antigen testing (coccidioidomycosis) CSF lymphocytic pleocytosis Elevated CSF proteins and lactate Low CSF glucose	Dilated perivascular spaces Basal ganglia pseudocysts Soap bubble brain lesions (cryptococcus neoformans)	We may see numerous acutely branching septate hyphae	Lab data/ Imaging	It is the most common brain fungal infection It is associated with HIV, immunosuppressive therapies, and organ transplants In may happen in immunocompetent patients undergoing invasive procedures ( neurosurgery) or exposed to contaminated devices or drugs Since brain biopsies are highly invasive and may may cause neurological deficits, we diagnose CNS fungal infections based on laboratory and imaging findings
CNS aspergillosis [54]	+	+/−	+/−	+	+	Positive galactomannan antigen testing (aspergillosis) CSF lymphocytic pleocytosis Elevated CSF proteins and lactate Low CSF glucose	Multiple abscesses Ring enhancement Peripheral low signal intensity on T2	We may see numerous acutely branching septate hyphae	Lab data/ Imaging	It is associated with HIV, immunosuppressive therapies, and organ transplants In may happen in immunocompetent patients undergoing invasive procedures ( neurosurgery) or exposed to contaminated devices or drugs Since brain biopsies are highly invasive and may may cause neurological deficits, we diagnose CNS fungal infections based on laboratory and imaging findings

ABBREVIATIONS

CNS=Central nervous system, AV=Arteriovenous, CSF=Cerebrospinal fluid, NF-2=Neurofibromatosis type 2, MEN-1=Multiple endocrine neoplasia, GFAP=Glial fibrillary acidic protein, HIV=Human immunodeficiency virus, BhCG=Human chorionic gonadotropin, ESR=Erythrocyte sedimentation rate, AFB=Acid fast bacilli, MRA=Magnetic resonance angiography, CTA=CT angiography

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The prevalence of Arnold Chiari malformation is unknown since most of the cases are accidentally found. The mortality rate of Arnold Chiari malformation depends on the subtype but type 3 has the highest mortality rate as a result of respiratory failure in infancy. Arnold Chiari malformation commonly affects adolescence and adulthood, but also has been seen in younger children. There is no racial predilection to Arnold Chiari malformation.

• The prevalence of Arnold Chiari malformation is unknown since most of the cases are accidentally found.^[1]
• It is believed that approximate prevalence is 0.1 to 0.5 percent worldwide.

• The mortality rate of Arnold Chiari malformation depends on the subtype.
• Type 3 has the highest mortality rate as a result of respiratory failure in infancy.

• Arnold Chiari malformation commonly affects adolescence and adulthood, but also has been seen in younger children.

• There is no racial predilection to Arnold Chiari malformation.
• Arnold Chiari malformation usually presents with back pain in whites and lower extremity weakness in African-Americans.

• Women are more commonly affected by Arnold Chiari malformation than men. The women to men ratio is approximately 3 to 1.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Common risk factors in the development of Arnold-Chiari malformation include lumbar-peritoneal shunt and multiple lumbar puncture.

• Common risk factors in the development of Arnold-Chiari malformation include:^[1][2]
  • Lumbar-peritoneal shunt
  • Multiple lumbar puncture

• Less common risk factors in the development of Arnold-Chiari malformation include:^[3][4][5]
  • Vitamin D-resistant rickets
  • Craniosynostosis
  • Osteopetrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

• The symptoms of (disease name) usually develop in the first/ second/ third decade of life, and start with symptoms such as ___.
• The symptoms of (disease name) typically develop ___ years after exposure to ___.
• If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

• Common complications of [disease name] include:
  • [Complication 1]
  • [Complication 2]
  • [Complication 3]

• Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [–]%.
• Depending on the extent of the [tumor/disease progression] at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor/good/excellent.
• The presence of [characteristic of disease] is associated with a particularly [good/poor] prognosis among patients with [disease/malignancy].
• [Subtype of disease/malignancy] is associated with the most favorable prognosis.
• The prognosis varies with the [characteristic] of tumor; [subtype of disease/malignancy] have the most favorable prognosis.

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