Sporadic schwannomas and neurofibromas

Clinical manifestations
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By Herbert B Newton MD

As tumors of peripheral nerve sheath origin, sporadic schwannomas and neurofibromas can originate from cranial nerves, spinal nerves or nerve roots, or peripheral nerves. Therefore, the clinical evolution and manifestations are variable, depending on the location and rate of growth of the tumor.

Schwannomas. Schwannomas make up 6% to 8% of all primary brain tumors, and 10% to 30% of all primary spinal cord tumors (Newton 1994; Newton et al 1995; Seppala et al 1995b). They usually present as solitary, sporadic tumors, unassociated with predisposing conditions such as neurofibromatosis type 1 or 2. In particular, only 5% of acoustic schwannomas are diagnosed in patients with neurofibromatosis type 1 or 2. There is a predilection for schwannomas to affect sensory roots more than motor or autonomic branches. In most series, females are affected slightly more often than males. Within the intracranial cavity, greater than 85% to 90% of schwannomas affect cranial nerve VIII, 0.8% to 8% are derived from cranial nerve V, and 0.5% to 1.9% develop from cranial nerve VII (Miller 1988; Macfarlane and King 1995; Strauss and Post 1995; Sarma et al 2002). Tumors of the remaining cranial nerves are extremely rare in patients without neurofibromatosis type 1 or 2. Rarely, schwannomas can develop within the parenchyma of the brain or intrasellar region (Sharma et al 1993; 1998; Sarma et al 2002; Honegger et al 2005).

Vestibular schwannoma. The majority of schwannomas (85% to 90%; approximately 2000 to 3000 per year) arise from the vestibular branch of cranial nerve VIII. Rarely, tumors can develop from the cochlear branch. Because the Schwann cell-glial junction is variable, the tumor location may vary and can range from a lateral position near the inner ear or inside the labyrinth, to a medial position at the porus acusticus, to completely within the cerebellopontine angle (Miller 1988; Macfarlane and King 1995; Neff et al 2003). Schwannomas can develop from either the superior or inferior division of the vestibular nerve, with an approximately equal incidence (Jackler and Pitts 1990). In general, these tumors are slow-growing and benign neoplasms that have an indolent evolution. In 75% to 80% of cases, the growth rate is estimated to be 1 mm to 2 mm per year (Wazen et al 1985; Thomsen and Tos 1990; Bederson et al 1991; Nedzelski et al 1992). The rate of growth may be slower in older patients (Rosenberg 2000). The growth of a vestibular schwannoma can be broken down into 3 stages: (1) canalicular, (2) cisternal, and (3) brainstem compressive (Miller 1988; Jackler and Pitts 1990; Selesnick and Jackler 1992). In the canalicular stage, the tumor gradually fills the internal auditory canal, expanding from a lateral position near the inner ear toward the porus acusticus. Adjacent nerves (VII and VIII) are compressed against the walls of the internal auditory canal and are often thinned out. Osseous erosion of the internal auditory canal is common, especially the posterior lip of the porus acusticus. With further growth, the tumor emerges from the porus acusticus into the cerebellopontine angle, and enters the cisternal stage. As the tumor expands into the cerebellopontine angle cistern, the seventh and eighth cranial nerves and the anterior inferior cerebellar artery are displaced. Typically, the seventh cranial nerve is stretched over the capsule of the tumor. The function of the facial nerve may progressively worsen as the cerebellopontine angle portion of the tumor causes stretching of the nerve over the anterior lip of the porus acusticus. Once the cerebellopontine angle cistern is filled, the tumor enters the brainstem compressive stage as contact is made with the pontomedullary junction. Progressive brainstem compression ensues as the tumor continues to enlarge. When the cerebellopontine angle portion of the tumor reaches 3 cm to 4 cm in diameter, the fourth ventricle is often shifted past the midline, and hydrocephalus may develop. During this same period, superior extension of the tumor usually causes displacement of the trigeminal nerve.

The most common symptoms of vestibular schwannomas are unilateral sensorineural hearing loss (96%), unsteadiness (77%), tinnitus (71%), headache (29%), mastoid pain or otalgia (28%), facial numbness, diplopia, and vertigo (Bentivoglio et al 1988; Miller 1988; Jackler and Pitts 1990; Selesnick and Jackler 1992; Macfarlane and King 1995; Matthies and Samii 1997a). In most patients, the initial symptom is unilateral sensorineural hearing loss; it may have been present from 1 to 5 years (mean 3.7 years) (Matthies and Samii 1997a). The loss is gradually progressive in 80% to 90% of cases, and sudden in 10% to 20% of cases (possibly caused by occlusion of the internal auditory artery). Sensorineural hearing loss develops from a combination of tumor-induced interference with cochlear vascular supply and compression of the cochlear nerve within the internal auditory canal. Mild unsteadiness is usually not the initial complaint, but has been present for several years in most patients. Tinnitus is usually unilateral, confined to the affected ear, low grade in intensity, and constant. Headache, mastoid pain, and otalgia are often present in patients with large tumors that impinge on local dural and osseous structures, or that have caused elevated intracranial pressure. Although rare, patients can present with an acute severe headache associated with nausea and emesis from schwannomas that have hemorrhaged (Kim et al 1998). Facial numbness is usually confined to the lower face; facial weakness is uncommon. Symptomatic paroxysmal vertigo is infrequent and is usually not accompanied by nausea.

On neurologic examination of patients with vestibular schwannoma, the most common finding is unilateral sensorineural hearing loss (Miller 1988; Jackler and Pitts 1990; Selesnick and Jackler 1992; Macfarlane and King 1995; Matthies and Samii 1997a). Approximately 90% to 95% of patients have abnormalities of hearing. Preservation of hearing is possible only if the tumor is small (less than 1.5 cm) or confined to the cerebellopontine angle cistern. In 50% of patients at presentation, hearing loss is the only neurologic sign. Although the symptom of unsteadiness is common, most patients have normal or mildly affected gait and station. In many of these patients, unsteadiness is related to dizziness and other signs of vestibular dysfunction (Matthies and Samii 1997a). Large tumors may cause frank ataxia or dysmetria from brainstem or cerebellar compression, but these signs are infrequent. In 7% to 15% of patients, particularly those with tumors larger than 4 cm in diameter, papilledema is present (Miller 1988; Macfarlane and King 1995). Horizontal nystagmus is often noted in patients with tumors greater than 2 cm in diameter (Miller 1988; Macfarlane and King 1995). Trigeminal dysfunction, typically in the form of a diminished corneal reflex or partial facial hypesthesia, is noted in more than half the patients; hemifacial anesthesia is rare (Selesnick and Jackler 1992). Diminished corneal sensation is present in 30% of medium-sized and 60% of large-sized vestibular tumors. Paresis of the lower cranial nerves (IX, X, XI, XII) is uncommon and appears as a late sign in large tumors that grow in a medial and inferior direction toward the jugular foramen (Hanabusa et al 2001). Long tract signs (eg, hemiparesis, spasticity, hyperactive reflexes) from severe brainstem compression are rare in modern series (Selesnick and Jackler 1992).

Trigeminal schwannoma. Trigeminal schwannomas can arise from any portion of the fifth cranial nerve (sensory or motor root, gasserian ganglion, 1 of 3 major divisions, or peripheral branches); however, the most common origin is ganglionic (McCormick et al 1988; Miller 1988; Pollack et al 1989; Strauss and Post 1995; Krishnamurthy et al 1998; Sarma et al 2002; Zhang et al 2009). These tumors can be categorized by origin of location; middle cranial fossa (50%), posterior fossa (30%), or dumbbell shaped with extension into middle and posterior fossae (20%). In general, the most common symptoms are referable to ipsilateral trigeminal nerve dysfunction (noted in 50% to 60% of patients) that has been present for months to years. Complaints initially consist of numbness in 1 or more of the trigeminal distributions (25% to 30%). Less often, the symptom is pain (20% to 25%), paresthesia (5% to 10%), or a combination of all 3 complaints. Although all 3 divisions can be involved, hemifacial anesthesia is distinctly rare. When pain occurs, it is usually constant and slowly progressive. The pain may sometimes resemble trigeminal neuralgia, although the paroxysms of pain are usually not associated with trigger zones and may last for hours, instead of seconds to minutes (McCormick et al 1988; Strauss and Post 1995). In patients presenting with facial pain, more than half have ganglionic tumors, and one third arise from the nerve root. Headache or diplopia is the initial symptom in 15% to 18% or 10% of patients, respectively. Loss of hearing, tinnitus, or visual disturbance is the initial complaint in less than 10% of patients. Rare or unusual symptoms include vertigo, seizure, gait difficulty, exophthalmos, and hemifacial spasm.

On neurologic examination at presentation, patients with trigeminal schwannoma typically have dysfunction of cranial nerve V (McCormick et al 1988; Strauss and Post 1995). Diminished sensation is evident along 1 or more of the trigeminal dermatomes in 80% to 90% of patients. In most of these cases, the corneal reflex will be weak or absent. Mild weakness of the muscles of mastication is found in 30% to 45% of patients. Abnormal function of other cranial nerves is noted in 75% of patients. The cranial nerves most commonly affected are VI (35%), VIII (32%), VII (23%), III (14%), II (10%), IX and X (8%), and IV (7%) (McCormick et al 1988; Strauss and Post 1995). Palsy of cranial nerve III occurs more often in middle fossa schwannomas; it is present at diagnosis in 50% of patients (Pollack et al 1989). Abnormalities of cranial nerves VIII, IX, X, and XI occur more frequently (30% to 50%) in posterior fossa schwannomas. Long tract signs (eg, hemiparesis, spasticity, hyperactive reflexes) are evident in 16% of trigeminal tumors. Although these signs can occur with middle fossa schwannomas, they are more common with posterior fossa tumors that compress the brainstem (Pollack et al 1989). Cerebellar dysfunction (ie, ataxia, dysmetria, dysarthria, nystagmus) is found in 23% of patients, and can result from compression of the cerebellum or brainstem. Exophthalmus and papilledema are present in 17% and 11% of patients, respectively. Facial-trigeminal synkinesis has been reported in a patient after recovery from surgery for a trigeminal schwannoma (Rubin et al 1999). During regeneration of the injured facial nerve, the masseter and pterygoid muscles were reinnervated, resulting in continuous deviation of the patients jaw.

Schwannomas of other cranial nerves. The majority (58%) of schwannomas of cranial nerve VII arise from the vertical segment of the nerve within the temporal bone (Miller 1988; Rocchi et al 1991; Kim et al 2003). Less often, the tumors occur near the tympanic membrane or cerebellopontine angle. In most patients (50% to 90%), the initial complaints consist of facial weakness and hearing loss. Other symptoms include tinnitus (60%), vertigo (34%), otalgia, facial pain, headache, and gait ataxia (Miller 1988; Rocchi et al 1991; Strauss and Post 1995; Chung et al 1998). The symptoms are slowly progressive (mean 6 to 7 years) in 80% of patients (Rocchi et al 1991). In the other 20%, the symptoms may have an acute onset, similar to Bell palsy, or may fluctuate. Neurologic signs usually consist of peripheral facial weakness and hearing loss; less common findings include facial sensory loss, diminished or absent corneal reflex, ataxia, nystagmus, loss of taste, and dry eyes.

Schwannomas of the cranial nerves that exit via the jugular foramen (IX, X, XI) may present with the classic jugular foramen syndrome: dysphagia, weakness and atrophy of sternocleidomastoid and trapezius muscles, hoarseness, and diminished taste (Miller 1988; Sweasey et al 1991; Strauss and Post 1995; Wilson et al 2005; Bulsara et al 2008). This usually occurs with tumors that are confined to the jugular foramen. Tumors with a significant posterior fossa component (eg, most glossopharyngeal schwannomas) present differently, mimicking vestibular tumors, with symptoms of sensorineural hearing loss, tinnitus, facial weakness and numbness, and ataxia (Strauss and Post 1995; Rapana et al 1997; Vorasubin et al 2009). On neurologic examination, the findings are variable but may include hearing loss, facial weakness and numbness, nystagmus, ataxia, papilledema, palatal weakness, reduced gag reflex, ipsilateral vocal cord paralysis, and weakness of the sternocleidomastoid and trapezius muscles. A recent review of the literature over the past 100 years found 42 cases of glossopharyngeal schwannoma (Vorasubin et al 2009). In 84% of the cases, patients presented with vestibulocochlear symptoms, along with midfrequency sensorineural hearing loss, which is different from the high-frequency pattern usually present in vestibular schwannomas.

Schwannomas of the ocular motor nerves (III, IV, VI) are extremely rare; tumors of cranial nerve III are the most common of this group (Miller 1988; Mehta et al 1990; Tung et al 1991; Jackowski et al 1994; Strauss and Post 1995; Santoreneos et al 1997; Mariniello et al 1999). Ocular motor schwannomas arise most often in the interpeduncular cistern and less often in the cavernous sinus or orbit. The duration of symptoms before diagnosis is typically shorter for this group of tumors than for other schwannomas, averaging 9 to 13 months (Mehta et al 1990; Tung et al 1991; Jackowski et al 1994; Santoreneos et al 1997). The presenting complaints are usually diplopia and headache. Other symptoms may include visual loss (compression of cranial nerve 2), facial sensory loss, weakness, or ataxia. Neurologic signs most commonly reflect palsy of the parent nerve (eg, exotropia, ptosis, anisocoria) and other cranial nerves affected by tumor compression (eg, visual loss, facial sensory loss). Hemiparesis, ataxia, or dysmetria may be noted if the tumor is compressing the brainstem.

Schwannomas of cranial nerve VII present with suboccipital or nuchal headache in 70% to 75% of cases, often associated with nausea and vomiting (Strauss and Post 1995). Due to frequent compression of nerves in the adjacent jugular foramen, other common (65% to 70%) symptoms include dysphagia, hoarseness, and weakness of sternocleidomastoid and trapezius muscles. In addition, patients may complain of weakness (60% to 65%), ataxia, vertigo, and facial numbness. The most consistent finding on neurologic examination is hemiatrophy and fasciculations of the tongue with ipsilateral deviation during protrusion. Other frequent signs include papilledema, ipsilateral palatal deviation, reduced gag reflex, hemiparesis and spasticity, nystagmus, ataxia, and weakness of the sternocleidomastoid and trapezius muscles.

Schwannomas of cranial nerve XII (ie, hypoglossal schwannomas) are very uncommon and present with a combination of tongue atrophy and weakness, along with vertigo, headache, and other symptoms related to compression of the cerebellum and brainstem (Tucker et al 2007). Rare schwannomas have been reported within or near the sella turcica (Maartens et al 2003). However, the origin of these tumors remains unclear. Some authors contend the tumors are derived from the lateral sellar nerve plexus of the cavernous sinus, with secondary extension into the sella; others suggest an origin from perivascular Schwann cells.

Schwannomas of the spine. Schwannomas of the spine usually develop from the nerve roots, with a predilection for the dorsal sensory branches. The evolution of symptoms is slowly progressive, with a median duration of 60 weeks before diagnosis (Newton et al 1995; Seppala et al 1995b; Conti et al 2004). They develop most often in the lower cervical region and at the thoracolumbar junction. The most common symptom in this group of patients is pain, either radicular (72%) or localized (59%) (Seppala et al 1995b; Conti et al 2004; Safavi-Abbasi et al 2008). Other frequent complaints include lower extremity weakness (60%), incontinence (33%), focal motor weakness (30%), gait difficulty (28%), and sensory loss. The neurologic examination often demonstrates radicular loss of reflexes and sensation. Focal muscle weakness and atrophy may be present. Myelopathic findings are noted in more than 50% of patients and include spastic paraparesis, hyperactive lower extremity reflexes, extensor plantar responses, reduction of lower extremity sensation, and a sensory level. On rare occasions, the presentation can be rapid with development of acute spinal cord symptoms. For example, several patients have now been reported with spinal schwannomas that have bled, causing spinal subarachnoid hemorrhage and a cauda equina syndrome (Cordan et al 1999; Parmar et al 2004). An uncommon form of spinal schwannoma is the intramedullary variety (Colosimo et al 2003). The source of Schwann cells is considered to be small perivascular bundles of peripheral nerves that are present within the spinal cord. The majority of intramedullary schwannomas (62%) occur in the cervical region.

Schwannomas of peripheral nerves. The most common sites of origin are the brachial plexus, the major nerve branches of the upper limb, and the major plexus and nerve branches of the lower limb (Lusk et al 1987; Ariel 1988; Miller 1988; Kim et al 2005). The tumors usually appear on the flexor aspects of the limbs, especially the elbows, knees, and wrists. The patient complains of a mass that was initially painless that has become tender. Further growth may result in paresthesias and pain. More severe neurologic deficits only develop when tumors grow in confined spaces (eg, under firm fascia or deep to the clavicle). The examination typically shows a mass that is tender to percussion and can be moved from side to side, but not in a longitudinal manner. Percussion of the mass can often induce painful paresthesias in the distribution of the nerve (similar to Tinel sign). In most cases, sensory and motor deficits in the distribution of the affected nerve are not present. Malignant schwannomas of peripheral nerves have a similar presentation; however, the symptoms often evolve more quickly due to rapid growth (Cashen et al 2004; Carli et al 2005; Anghileri et al 2006; Widemann 2009). Patients with malignant tumors may have more severe motor and sensory deficits in the distribution of the affected nerve. Malignant peripheral tumors are most common in adults but occur in patients younger than 20 years of age in 10% to 20% of cases (Carli et al 2005; Gupta and Maniker 2007). Although uncommon (4.6%), patients without neurofibromatosis type1 or 2 can develop multiple schwannomas of the peripheral nerves (Ogose et al 1998). In these cases, the tumors can be located superficially or in deep tissues and tend to be smaller than their counterparts in patients with NF1 or NF2 (Anghileri et al 2006).

Neurofibromas. Small cutaneous terminal nerves are the typical location for neurofibromas in patients without neurofibromatosis type 1 or 2 (Ariel 1988; Miller 1988; Kim et al 2005). In general, neurofibromas are considered the most common tumors of peripheral nerves. Other frequent sites include the brachial plexus, major nerves and branches of the upper extremity, and major nerves of the lower extremity (Lusk et al 1987; Miller 1988). According to several reviews of brachial plexus tumors, neurofibromas account for 46% to 54% of all resected neoplasms (Lusk et al 1987; Kim et al 2005). Similar to schwannomas, neurofibromas of the peripheral nerves present with a painless mass. The mass may become tender as it enlarges, although less often than schwannomas. Deficits of sensation and motor function are more likely with neurofibromas than schwannomas, because the parent nerve is usually engulfed within the growing tumor. Although uncommon, sporadic neurofibromas can involve the cranial cavity, orbit, cranial nerves, and spine (Carterlliei and Swoboda 2000; Lee et al 2000). When they do occur, their clinical presentation and evolution are similar to that of schwannomas of the same location (Sanguinetti et al 1993; Seppala et al 1995a). Malignant neurofibromas usually occur in patients with neurofibromatosis type 1, but can rarely occur in a sporadic fashion. Their presentation is similar to regular neurofibromas, with the presence of a painful, growing mass, along with abnormalities of sensation and strength in the distribution of the affected parent nerve. Symptoms generally evolve more rapidly with these tumors. The patients often have systemic symptoms, such as weight loss and fatigue. The neurologic examination may be normal, but more typically demonstrates loss of sensation and weakness consistent with the parent nerve.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors