A previously healthy 16-year-old adolescent boy presented with pallor, blurry vision, fatigue, and dyspnea on exertion. Physical examination demonstrated hypertension and bilateral optic nerve swelling. Laboratory testing revealed pancytopenia. Pediatric hematology, ophthalmology and neurology were consulted and a life-threatening diagnosis was made.

A previously healthy 16-year-old adolescent boy presented to his local emergency department because his mother thought he looked pale. For 2 weeks, the patient had experienced occasional blurred vision (specifically, central blurring with difficulty looking at the school whiteboard) and 2 frontal morning headaches, which improved with standing. The headaches did not wake him from sleep. He also reported 2 weeks of mild fatigue, weight loss, heart palpitations, and 3 days of nonproductive cough. The palpitations and lightheadedness worsened with exercise. He denied sick contacts.

Physical examination in the emergency department demonstrated tachycardia (heart rate: 95–120 bpm), mild systolic hypertension while sitting (120–150/60–80 mm Hg), and a normal respiratory rate (14–20 respirations per minute). Oxygen saturation was 100% on room air. He was afebrile with conjunctival pallor and had a grade III/VI precordial systolic ejection murmur and bilateral optic disc edema on fundoscopic examination. Laboratory results revealed pancytopenia with a white blood cell count of 860/mm3 (85% lymphocytes, 11% neutrophils, 1% monocytes, 1% metamyelocytes, 1% atypical lymphocytes, 1% plasma cells), absolute neutrophil count (ANC) of 90/mm3, hemoglobin level of 3.7 g/dL (mean corpuscular volume: 119 fL; red blood cell distribution width: 15%; reticulocyte: 1.5%), and platelet count of 29 000/mm3. The laboratory results raised concern for bone marrow dysfunction, particularly the presence of plasma cells and metamyelocytes, macrocytic red cells, and reticulocytopenia that was inappropriate for the extent of anemia. He was transferred to a tertiary center for further evaluation.

Dr Hall, what is your differential diagnosis and next steps for this child?

The patient has severe pancytopenia. In adolescents, the differential diagnosis of pancytopenia is broad. The most common etiology is infection. The second most common cause is bone marrow failure, which may be idiopathic, acquired, or inherited. In adolescents, the most common form of bone marrow failure is aplastic anemia (AA).1  Paroxysmal nocturnal hematuria (PNH), a rare, acquired complement-mediated disease with autoimmune destruction of red blood cells, can present with pancytopenia. Leukemia, other malignancies, and exposures to medications or environmental chemicals should also be considered. Autoimmune conditions, such as systemic lupus erythematosus, less commonly cause pancytopenia. Finally, caloric and nutritional deficiencies, such as copper and B12, can result in pancytopenia.2,3 

The initial workup of an adolescent with pancytopenia includes laboratory results that provide diagnostic direction and identify potential comorbid life-threatening problems. The workup should include the following: complete blood count, reticulocyte count, peripheral blood smear, hemolysis laboratory tests (bilirubin, haptoglobin, lactate dehydrogenase), metabolic panel, phosphorus, uric acid (to identify tumor lysis syndrome), liver enzymes (to consider autoimmune and viral hepatitis), and bone marrow biopsy and aspirate. Flow cytometry of marrow or blood helps identify leukemia or PNH. Infectious workup includes viral studies for parvovirus B19; HIV; viral hepatitis A, B, and C; Epstein-Barr virus; cytomegalovirus; human herpesvirus 6; and varicella zoster virus.

This patient had pancytopenia with macrocytic red cells. The differential for pancytopenia with macrocytosis includes nutritional deficiency, liver disease, myelodysplastic syndrome, or bone marrow failure.

Additional history was obtained, and a comprehensive physical examination was performed. The patient lived in Senegal from age 1 to 11 years and had no foreign travel in the past 5 years. The patient had no known toxic exposures and denied alcohol, tobacco, or other drug use. He had never received blood products. Family history was significant for a maternal aunt and grandmother who required red blood cell transfusions in Senegal for unknown reasons. The patient’s young cousin took acetazolamide for idiopathic intracranial hypertension (IIH), with no known hereditary or genetic basis for IIH.4  There was no family history of cancer or hemoglobinopathy. He had not been febrile in the recent months. Physical examination revealed no hepatosplenomegaly, lymphadenopathy, rashes, bruising, or petechiae and confirmed conjunctival pallor, systolic murmur, hypertension, and bilateral optic disc swelling as well as diffuse intraretinal hemorrhages.

Further laboratory assessments revealed a normal comprehensive metabolic panel and a negative urine toxicology screen. Repeat laboratory tests confirmed pancytopenia: white blood cell count of 2350 mm3, ANC of 50/mm3, hemoglobin level of 4.9 g/dL (mean corpuscular volume: 100.7), and platelet count of 73 000/mm3 (after platelet transfusion). The patient was hemodynamically stable and admitted to a pediatric floor. He was transfused to maintain his platelet count >20 000/mm3 and hemoglobin level >7.0 g/dL. The increase in total white blood cell count was likely secondary to an inflammatory response to a platelet transfusion, during which the patient had a fever.

Viral studies (listed above) were negative. The peripheral blood flow cytometry result was negative for a PNH clone or a leukemic clone. Hemoglobin electrophoresis revealed elevated hemoglobin F (9%), which is often present in patients with bone marrow failure.

A bone marrow biopsy and aspirate were performed. The patient’s bone marrow biopsy specimen was “severely hypocellular” (<5% cellularity) without excess reticulin fibrosis, and “the cellularity [was] primarily comprised of erythroid precursors and mature lymphocytes. There [were] no definitive megakaryocytes identified.” On bone marrow aspirate, no megakaryocytes or abnormal blasts were seen, and there was no evidence of other infiltrative malignancies, such as sarcoma or neuroblastoma.

Although intracranial hemorrhage, anemia-related heart failure, and sepsis may have a similar presentation, they were not thought to contribute to this patient’s presentation because he did not have focal neurologic examination findings, edema, crackles on examination, dyspnea at rest, hypotension, or fever.

Ophthalmology was consulted for blurry vision and optic disc swelling. Dr Stroh, what do you make of the vision changes and optic disc swelling?

On initial ophthalmologic examination, the patient’s visual acuity was 20/70 in the right eye and 20/30 in the left eye. He had normal ocular motility and visual fields to confrontation, and his pupils were equal, round, and reactive to light; his cornea, anterior chamber, iris, and crystalline lens were normal. Fundus examination of each eye revealed severe optic nerve swelling, dilated and tortuous veins, diffuse intraretinal hemorrhages, macular edema, and star-shaped perifoveal exudates bilaterally (Fig 1). Optical coherence tomography (OCT) of the macula (Fig 2) and optic nerves confirmed significant edema.

FIGURE 1

Wide-field Optos photographs of the retina of the right (A) and left (B) eyes at the time of presentation, demonstrating bilateral severe disc swelling, extensive peripapillary and peripheral intraretinal hemorrhages, tortuous veins, and star-shaped perifoveal exudates. Repeat photographs of the right (C) and left (D) eyes 8 weeks later, demonstrating resolution of disc swelling and retinal hemorrhages, with straightening of veins and a few remaining exudates.

FIGURE 1

Wide-field Optos photographs of the retina of the right (A) and left (B) eyes at the time of presentation, demonstrating bilateral severe disc swelling, extensive peripapillary and peripheral intraretinal hemorrhages, tortuous veins, and star-shaped perifoveal exudates. Repeat photographs of the right (C) and left (D) eyes 8 weeks later, demonstrating resolution of disc swelling and retinal hemorrhages, with straightening of veins and a few remaining exudates.

Close modal
FIGURE 2

Spectral domain OCT line scan through macula of the right (A) and left (B) eyes at the time of presentation, demonstrating peripapillary (asterisk) and submacular fluid (broken arrow) as well as interstitial macula fluid (solid arrow) and exudates. Repeat OCT of the right (C) and left (D) macula 8 weeks later, demonstrating resolution of subretinal and interstitial fluid and irregularity of the outer retina.

FIGURE 2

Spectral domain OCT line scan through macula of the right (A) and left (B) eyes at the time of presentation, demonstrating peripapillary (asterisk) and submacular fluid (broken arrow) as well as interstitial macula fluid (solid arrow) and exudates. Repeat OCT of the right (C) and left (D) macula 8 weeks later, demonstrating resolution of subretinal and interstitial fluid and irregularity of the outer retina.

Close modal

Bilateral optic disc swelling may be caused by increased intracranial pressure (ICP), infectious or inflammatory causes, and toxic or nutritional insults. Specific causes include bilateral vein occlusions and malignant hypertensive retinopathy.3  Optic neuritis, compressive optic neuropathy, and anterior ischemic optic neuropathy are usually unilateral but occasionally present with bilateral involvement.

MRI and magnetic resonance venography (MRV) brain imaging and lumbar puncture are necessary to look for optic nerve enhancement, obstructive hydrocephalus, or sinus venous thrombosis. None of these were found on this patient’s MRI and MRV. The patient did have hypertension, so hypertensive retinopathy was on the differential diagnosis. When more common causes of optic disc swelling are eliminated, it is important to investigate hematologic (such as anemia and hematologic malignancies) or infectious etiologies (such as Lyme disease, bartonella, and syphilis). In this patient, central retinal vein occlusion was less likely because fluorescein angiography did not demonstrate delayed filling or capillary nonperfusion.

Are retinal hemorrhages commonly associated with optic disc swelling?

Peripapillary splinter hemorrhages are commonly seen with papilledema from increased ICP. Papilledema is sometimes associated with diffuse retinal findings, like macular edema, retinal pigment epithelial changes, macular star exudates, and intraretinal hemorrhages in the posterior pole.5,6  Most retinal changes resolve without vision loss from optic nerve damage.5  Papilledema alone can cause diffuse intraretinal hemorrhages outside the peripapillary region, although this is uncommon.7  Intraretinal hemorrhages outside the peripapillary region raise concern for a primary vascular disorder, such as retinal vein occlusion, hypertensive retinopathy, leukemic retinopathy, or hyperviscosity syndrome.

In this case, optic disc swelling occurred in the setting of the patient’s AA. Severe anemia can cause retinopathy characterized by diffuse intraretinal hemorrhages8 ; previous case reports have described papilledema in AA.912  Two main mechanisms of anemia-induced ICP have been proposed. First, overcirculation of blood through the choroid plexus (due to elevated cardiac output occurring secondary to anemia) can cause cerebrospinal fluid (CSF) overproduction. Second, relative cerebral hypoxia activates autoregulatory mechanisms causing overcirculation that may elevate ICP. Raised ICP causes increased optic nerve sheath pressure, leading to elevated ophthalmic venous pressure and reduced central retinal venous outflow and capillary perfusion.13 

In this patient, there may also be a component of central retinal vein occlusion despite negative imaging findings. Although there was no evidence of delayed venous filling on fluorescein angiography, the phenomenon of severe retinal hemorrhages, tortuous vessels, and disc swelling without delayed venous filling (as seen in this patient) has been described before as central retinal vein occlusion in AA patients.10  These patients have been reported to recover vision and demonstrate retinal hemorrhage resolution in the setting of anemia and thrombocytopenia normalization. In this patient, the disc swelling is likely caused by local hematologic effects on the nerves, but it is possible elevated ICP augmented the nerve edema.

Severe anemia reduces the oxygen-carrying capacity of the blood. The patient’s vital signs reflected physiologic compensation for a state of reduced oxygen-carrying capacity. Notably, the patient demonstrated normal oxygen saturation, tachycardia, increased systolic blood pressure, and wide pulse pressure. The increased heart rate and decreased total systemic vascular resistance (diastolic blood pressure) facilitate an increase in cardiac output. Increased systolic pressures help maintain stable cerebral perfusion pressure and likely explain the patient’s increased ICP, which can cause blurry vision, papilledema, and retinal hemorrhages.

Once retinal hemorrhages had been identified, the patient’s platelet count transfusion threshold was changed to 100 000/mm3. Dr Armstrong, what is your initial approach to the patient’s clinical picture?

Optic nerve edema is a common neurologic sign, frequently referred to neurology after an ophthalmologic evaluation. Elevated ICP, as was the concern here, is among many causes of optic nerve swelling.14 

The presence of disc swelling in the setting of increased ICP is a relative emergency. If the optic nerve remains under prolonged pressure, permanent vision loss can occur. After obtaining magnetic resonance head imaging, a lumbar puncture should be pursued to evaluate both CSF and opening pressure to assess for ICP.

Patients with elevated ICP frequently present with new-onset headache that may be positional, worse with lying down or Valsalva maneuver, and often accompanied by pulsatile tinnitus or eye pain. The patient’s rare morning headaches that improved with standing along with the presence of optic nerve edema were suggestive of elevated ICP. The initial differential diagnosis for the patient’s optic nerve edema included IIH, disc swelling related to hematologic abnormalities, oncologic processes, obstructive hydrocephalus, bilateral nonarteritic anterior ischemic optic neuropathy, and sinus venous thrombosis.

In this patient, MRI showed partial empty sella sign (a flattened pituitary gland), suggestive of IIH (Fig 3). Other signs of elevated ICP on imaging may include optic disc edema, flattening of the posterior globes of the eyes, optic nerve sheath enlargement, transverse venous sinus stenosis, and cerebellar tonsillar herniation. There was no sign of obstructive hydrocephalus, masses, abnormal enhancement, or venous sinus thrombosis.

FIGURE 3

Partial empty sella sign in our patient (arrow) visible on MRI and MRV with contrast.

FIGURE 3

Partial empty sella sign in our patient (arrow) visible on MRI and MRV with contrast.

Close modal

As recommended, a lumbar puncture was performed. The patient’s opening pressure was 29 cm H2O. This was abnormal because it fell just above the 90th percentile (28 cm H2O)15  for his age. CSF was drained to a closing pressure of 15 cm H20. CSF cytology was inconsistent with infection or inflammation and showed a red blood cell count of 30/mm3, white blood cell count of 0/mm3, protein level of 20.3 mg/dL, and glucose level of 56 mg/dL (serum glucose was 88 mg/dL). Lymphocytes, monocytes, and atypical lymphocytes were present without blasts.

These findings excluded primary neurologic processes from the differential diagnosis. Dr Armstrong, what is the best treatment approach to the patient’s increased ICP?

For initial relief of his elevated ICP, the patient’s CSF was reduced from 29 to 15 cm H2O. He was then started on acetazolamide at 250 mg bid, which was increased to 1000 mg bid by discharge. Although correcting the patient’s hemoglobin should correct the hemodynamics that caused the increased ICP, the treatment standard is to continue acetazolamide until disc swelling resolves.16  Cessation of acetazolamide without ensuring that ICP is permanently normal increases the risk for irreversible vision loss. Ophthalmology continued outpatient monitoring and provided strict return precautions, including worsening vision or headache because this would be an indication for urgently repeating a therapeutic lumbar puncture.

How did the bone marrow biopsy help guide the diagnosis?

A severely hypocellular bone marrow in the absence of infectious, oncologic, autoimmune, or nutritional causes for pancytopenia is consistent with the diagnosis of idiopathic AA. AA is categorized on the basis of the degree of anemia, thrombocytopenia, and neutropenia. Severe aplastic anemia (SAA) is characterized by a reticulocyte count of <20 000/μL, platelet count of <20 000/μL, and ANC of <500/μL. This patient’s initial ANC was <200/μL, so he met the criteria for very SAA.17  Elevated hemoglobin F and macrocytosis also supported the diagnosis of SAA. Fungal and Pneumocystis prophylaxis was started in this neutropenic patient, pending definitive treatment.

Genetic testing is commonly performed for children and young adults with bone marrow failure because finding certain mutations can guide treatment planning. The patient’s peripheral blood was sent for a 59-gene sequencing panel, which excluded known inherited bone marrow failure syndromes. Deep sequencing revealed biallelic myeloproliferative leukemia virus oncogene (MPL) gene missense mutations, one causing a pathogenic single nucleotide change (c.769C>T) and another causing a variant of unknown significance single nucleotide change (c.1454C>T). The MPL gene on chromosome 1 encodes for the thrombopoietin receptor involved in thrombopoiesis and hematopoietic stem cell function. Mutations in the MPL gene are described in diseases such as myelofibrosis and congenital amegakaryocytic thrombocytopenia18,19  and in essential thrombocythemia and myeloproliferative neoplasms that are more common in adults.20  More recently, next-generation sequencing has identified MPL mutations in cases of AA, which are more consistent with this patient’s presentation and bone marrow pathology.21,22 

Given the diagnosis of SAA complicated by papilledema, what was the treatment plan?

The current standard of care for AA is hematopoietic stem cell transplant (HSCT) if a matched sibling donor (MSD) is available or immunosuppressive therapy (IST) if HSCT is not an option. The most common IST regimens are antithymocyte globulin and cyclosporine.17  Emerging evidence supports the use of eltrombopag, a thrombopoietin receptor agonist, in cases of AA when no MSD is available and/or when response to traditional IST fails.23  Alternative donors for HSCT are experimental and include matched unrelated or haploidentical donors.

For this patient, an MPL gene mutation raised concerns for increased risk of developing myelodysplastic syndrome, a clonal hematopoietic stem cell disorder that can lead to leukemia. Unfortunately, the patient’s hypocellular bone marrow aspirate precluded quantification of the cells with the MPL gene mutation; however, the presence of >10% of a clonal population of cells carrying a somatic MPL mutation predicts a longer course of pancytopenia, refractoriness to IST, and a higher risk of progression to myelodysplastic syndrome.24  The patient did not have an MSD, so the hematology team discussed the risks and benefits of IST (standard of care) versus experimental, nonmyeloablative haploidentical HSCT with the patient and his family.

The patient’s mother underwent genetic testing because she was a potential haploidentical stem cell donor. This testing identified her as a carrier of the same MPL gene variant of unknown significance. This finding demonstrates that the patient had inherited a germline MPL mutation from his mother. The mother had no other marrow cytogenic abnormalities, PNH clones, or fibrosis. The patient’s father was not available for testing. The mother’s bone marrow biopsy specimen demonstrated normal cellularity and maturation, and flow cytometry showed no abnormal cell population. She was deemed an appropriate haploidentical HSCT donor, and the family elected to undergo experimental haploidentical HSCT. At our center, haploidentical bone marrow transplant is offered to patients who lack an HLA-matched donor and who wish to participate in a clinical trial. In a recent study, success was demonstrated in nonrefractory SAA with haploidentical HSCT without initial IST.25 

More data exist for haploidentical HSCT in the treatment of refractory SAA for patients without an MSD.26,27  In 1 study, researchers demonstrated that 94% of patients achieved successful engraftment with a 3-year survival of 89%,28  with similar findings in a registry-based comparison.29  Further, post-transplantation cyclophosphamide (which our patient received) has been shown to minimize significant graft-versus-host-disease.30 

His nonmyeloablative conditioning regimen included antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation. Our patient had successful engraftment at day 14. He continues to have 100% donor chimerism and has normal blood counts. His new blood and bone marrow have not been sent for MPL mutation testing.

This case represents a unique presentation of SAA with a previously unreported inherited MPL gene mutation and that is complicated by increased ICP and associated sequelae. The patient’s initial symptoms were subtle: conjunctival pallor, exercised-induced lightheadedness, rare headache, and insidious vision changes. Although patients with AA may present with headaches, increased ICP is a less-common presentation, perhaps because of prompt evaluation and treatment of underlying anemia before progression of increased ICP.

In studies, researchers describe an association between several types of anemia and papilledema or increased ICP9,11,12,3134  along with other forms of anemia, including iron deficiency anemia,35,36  pernicious anemia,37  hemolytic anemia,38  and sickle cell anemia.33  The majority of symptoms resolve with treatment of the underlying condition.

The patient was initially supported with transfusions as a bridge to haploidentical bone marrow transplant. For his increased ICP, he was treated with acetazolamide, which has been shown to improve vision outcomes.39,40  Three months after initial presentation, his vision improved to 20/20 in both eyes. The patient’s optic disc swelling and intraretinal hemorrhages improved substantially (Fig 1). OCT of the macula revealed resolution of interstitial and subretinal fluid, with some irregularity of the outer retina (Fig 3). During this time, he was weaned off acetazolamide.

After receiving a nonmyeloablative haploidentical HSCT, the patient recovered without significant complication. He has persistent BK viremia (a known potential consequence of HSCT) without clinical symptoms. He has normal blood cell counts and is without visual complaints. He has 100% donor T-cell chimerism, confirming persistent stem cell engraftment. Overall, he responded well to treatment, had few complications, and continues to be monitored.

We thank the patient, his family, and the many care teams involved in this patient’s care. Thanks to Dr Reza Manesh for his comments on the article.

FUNDING: No external funding.

Dr Berk was the initial author and led the majority of the writing; Dr Hall contributed to the Hematology section; Drs Stroh and Mishra contributed to the Ophthalmology section; Dr Armstrong contributed to the Neurology section; Drs Pecker and Lau served as senior authors, provided guidance, and contributed to the genetic discussion, as well as to the overall paper; and all authors approved the final manuscript as submitted.

Dr Berk’s current affiliation is Department of Pediatrics and Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI.

     
  • AA

    aplastic anemia

  •  
  • ANC

    absolute neutrophil count

  •  
  • CSF

    cerebrospinal fluid

  •  
  • HSCT

    hematopoietic stem cell transplant

  •  
  • ICP

    intracranial pressure

  •  
  • IIH

    idiopathic intracranial hypertension

  •  
  • IST

    immunosuppressive therapy

  •  
  • MPL

    myeloproliferative leukemia virus oncogene

  •  
  • MRV

    magnetic resonance venography

  •  
  • MSD

    matched sibling donor

  •  
  • OCT

    optical coherence tomography

  •  
  • PNH

    paroxysmal nocturnal hematuria

1
Weinzierl
EP
,
Arber
DA
.
The differential diagnosis and bone marrow evaluation of new-onset pancytopenia
.
Am J Clin Pathol
.
2013
;
139
(
1
):
9
29
2
Haddad
AS
,
Subbiah
V
,
Lichtin
AE
,
Theil
KS
,
Maciejewski
JP
.
Hypocupremia and bone marrow failure
.
Haematologica
.
2008
;
93
(
1
):
e1
e5
3
Green
R
.
Anemias beyond B12 and iron deficiency: the buzz about other B’s, elementary, and nonelementary problems
.
Hematology Am Soc Hematol Educ Program
.
2012
;
2012
(
1
):
492
498
4
Wall
M
,
Kupersmith
MJ
,
Kieburtz
KD
, et al;
NORDIC Idiopathic Intracranial Hypertension Study Group
.
The idiopathic intracranial hypertension treatment trial: clinical profile at baseline
.
JAMA Neurol
.
2014
;
71
(
6
):
693
701
5
Talks
SJ
,
Mossa
F
,
Elston
JS
.
The contribution of macular changes to visual loss in benign intracranial hypertension
.
Eye (Lond)
.
1998
;
12
(
pt 5
):
806
808
6
Tawse
KL
,
Hedges
TR
 III
,
Gobuty
M
,
Mendoza-Santiesteban
C
.
Optical coherence tomography shows retinal abnormalities associated with optic nerve disease
.
Br J Ophthalmol
.
2014
;
98
(
suppl 2
):
ii30
-
ii33
7
Keane
JR
.
Papilledema with unusual ocular hemorrhages
.
Arch Ophthalmol
.
1981
;
99
(
2
):
262
263
8
Trivedi
BP
,
Ravindran
M
,
Pawar
N
,
Ramakrishnan
R
,
Shelke
V
.
Iron deficiency anemia presenting with macular star
.
J AAPOS
.
2015
;
19
(
5
):
486
487
9
Mohla
A
,
Oworu
O
,
Hutchinson
C
.
Aplastic anaemia presenting with features of raised intracranial pressure
.
J R Soc Med
.
2006
;
99
(
6
):
315
316
10
Mansour
AM
,
Salti
HI
,
Han
DP
, et al
.
Ocular findings in aplastic anemia
.
Ophthalmologica
.
2000
;
214
(
6
):
399
402
11
Nazir
SA
,
Siatkowski
RM
.
Pseudotumor cerebri in idiopathic aplastic anemia
.
J AAPOS
.
2003
;
7
(
1
):
71
74
12
Jeng
MR
,
Rieman
M
,
Bhakta
M
,
Helton
K
,
Wang
WC
.
Pseudotumor cerebri in two adolescents with acquired aplastic anemia
.
J Pediatr Hematol Oncol
.
2002
;
24
(
9
):
765
768
13
Hayreh
SS
,
Edwards
J
.
Ophthalmic arterial and venous pressures. Effects of acute intracranial hypertension
.
Br J Ophthalmol
.
1971
;
55
(
10
):
649
663
14
Pérez-Cambrodí
RJ
,
Gómez-Hurtado Cubillana
A
,
Merino-Suárez
ML
,
Piñero-Llorens
DP
,
Laria-Ochaita
C
.
Optic neuritis in pediatric population: a review in current tendencies of diagnosis and management
.
J Optom
.
2014
;
7
(
3
):
125
130
15
Avery
RA
,
Shah
SS
,
Licht
DJ
, et al
.
Reference range for cerebrospinal fluid opening pressure in children
.
N Engl J Med
.
2010
;
363
(
9
):
891
893
16
Matthews
YY
.
Drugs used in childhood idiopathic or benign intracranial hypertension
.
Arch Dis Child Educ Pract Ed
.
2008
;
93
(
1
):
19
25
17
Sharma
R
,
Nalepa
G
.
Evaluation and management of chronic pancytopenia
.
Pediatr Rev
.
2016
;
37
(
3
):
101
111–113
18
Pardanani
AD
,
Levine
RL
,
Lasho
T
, et al
.
MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients
.
Blood
.
2006
;
108
(
10
):
3472
3476
19
Ballmaier
M
,
Germeshausen
M
,
Schulze
H
, et al
.
c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia
.
Blood
.
2001
;
97
(
1
):
139
146
20
Frawley
T
,
O’Brien
CP
,
Conneally
E
, et al
.
Development of a targeted next-generation sequencing assay to detect diagnostically relevant mutations of JAK2, CALR, and MPL in myeloproliferative neoplasms
.
Genet Test Mol Biomarkers
.
2018
;
22
(
2
):
98
103
21
Keel
SB
,
Scott
A
,
Sanchez-Bonilla
M
, et al
.
Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients
.
Haematologica
.
2016
;
101
(
11
):
1343
1350
22
Walne
AJ
,
Dokal
A
,
Plagnol
V
, et al
.
Exome sequencing identifies MPL as a causative gene in familial aplastic anemia
.
Haematologica
.
2012
;
97
(
4
):
524
528
23
Olnes
MJ
,
Scheinberg
P
,
Calvo
KR
, et al
.
Eltrombopag and improved hematopoiesis in refractory aplastic anemia
.
N Engl J Med
.
2012
;
367
(
1
):
11
19
24
Kulasekararaj
AG
,
Jiang
J
,
Smith
AE
, et al
.
Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome
.
Blood
.
2014
;
124
(
17
):
2698
2704
25
Xu
ZL
,
Zhou
M
,
Jia
JS
, et al
.
Immunosuppressive therapy versus haploidentical transplantation in adults with acquired severe aplastic anemia [published online ahead of print January 22, 2019]
.
Bone Marrow Transplant
. doi:
26
Peslak
SA
,
Olson
T
,
Babushok
DV
.
Diagnosis and treatment of aplastic anemia
.
Curr Treat Options Oncol
.
2017
;
18
(
12
):
70
27
Georges
GE
,
Storb
R
.
Hematopoietic stem cell transplantation for acquired aplastic anemia
.
Curr Opin Hematol
.
2016
;
23
(
6
):
495
500
28
Xu
LP
,
Wang
SQ
,
Wu
DP
, et al
.
Haplo-identical transplantation for acquired severe aplastic anaemia in a multicentre prospective study
.
Br J Haematol
.
2016
;
175
(
2
):
265
274
29
Xu
LP
,
Zhang
XH
,
Wang
FR
, et al
.
Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia
.
Bone Marrow Transplant
.
2017
;
52
(
3
):
381
387
30
DeZern
AE
,
Zahurak
M
,
Symons
H
, et al
.
Alternative donor transplantation with high-dose post-transplantation cyclophosphamide for refractory severe aplastic anemia
.
Biol Blood Marrow Transplant
.
2017
;
23
(
3
):
498
504
31
Vargiami
E
,
Zafeiriou
DI
,
Gombakis
NP
,
Kirkham
FJ
,
Athanasiou-Metaxa
M
.
Hemolytic anemia presenting with idiopathic intracranial hypertension
.
Pediatr Neurol
.
2008
;
38
(
1
):
53
54
32
Lilley
ER
,
Bruggers
CS
,
Pollock
SC
.
Papilledema in a patient with aplastic anemia
.
Arch Ophthalmol
.
1990
;
108
(
12
):
1674
1675
33
Henry
M
,
Driscoll
MC
,
Miller
M
,
Chang
T
,
Minniti
CP
.
Pseudotumor cerebri in children with sickle cell disease: a case series
.
Pediatrics
.
2004
;
113
(
3 pt 1
). Available at: www.pediatrics.org/cgi/content/full/113/3/e265
34
Biousse
V
,
Rucker
JC
,
Vignal
C
, et al
.
Anemia and papilledema
.
Am J Ophthalmol
.
2003
;
135
(
4
):
437
446
35
Stoebner
R
,
Kiser
R
,
Alperin
JB
.
Iron deficiency anemia and papilledema. Rapid resolution with oral iron therapy
.
Am J Dig Dis
.
1970
;
15
(
10
):
919
922
36
Forman
EB
,
O’Byrne
JJ
,
Capra
L
,
McElnea
E
,
King
MD
.
Idiopathic intracranial hypertension associated with iron-deficiency anaemia
.
Arch Dis Child
.
2013
;
98
(
6
):
418
37
Murphy
TE
,
Costanzi
JJ
.
Pseudotumor cerebri associated with pernicious anemia
.
Ann Intern Med
.
1969
;
70
(
4
):
777
782
38
Taylor
JP
,
Galetta
SL
,
Asbury
AK
,
Volpe
NJ
.
Hemolytic anemia presenting as idiopathic intracranial hypertension
.
Neurology
.
2002
;
59
(
6
):
960
961
39
Wall
M
,
McDermott
MP
,
Kieburtz
KD
, et al;
NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee
.
Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial
.
JAMA
.
2014
;
311
(
16
):
1641
1651
40
Ball
AK
,
Howman
A
,
Wheatley
K
, et al
.
A randomised controlled trial of treatment for idiopathic intracranial hypertension
.
J Neurol
.
2011
;
258
(
5
):
874
881

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.