Clinical manifestations and diagnosis of central nervous system tumors in children

INTRODUCTION — Central nervous system (CNS) tumors include both nonmalignant and malignant tumors of the brain and spinal cord. Primary malignant CNS tumors are the second most common childhood malignancies, after hematologic malignancies, and are the most common pediatric solid organ tumor [1]. They are the leading cause of death from childhood cancer, surpassing the mortality rate of acute lymphoblastic leukemia [2].

A general overview on the clinical manifestations and diagnosis of CNS tumors in children will be reviewed here. An overview of the management and the epidemiology of CNS tumors in children are discussed separately. (See "Overview of the management of central nervous system tumors in children" and "Epidemiology and classification of central nervous system tumors in children".)

The clinical manifestations and diagnosis of the following specific CNS tumors that occur in children are discussed separately.

●Low-grade gliomas (see "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors")

●Malignant gliomas (see "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas")

●Medulloblastoma (see "Histopathology, genetics, and molecular groups of medulloblastoma")

●Craniopharyngioma (see "Craniopharyngioma")

●Ependymoma (see "Intracranial ependymoma and other ependymal tumors")

●Focal brainstem glioma (see "Focal brainstem glioma")

●Germ cell tumors (see "Intracranial germ cell tumors")

●Intradural nerve sheath tumors, such as schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (see "Intradural nerve sheath tumors")

●Meningioma (see "Epidemiology, pathology, clinical features, and diagnosis of meningioma")

●Spinal cord tumors (see "Spinal cord tumors")

●Tuberous sclerosis (see "Tuberous sclerosis complex: Clinical features")

●Uncommon brain tumors (see "Uncommon brain tumors")

CLINICAL MANIFESTATIONS — CNS tumors can produce symptoms and signs by local invasion; compression of adjacent structures; and increased intracranial pressure (ICP) by either a mass effect, which compresses normal CNS structures, or by causing obstruction of cerebrospinal fluid flow, resulting in hydrocephalus. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)

The clinical manifestations of childhood CNS tumors may be subtle and/or nonspecific and vary with the child's age (table 1) and tumor location (table 2) [3,4].

Age of the patient — In infants, unfused cranial sutures can accommodate rising ICP without acutely compromising the neurologic status; hence, macrocephaly is the most common presenting symptom in this age group [4]. In addition, infants and young children may be unable to articulate certain symptoms (eg, headaches) and therefore are more likely to present with irritability. Nausea and vomiting are common presenting symptoms at any age. In older children and adolescents, other common findings include headache, abnormal gait, poor coordination, papilledema, and seizures (table 1).

Tumor location — Common symptoms based upon the tumor location include the following (table 2 and figure 1) [4]:

●Posterior fossa tumors – Nausea, vomiting, headache, and abnormal gait and coordination.

●Brainstem tumors – Abnormal gait and coordination and cranial nerve palsies.

●Spinal cord tumors – Back pain and/or weakness and abnormal gait.

●Supratentorial and central tumors – Symptoms are generally nonspecific, and, therefore, these tumors tend to have longer delays in their diagnosis from the onset of the first symptoms [5]. The most common presenting symptoms are headache and seizures [5].

Common presenting signs and symptoms — The following is a discussion of some of the more common signs and symptoms in children with CNS tumors. Additional signs and symptoms are summarized in the tables (table 1 and table 2).

Headache — Headache is the most common manifestation of CNS tumors, occurring in approximately one-third of affected children. As mentioned above, infants and young children may be unable to articulate the source of their discomfort and are more likely to present with irritability. (See 'Age of the patient' above.)

Headaches associated with CNS tumors generally are thought to be due to increased ICP. These headaches are classically described as an early morning headache that is often relieved by vomiting. However, many children do not present with these classic symptoms. This was illustrated in a case series of 200 children with CNS tumors that recorded the pattern of headaches in 71 of 112 patients who presented with headaches [6]. Headaches were nocturnal or occurred in the early morning in 43 patients, occurred during the daytime or early evening in 15, and were continuous in the remaining 13.

Headaches may be either focal or diffuse. A misdiagnosis of migraine or tension headaches is sometimes made prior to detecting the CNS tumor. However, the presence of other CNS manifestations with the headache can differentiate headaches associated with increased ICP from other causes. In the case series described above, all patients with headaches had one or more other symptoms suggestive of a brain tumor (eg, vomiting, vision impairment, unsteady gait, changes in behavior or school performance, sleep disturbances, and/or growth impairment) [6].

Children with persistent headaches should be assessed by a thorough history and physical examination for any signs and symptoms suggestive of CNS tumors. A child with a history of headaches accompanied by other signs of increased ICP or localizing neurologic symptoms (table 1 and table 2) should be further evaluated by neuroimaging. (See 'Diagnosis' below.)

Nausea and vomiting — Nausea and vomiting are common presenting symptoms of CNS tumors in children at any age [4]. Posterior fossa tumors are particularly likely to cause nausea and vomiting.

Because nausea and vomiting are nonspecific symptoms, children who present with isolated nausea and vomiting may have a prolonged symptom interval prior to diagnosis of the CNS tumor. It is therefore important for clinicians to have a high index of suspicion for a brain tumor when evaluating children with recurrent or persistent nausea and vomiting. Often, it is the development of additional signs and symptoms (eg, unsteady gait, headaches, cranial nerve palsies) that alerts the clinician to the possibility of a brain tumor [7]. In a retrospective study of 21 infants and young children (<3 years of age) diagnosed with brain tumors at a single institution, three of the children (14 percent) presented with vomiting and underwent initial evaluation with abdominal imaging, where working diagnoses were pyloric stenosis, viral gastritis, or gastrointestinal reflux, and were later found to have large and aggressive brain tumors [8].

Ataxia and gait abnormalities — Ataxia and difficulty with coordination are frequently present in children with posterior fossa lesions. Initial cerebellar dysfunction may be insidious with clumsiness, worsening handwriting, changes in speech, or difficulty in motor skills such as running or hopping. Abnormal gait is also a common presenting sign in patients with spinal cord tumors. (See "Approach to the child with acute ataxia".)

Seizures — Seizures may be a clinical finding, particularly in patients with low-grade supratentorial lesions [9]. Seizures may be an isolated finding or accompanied by other localizing signs and symptoms. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features".)

Cranial nerve palsies — Cranial neuropathies, such as diplopia, nystagmus, inability to adduct the eye during attempted lateral gaze, facial palsy, drooling, and difficulties with swallowing, suggest underlying brainstem pathology. Younger children may not be able to complain of diplopia. Instead, they may squint, cover one eye with their hand, or tilt their head to one side. Parinaud syndrome describes a constellation of neuro-ocular findings that are associated with pineal or midbrain tumors (table 3). (See "Detailed neurologic assessment of infants and children", section on 'Cranial nerves'.)

Impaired vision — Vision impairment may be due to cranial neuropathy (eg, diplopia) from a brainstem lesion, increased ICP leading to papilledema, or a lesion along the optic pathway that courses from the occipital pole of the cerebral cortex through the optic chiasm to the retina. Chiasmatic tumors often present with a complex visual field loss and decrement in visual acuity. Lesions that are located more posteriorly in the optic tract demonstrate some degree of hemianopsia. (See "Approach to the pediatric patient with acute vision change".)

Torticollis — Torticollis or head tilt is often underestimated as a first symptom of CNS tumors. Torticollis can occur with posterior fossa tumors and cervical spinal cord tumors [10]. In a retrospective series of 54 consecutive children diagnosed with cervical spinal cord tumors (21 patients) and posterior fossa tumors (33 patients), 22 percent presented with torticollis as the first sign [10]. The average time from the onset of torticollis to establishing diagnosis was 9.6 weeks. In nearly all children, torticollis resolved after surgical treatment. In another study, torticollis was reported in 7 percent of infants and young children (<4 years old) with brain tumors and less frequently among older children and adolescents (table 1) [4]. Sudden-onset nontraumatic torticollis should therefore raise a suspicion of spinal cord tumor or posterior fossa tumor, particularly in the presence of any other focal signs or in a young child. Tumors that arise from the floor of the fourth ventricle are often associated with torticollis and ataxia. (See "Acquired torticollis in children".)

Papilledema — Papilledema refers to bilateral optic disc swelling that is due to ICP (picture 1). It occurs when ICP is transmitted to the optic nerve sheath. It is a physical finding in approximately 10 to 15 percent of children with CNS tumors and is more frequent in patients with posterior fossa lesions [4]. (See "Overview and differential diagnosis of papilledema".)

Macrocephaly — In infants, unfused cranial sutures can accommodate an expanding intracranial mass and rising ICP without acutely compromising the neurologic status; hence, macrocephaly is the most common presenting symptom in this age group [4,11]. Infants may also present with bulging fontanelle and/or splayed sutures [6,11]. Macrocephaly can also be seen in older children with brain tumors, but it is less common in this age group compared with infants. (See "Macrocephaly in infants and children: Etiology and evaluation".)

Developmental delay and behavioral changes — Infants and young children may present with irritability and failure to achieve developmental milestones (table 4A-B) [4]. Changes in behavior or personality and declining school performance are subtle signs of increased ICP in older children.

Psychiatric symptoms — Psychiatric symptoms due to brain tumors are more commonly reported in adults than children [12,13]. Such symptoms can be less obvious in children and more challenging to diagnose. Examples include personality changes, eating disorders, obsessions and compulsions, and psychotic symptoms [14-16].

In a review of 33 children with brain tumors who presented with psychiatric symptoms, supratentorial tumors were most commonly implicated [12]. Only two patients presented with isolated psychiatric symptoms; the remaining patients had a combination of psychiatric and neurologic symptoms. The mean delay between symptoms and brain tumor diagnosis was 18 months. Psychiatric symptoms remitted or improved in most patients after resection or other treatment of the tumor.

Endocrinopathies — Endocrine abnormalities (eg, growth impairment, arginine vasopressin deficiency [AVP-D, previously called central diabetes insipidus], precocious puberty, and obesity) may be present at the time of diagnosis in children with chiasmatic/hypothalamic lesions such as craniopharyngioma [17]. (See "Craniopharyngioma", section on 'Clinical presentation'.)

Diencephalic syndrome is a rare consequence of hypothalamic tumors and is characterized by failure to thrive with severe emaciation but normal linear growth, increased appetite, and hyperactivity [18-20].

Neurocutaneous syndromes — Children with neurocutaneous syndromes (eg, tuberous sclerosis [TS], neurofibromatosis type 1 [NF1]) are at increased risk of developing brain tumors [21]. Patients with TS may have associated hypopigmented macules (ash leaf spots), shagreen patches in the younger age group, and adenoma sebaceum in adolescence. TS is associated with subependymal giant cell astrocytomas. Children with NF1 have café au lait spots, axillary freckling, neurofibromas, or Lisch nodules (especially in older children). NF1 is associated with optic pathway/chiasmal gliomas and other CNS tumors. (See "Tuberous sclerosis complex: Clinical features" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Congenital central nervous system tumors — Congenital CNS tumors are rare, representing less than 2 percent of all childhood brain tumors. They are usually diagnosed because of macrocephaly or a tense fontanel noted at birth, as a result of the tumor itself or secondary to hydrocephalus [22,23]. Hydrocephalus can be due to direct compression and obstruction of the ventricular system or from increased cerebrospinal fluid production from choroid plexus tumor [23]. Neurologic symptoms as initial symptoms are comparatively rare [23]. In some cases, antenatal ultrasound detects the lesion prior to delivery [22]; fetal magnetic resonance imaging (MRI) has considerably improved the prenatal diagnosis of these lesions, enabling better management planning, including pregnancy and delivery management, postnatal surgery, and adjuvant therapy [24]. In approximately one-third of pregnancies, polyhydramnios secondary to depressed swallowing from hypothalamic dysfunction is the most common feature [24]. Caesarean section may be required to prevent dystocia, with the fetus being at significant risk for tumor rupture and exsanguination [23]. The outcome is related to the histology, size, and location of the tumor and the condition of the infant at the time of diagnosis; it is generally poor because of tumor size and location [23,24].

Spinal tumors — Peripheral or back pain, focal weakness, gait abnormalities, and spinal deformity are the most common presenting symptoms of a spinal cord tumor [25]. In a case series of 35 children with spinal tumors, presenting complaints included pain localized to the back, neck, or extremities (n = 20); extremity weakness (n = 16); gait abnormalities (n = 14); and scoliosis (n = 3) [26]. Young children may have difficulty localizing back pain and may complain of abdominal pain instead [25]. Cervical tumors may present with torticollis, which may be misdiagnosed as lymphadenopathy or local trauma, leading to delayed diagnosis [25].

DIAGNOSIS — The diagnosis of a CNS tumor is based upon identification of the lesion by neuroimaging, either by magnetic resonance imaging (MRI) or computed tomography (CT). Histologic examination is required to make a diagnosis of the specific tumor type. (See 'Histology' below.)

Childhood brain tumors have a heterogeneous presentation dependent on the tumor location and biology and the age of the child. This often leads to a prolonged symptom interval, which is associated with increased morbidity, increased cognitive impairment, and psychosocial distress for the patient, family, and health care providers [3,27]. Knowledge of normal developmental milestones (table 4A-B) is essential in diagnosing brain tumors in infants and young children as these patients may present with subtle, nonspecific signs, such as developmental delay, and can be easily misdiagnosed. In the United Kingdom, a systematic review reported median symptom intervals from time between symptom onset and diagnosis of brain tumors in children to range between 2.5 and 3.5 months [27].

Neuroimaging

Indications — The decision of when to obtain imaging studies is based upon the clinical suspicion that the signs and symptoms are due to a brain tumor. A 2010 evidence-based guideline developed in the United Kingdom to minimize delays in diagnosis established the following indications for neuroimaging in children with a suspected brain tumor [27]:

●Persistent headache (defined as a continuous or recurrent headache lasting for >4 weeks) with any of the following features:

•Wakes a child from sleep

•Occurs upon waking

•Occurs in a child <4 years of age

•Associated with disorientation or confusion

●Persistent vomiting upon waking

●Visual findings, including any of the following:

•Papilledema (picture 1)

•Optic atrophy (picture 2)

•New-onset nystagmus

•Reduced acuity not due to refractive error

•Visual field reduction

•Proptosis

•New-onset paralytic (noncomitant) squint

●Motor findings, including any of the following:

•Regression in motor skills (table 4B)

•Focal motor weakness

•Abnormal gait and/or coordination

•Bell's palsy with no improvement over four weeks

•Swallowing difficulties without an identifiable local cause

In addition, neuroimaging is generally warranted in most children presenting with new-onset seizures (other than simple febrile seizures) or depressed consciousness. The role of neuroimaging in these conditions is discussed separately. (See "Clinical features and evaluation of febrile seizures", section on 'Neuroimaging' and "Evaluation of stupor and coma in children", section on 'Neuroimaging' and "Seizures and epilepsy in children: Clinical and laboratory diagnosis", section on 'Neuroimaging'.)

The role of neuroimaging in infants and children with macrocephaly is also discussed separately. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Neuroimaging'.)

Choice of modality — MRI provides superior imaging compared with CT for brain tumors; however, CT is often the first imaging study performed because it is more widely available, has a shorter required study time, and usually does not require sedation [28]. CT is the preferred initial study in an emergent situation with a medically unstable child in whom elevated intracranial pressure (ICP) is suspected. However, it is important to note that a normal CT study does not completely exclude the possibility of a brain lesion.

MRI imaging is the modality of choice with a child suspected to have a primary spinal tumor. MRI of the spine is also performed in staging brain tumors that have a predilection for leptomeningeal spread. (See 'Magnetic resonance imaging' below.)

The following discussion is a summary of the different neuroimaging modalities used in the diagnosis of CNS tumors. A more in-depth discussion of neuroimaging in the diagnosis of brain tumors is found separately. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Neuroimaging features'.)

Magnetic resonance imaging — MRI is the best neuroimaging modality for brain tumors. Compared with CT, it provides more detailed images of parenchymal lesions and is more sensitive in detecting lesions within the posterior fossa, subarachnoid spaces, and leptomeninges (image 1 and image 2 and image 3 and image 4 and image 5).

Gadolinium-enhanced MRI can also provide information that may indicate a specific tumor type. It is the imaging modality of choice for a child with a suspected spinal cord lesion because it is less invasive than CT myelogram and provides superior imaging of soft tissue structures [25]. If a spinal cord tumor is suspected, rapid imaging is critical for detection of the lesion prior to spinal cord compression, which may result in permanent neurologic damage [25,29-32]. (See "Clinical features and diagnosis of cervical radiculopathy", section on 'Imaging studies'.)

MRI is also used to stage tumors that have a predilection for leptomeningeal spread. In children, these tumors include medulloblastomas, atypical teratoid rhabdoid tumors, ependymomas, germinomas, and high-grade astrocytomas. MRI of the spine should be obtained prior to lumbar puncture or surgical intervention for optimal staging in order to avoid confusion resulting from procedural artifact or blood. If preoperative imaging is not possible, the staging MRI of the spine should be obtained at least 14 days after surgery in order to minimize any changes that are related to the surgical procedure.

Magnetic resonance spectroscopy, a supplementation to traditional MRI, can differentiate locally infiltrative brain tumors from other intracranial lesions by detecting the presence of specific metabolic signals (eg, N-acetylaspartate, choline, and lactate) that are present in brain tumor tissue. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Role of advanced imaging techniques'.)

Positron emission tomography scans — Positron emission tomography (PET) scans are not routinely used at all centers as part of standard work-up for brain tumors, but they can provide useful information to supplement those from MRI scans. PET scans utilize a positron-emitting radionuclide isotope coupled with a sugar (eg, fluorodeoxyglucose) to differentiate malignant lesions with a high metabolic rate from more benign lesions and surrounding tissue with a lower metabolic rate.

PET scan is useful in determining the areas of maximum glucose utilization within the tumor, which can guide the neurosurgeon to biopsy the location within the tumor with the most aggressive behavior. It is also used to differentiate recurrent tumor from changes due to radiotherapy.

Histology — Children in whom neuroimaging confirms the presence of a mass should be referred to a pediatric neurosurgeon for further evaluation. The next diagnostic step is to obtain tissue to establish the histologic diagnosis and, whenever possible, reduce the tumor burden for most CNS tumors. The long-term prognosis of some types of tumors, such as medulloblastoma and ependymoma, is dependent on the degree of surgical resection. Postsurgical therapy, which may include radiation and/or chemotherapy, is dependent upon the histologic diagnosis. (See "Overview of the management of central nervous system tumors in children".)

DIFFERENTIAL DIAGNOSIS

Diagnostic pitfalls — Since many of the signs and symptoms of childhood CNS tumors are nonspecific and heterogeneous, CNS tumors can be misdiagnosed as common childhood conditions (eg, viral gastroenteritis, tension and migraine headaches). Less common neurologic conditions that may mimic the presentation of a brain tumor include brain abscesses, intracranial hemorrhage, non-neoplastic hydrocephalus, arteriovenous malformations, aneurysms, or indolent viral infections.

Children with CNS tumors generally present with more than one tumor-associated symptom or sign, which allows CNS tumors to be distinguished clinically from other conditions. For example, as discussed above, children with headaches associated with CNS tumors typically have other CNS manifestations, including vomiting, vision impairment, unsteady gait, changes in behavior or school performance, sleep disturbances, and growth impairment [6]. However, neuroimaging is needed to definitely differentiate CNS tumors from other diagnoses and should be performed in any child suspected of having a CNS lesion. (See 'Indications' above.)

SUMMARY AND RECOMMENDATIONS

●The clinical manifestations of childhood central nervous system (CNS) tumors may be subtle and/or nonspecific and vary with the child's age (table 1) and tumor location (table 2). (See 'Age of the patient' above and 'Tumor location' above.)

●Pediatric patients with CNS tumors may present with nonspecific signs and symptoms that occur commonly in children (eg, headache, nausea and vomiting, developmental and behavioral problems) and symptoms that are more suggestive of CNS pathology (eg, ataxia, cranial nerve palsies, impaired vision, seizures, papilledema, macrocephaly). (See 'Common presenting signs and symptoms' above.)

●The diagnosis of a CNS tumor is based upon identification of the lesion by neuroimaging (either by magnetic resonance imaging [MRI] or computed tomography [CT]). Histologic examination is required to make a diagnosis of the specific tumor type. (See 'Neuroimaging' above and 'Histology' above.)

●Indications for neuroimaging in children with suspected brain tumors include (see 'Indications' above):

•Persistent headache (defined as a continuous or recurrent headache lasting for >4 weeks) with any of the following features:

-Wakes a child from sleep

-Occurs upon waking

-Occurs in a child <4 years of age

-Associated with disorientation or confusion

•Persistent vomiting upon waking.

•Visual findings, including any of the following:

-Papilledema (picture 1)

-Optic atrophy (picture 2)

-New-onset nystagmus

-Reduced acuity not due to refractive error

-Visual field reduction

-Proptosis

-New-onset paralytic (noncomitant) squint

•Motor findings, including any of the following:

-Regression in motor skills (table 4B)

-Focal motor weakness

-Abnormal gait and/or coordination

-Bell's palsy with no improvement over four weeks

-Swallowing difficulties without an identifiable local cause

•Neuroimaging is generally warranted in most children presenting with seizures (other than simple febrile seizures) or depressed consciousness. (See "Clinical features and evaluation of febrile seizures", section on 'Neuroimaging' and "Evaluation of stupor and coma in children", section on 'Neuroimaging' and "Seizures and epilepsy in children: Clinical and laboratory diagnosis", section on 'Neuroimaging'.)

•The role of neuroimaging in infants and children with macrocephaly is discussed separately. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Neuroimaging'.)

●MRI provides superior imaging compared with CT for brain tumors; however, CT is often the first imaging study performed because it is more widely available, has a shorter required study time, and usually does not require sedation. MRI imaging is the diagnostic modality of choice in a child suspected of having a spinal tumor. (See 'Neuroimaging' above.)

●Children in whom neuroimaging confirms the presence of a mass should be referred to a pediatric neurosurgeon for further evaluation. Obtaining tissue to establish the histologic diagnosis is the next diagnostic step for most childhood CNS tumors. (See 'Diagnosis' above and "Overview of the management of central nervous system tumors in children".)

●Because the clinical presentations of childhood CNS tumors can be nonspecific and heterogeneous, CNS tumors can often be initially misdiagnosed. Conditions that may mimic CNS tumors include common childhood disorders (eg viral gastroenteritis, migraine and tension headache) and, less commonly, other intracranial space-occupying lesions. Children with CNS tumors often present with more than one tumor-associated symptom or sign, which allows CNS tumors to be distinguished clinically from other conditions. However, neuroimaging is needed to definitively differentiate CNS tumors from other diagnoses and should be performed in any child suspected of having a CNS lesion. (See 'Differential diagnosis' above.)