Clinical manifestations

Presentation and course

The presenting features depend on the size and location of the hemorrhage. Headache and focal brainstem signs are seen in most patients. Headaches are usually associated with vomiting and are more common in women or patients younger than 70 years of age (58). However, the frequency of headaches is not as common with deep hematomas (brainstem) compared to lobar or cerebellar hemorrhages (58). Depending on the location of the hemorrhage, the patient may present with diplopia, incoordination, cranial nerve signs, vertigo, tinnitus, hyperacusis, tremor, dysarthria, dystonia, hyperthermia (77), breathing dysfunction, and long-tract signs (16). With large hemorrhages, especially in patients with hypertension or an underlying vascular malformation, there may be a rapid progression to coma. Intracranial hemorrhage is an important cause of acute neurologic dysfunction and accurate early diagnosis of cortical versus brainstem hemorrhage, with initiation of appropriate therapy, may help to minimize morbidity (85).

Most hemorrhages occur in the ventral region of the brainstem. This region is supplied by 3 groups of arteries. The paramedian branches supply the basal region. Short and long circumferential arteries supply the tegmentum. Hemorrhages commonly occur in the distal branches of these arteries (37). In the pons, hemorrhages restricted to the basal region involve the pontine nuclei, corticospinal, corticobulbar, and corticopontine tracts. Hemorrhages in the circumferential arterial territory involve cranial nerves, sensory tracts, autonomic tracts, and cerebellar peduncles. In the pons, lesions in the short circumferential artery distribution usually result in ipsilateral cerebellar disturbances and autonomic disturbances, and contralateral sensory deficits. Lesions of the long circumferential arteries, in addition to the cerebellar and sensory deficits, also involve cranial nerves producing lateral gaze palsy, and facial sensory or motor disturbances. Pontine hemorrhages may also become clinically manifest due to isolated eye and facial pain, described as salt-and-pepper pain (14).

Pontine hemorrhage. Patients with a large central hemorrhage present with a progressive decrease in the level of consciousness rapidly leading to coma. Bilateral bulbar muscle weakness, "pinpoint" pupils, hyperthermia, and hyperventilation are common associated findings (82). This presentation is seen most often in patients with uncontrolled hypertension (22). Contralateral hyperhidrosis in the subacute or late phase after pontine hemorrhage may be seen. This is thought to be secondary to disruption of contralateral inhibitory sweating pathway (78). Up to one third of patients may develop a severe headache before the onset of focal signs (22). Vomiting may be seen in 20% of patients, and seizures (mostly flexor spasms and not true convulsions) have been reported in 30% of patients (22).

Physical examination reveals an increased temperature and abnormal breathing patterns in 70% of patients. Ophthalmological examination may show small pupils, absence of horizontal eye movements, and ocular bobbing.

With large hemorrhages, bulbar musculature is invariably affected. This may increase the risk of aspiration. Silent aspiration may be difficult to recognize in the comatose patient. Massive pontine hemorrhage is invariably fatal; 80% of patients die within 48 hours (82). In a large study, 70% of the patients were comatose at admission, and 78% were dead in 48 hours (22). Most hemorrhages occurred in the midpons at the junction of basis pontis and tegmentum. Hemorrhages frequently spread to the midbrain but rarely into the medulla. They frequently rupture into the fourth ventricle (22). Pontine microbleeds have been described in the setting of CADASIL (66).

Smaller hemorrhages in the tegmentum or basal regions may present with focal signs and no alteration in consciousness (81). Such small hemorrhages are usually unsuspected until after the CT or MR scans. Hemorrhages restricted to the basal region present with hemiplegic deficits or ataxia-hemiparesis (29; 79). There are rare reports of auditory hallucinosis (09). Clinically, such syndromes are indistinguishable from lacunar infarction in the same region. With hemorrhages restricted to the lateral tegmentum, sensory deficits, ataxia, and oculomotor abnormalities (one-and-one-half syndrome, internuclear ophthalmoplegia, horizontal gaze palsies and ocular bobbing) are common findings (70; 10). Isolated symptoms such as sixth nerve palsy, sometimes bilateral (39), hemisensory or isolated facial sensory (94) disturbances, or trigeminal neuropathy (06) have been reported with small hemorrhages. Dystonia may be associated with pontomesencephalic lesions (47). Phantom arm and leg phenomena have been noted after pontine hemorrhage (90). Early recovery is seen in most patients, and complete resolution of deficits is common. In a study of 80 patients with primary pontine hemorrhage, the initial level of consciousness and the transaxial size of hematoma on CT were strongly related to the outcome (63).

Midbrain hemorrhage. Spontaneous midbrain hemorrhages were considered rare until relatively recently. The first case was reported in 1949 (80). The clinical diagnosis of a brainstem tumor was changed to hemorrhage after the surgery. Between 1978 and 1991, more than 20 additional patients were reported in the literature (81). In most patients, the diagnosis of midbrain hemorrhage was not suspected until after a CT or MRI. Isolated case reports may reveal subtle or minimal symptoms due to restricted involvement such as monoaural tinnitus due to contralateral inferior colliculus hemorrhage (86). Neuro-ophthalmological involvement is prominent in most patients. Third nerve dysfunction, skew-deviation, gaze palsy (especially in the vertical axis), and pupillary irregularities are common (38). Parinaud syndrome (superior gaze palsy, pupillary dysfunction, and tonic downward and medial deviation of the eyes) is seen with hemorrhages in close proximity to the posterior commissure (26; 81). Third nerve involvement may be unilateral or bilateral. With unilateral involvement, there may be partial or complete paralysis of function, and the affected lesion may involve the nucleus or the third nerve fascicle. With fascicular involvement, motor long tracts may be affected in the cerebral peduncle (Weber syndrome). Isolated fourth nerve palsy may also be a rare manifestation (44; 72). Patients may have ataxia (from involvement of the superior cerebellar tract in the midbrain), sensory dysfunction (06), and motor dysfunction (from involvement of the long tracts passing through the midbrain). Unilateral asterixis (26), cheiro-oral syndrome (sensory disturbance around the arms and mouth) (97), and behavioral abnormalities (57) have occasionally been demonstrated. Hemorrhages close to the aqueduct can produce an acute hydrocephalus that may need urgent surgical intervention. Recovery in most patients with a small hemorrhage is rapid and often complete. In patients with an underlying arteriovenous malformation, recurrence may commonly be seen (01). Arauz and colleagues estimated that cavernomas greater than 18 mm are prone to recurrent bleeding (02).

Medullary hemorrhage. Hemorrhage in the medulla is the least common type of brainstem hemorrhage; the first report was published in 1964 and discussed a patient who had Wallenberg syndrome (40). A brainstem tumor was suspected. Surgery revealed an unexpected hemorrhage. On occasion, tumors such as hemangioblastoma may cause medullary hemorrhage (76). Posttreatment radiation injury of tumors in this region may also lead to hemorrhage (46). In most patients, it has been difficult to determine if the hemorrhage was confined to the medulla or extended into the pons (03; 75; 19; 81). Vertigo, ataxia, lower cranial nerve abnormalities, and breathing dysfunction can develop with hemorrhages in the medulla (81). Central hypoventilation can develop suddenly and early after the hemorrhage and can lead to respiratory arrest (81). Breathing difficulties are particularly bothersome during sleep resulting in repeated apneic spells (92). Headache is common, and neck stiffness has been reported. Tongue weakness, down beating nystagmus (74), and autonomic dysfunction may be seen. Breathing difficulties may not resolve for a long time, and some patients may require tracheostomy for ventilatory support. The occasional patient may be severely disabled with the vertigo or ataxia. Early neurologic deterioration is a marker of poor prognosis (43).

Prognosis and complications

The prognosis with brainstem hemorrhage depends on the size and location of the hemorrhage. With large pontine hemorrhages that involve the basis pontis and tegmentum, 78% of patients may die in the first 48 hours, with the majority dying in the first 24 hours. A prognostic scale for pontine hemorrhage that emphasizes the critical impact of low Glasgow Coma Scale (< 6), absence of pupillary reflex, and blood glucose of 180 mg/dL or greater has been developed (56). Whereas other authors have determined slightly disparate thresholds for such prognostic variables, the same factors have been linked with high mortality (52). Autonomic dysfunction and respiratory arrest are the common causes of early death. Later, pneumonia and other infections, venous thrombosis with pulmonary emboli, and other systemic causes may complicate recovery. A high correlation has been observed between a poor outcome (Glasgow outcome score < 4) and hematoma volume greater than 4 mL, ventral hemorrhage, and necessity for mechanical ventilation (96). Aggressive management may also lead to good prognosis in selected cases (87), but brainstem hematomas generally have a poor prognosis (73; 04).

In patients with small hemorrhages located in the pontine tegmentum or the midbrain, prognosis for recovery is excellent. Recovery begins within 24 hours, and most patients may be discharged from the hospital within a week. In our experience, a complete recovery occurs 6 weeks to 8 weeks after the onset. Recurrence may occur in patients with an arteriovenous malformation (01). In patients with milder symptoms and no defined etiology, recurrence is rare.

A multivariate analysis demonstrated bilateral hematoma extension, a Glasgow Coma Scale score of less than or equal to 8, presence of hydrocephalus, gender, and hematoma volume to all be significantly associated with 3-month mortality, whereas Glasgow Coma Scale score less than or equal to 8, the presence of a pupillary abnormality, and hematoma volume were found to be associated with the 3-month poor outcome (88).

Huang and colleagues developed and validated a prognostic scale specifically for pontine hemorrhages (34).

Clinical vignette

A 43-year-old woman presented with several months of fluctuating headaches that culminated in acute presentation with severe headache, marked hypertension, diplopia, bilateral numbness, and paraparesis. MRI revealed a large cavernous angioma of the pons with evidence of recurrent hemorrhage. Although surgical evacuation was considered, it was deferred due to the deep location and expected high complication rate. Conservative medical management over 4 years was punctuated by recurrent bleeds with chronic fatigue, diplopia, and bladder dysfunction although her sensory and motor deficits improved with time.

Biological basis

Etiology and pathogenesis

The most common underlying problem with large hemorrhages is uncontrolled hypertension (22), as may be seen in more than 80% of patients with large pontine hemorrhages. Arteriovenous malformations may account for a small minority of patients, especially with recurrent hemorrhages. Patients with no obvious underlying etiology may have a milder clinical course. In 1 report of 164 patients with posterior fossa vascular malformation, arteriovenous malformations had the greatest tendency to bleed (54). Among the 12 lesions that bled, 9 lesions were arteriovenous malformations, and 3 lesions were venous angiomas (54). Most of the arteriovenous malformations were in the pons. Besides arteriovenous malformations, telangiectasias and cavernous or venous malformations also frequently occur in the brainstem. Telangiectasias and venous malformations rarely bleed. Of the 27 lesions in the above-mentioned series, none were associated with any sign of remote or recent hemorrhage. Other rare etiologies include hemorrhage into a tumor, brainstem infarction or cyst, vasculitis, trauma, postradiation degeneration, aneurysms, and amyloid (64; 59; 18; 53; 100; 46; 95; 42; 89; 67). Repeated hemorrhage has also been reported from a melanoma mistaken as a cavernoma (95). Drug-induced hemorrhage is rare in the brainstem. It may be seen with an overdose of anticoagulants, or it may be related to “street” drug or methamphetamine abuse (08; 61; 17; 99). A massive brainstem hemorrhage in association with acute necrotizing encephalopathy has also been reported (91). An analysis of warfarin-related hemorrhage revealed that brainstem intracerebral hemorrhage may be more frequent (24.0% vs. 6.1%; P=0.005) with excessive anticoagulation (INR> 3.0) compared with those in therapeutic range (48). Brainstem hemorrhage has been described as a feature of coronavirus disease 2019 (COVID-19) (23; 27). Duret hemorrhages result secondary to increased intracranial hypertension more often after trauma and in craniocerebral trauma victims with rapidly evolving descending transtentorial herniation. Duret hemorrhages are typically located in the ventral and paramedian aspects of the upper brainstem (mesencephalon and pons). The pathophysiology of Duret hemorrhage remains under debate: arterial origin (stretching and laceration of pontine perforating branches of the basilar artery) versus venous origin (thrombosis and venous infarction). Multifactorial causation seems likely (69).

In patients with small hemorrhages, investigations such as angiography and MRI, often fail to show an underlying etiology. In the absence of any obvious etiology, telangiectasias or venous malformations are often proposed as the lesions responsible for the hemorrhage. However, such lesions are rarely found during surgery or at autopsy. In addition, because of their small size, they may be completely destroyed within the hematoma. Between telangiectasias are commonly found incidentally at autopsy and seldom show signs of bleeding when examined at that time, the relationship between such lesions and brainstem hemorrhage requires further study.

The most common cause of pontine hemorrhage is a rupture of the intraparenchymal branches of the basilar arteries. Usually, the bleeding vessel is a perforator, and the hemorrhage is at its distal end (22). The hemorrhage commonly occurs at the junction of the basis pontis and tegmentum. In a study, topographic correspondence has been documented between hypertensive pontine microhemorrhages and larger primary pontine hemorrhages. This may provide evidence that the 2 lesions share some etiologic basis (36). The hematoma may travel superiorly into the midbrain or into the cerebellar peduncles but rarely extends into the medulla. Large hemorrhages frequently rupture into the fourth ventricle (22). The presence of hemorrhage into the third ventricle is an independent negative predictor of outcome (83).

Hypertensive patients develop fibrinoid necrosis or microaneurysms in the small arteries of the brainstem. Fibrinoid necrosis results in segmental destruction of the vessel wall leading to arterial occlusion or rupture. Microaneurysms are present in large numbers in the basal ganglion, thalamus, and pons. Cerebral hypertensive hemorrhage is frequent in these regions of the brain. Such aneurysms are rarely seen in normotensive young individuals. Their numbers increase with longstanding hypertension. In the series of Cole and Yates, microaneurysms were seen in 46% of hypertensive patients and in 7% of normotensive patients (20). None of the normotensive individuals had brainstem lesions, whereas 15 lesions were present in the hypertensive individuals. A direct relationship between the microaneurysms and hypertensive hemorrhage is difficult to establish. Perianeurysmal hemorrhage is demonstrated occasionally, suggesting a possible relationship to a large hemorrhage. Usually the hemorrhage is extensive, and the microaneurysm may be destroyed during the event.

The relationship between preexisting ischemic infarction and brainstem hemorrhage (ie, hemorrhagic infarction vs. true primary hematoma) has remained a subject of controversy and may occasionally be difficult to distinguish (31); however, in most patients the differentiation is easy. Distinction between a diffuse widespread hemorrhage and a subependymal hematoma has also been promoted by advocates of early surgery in brainstem hematomas. Diffuse deep hemorrhages are seen in individuals with uncontrolled hypertension and are difficult to treat surgically. Subependymal hematoma may result from rupture of vascular malformations. Patients with the latter lesions have milder symptoms and may do well with surgical evacuation of the blood (49).

Epidemiology

There are little prospective data on the frequency of brainstem hemorrhage. Pre-CT studies estimated the incidence to be 6% of brain hemorrhages (31). The low incidence reflected only the inclusion of patients with severe disease. Studies in the last 2 decades, with wider CT use, report a higher incidence of 13% to 22%. There are no comparative series for the incidence of hemorrhage in the midbrain or the medulla (31).

Prevention

Early and effective therapy of hypertension is the best way to prevent fibrinoid necrosis or formation of microaneurysms. Surgical resection or embolization of arteriovenous malformations may prevent subsequent hemorrhages.

Small vascular malformations are commonly seen at autopsy. MRI technology has made the diagnosis easier as such lesions may be associated with small, old hemorrhages. For acute hemorrhage, CT scan is considered better than MRI, but the literature indicates that MRI can identify hyperacute hemorrhages within 2 hours (45). Also, MRI has been shown to be effective for the detection of old lacunar hemorrhage (41). The "cryptic" malformations are being diagnosed with greater frequency. It is not known if treatment of such lesions will decrease the incidence of smaller subependymal hemorrhages.

Differential diagnosis

The classical presentation with rapid loss of consciousness, pinpoint pupils, and hyperthermia in a hypertensive individual is recognized easily as secondary to a large pontine hemorrhage. Rarely, a "locked-in" syndrome from basilar artery occlusion may produce a similar picture. Smaller hemorrhages may cause no headache and mild symptoms. These are difficult to separate clinically from an infarction in the pons or in other brainstem regions. In patients with progressive symptoms, brain tumors may be suspected. Investigations, including a contrast-infused CT, MRI, and angiography may be needed to rule out brainstem infarction, tumors, or arteriovenous malformations. It should be noted that for diagnosis of acute hemorrhage, CT scan is usually sufficient.

Diagnostic workup

Patients presenting with brainstem hemorrhage, especially in the pons, need urgent evaluation of the pulmonary status, as they may be at risk for aspiration or respiratory arrest. Blood pressure and cardiac dysfunction should be monitored continuously and may require urgent attention. Investigation of the cause of hypertension sometimes requires the assistance of a general internist.

Neurologically, the initial investigation is a CT scan of the head to localize the lesion and estimate its size. Cranial CT scan and MRI remain the most important tools for diagnosis. A high attenuation mass localized to the brainstem with densitometry consistent with blood is typical of hemorrhage. Gradual resolution with repeated CT examination is typical. MRI is helpful in size estimation of the hemorrhage in sagittal views. Signs of smaller previous hemorrhage may also be demonstrated on MRI. Follow-up CT scanning with contrast may reveal a vascular malformation or underlying tumor. If an aneurysm or vascular malformation is suspected, cerebral angiography may be necessary. Extension of the hemorrhage or edema may produce further compromise, resulting in deterioration of the clinical status, which may require repeated scanning. Follow-up scan is recommended 4 weeks to 6 weeks after the ictal event.

Although CT scans immediately become positive after a hemorrhage, MRI is useful in determining the etiology of the hemorrhage (60). The CT angiography (CTA) spot sign, suggesting an actively bleeding lesion, has also been described in the pons (62). The characteristic morphology of various types of lesions, including the so-called "cryptic" malformation has become relatively easy to diagnosis with MRI. Multiple hemorrhages of various ages may be seen in vascular malformations. MRI is also useful to differentiate between acute hemorrhage (intracellular deoxyhemoglobin), subacute hemorrhage (intracellular and free methemoglobin), and chronic hemorrhage (hemosiderin) (25). Felber reported that MRI could reliably identify hematomas at various stages, but for the hyperacute hemorrhage, CT is the investigation of choice. The presence of brainstem compression, readily identified on CT, in cerebellar hemorrhage markedly worsens prognosis (12). The black butterfly sign on T2* MRI has been described as a marker of venous congestion and potential hemorrhage in the presence of a fistula (24).

Cerebral angiography is rarely necessary in most patients with cerebral hemorrhage as the diagnostic yield is usually low with the test. The test should be ordered only if an arteriovenous malformation or an aneurysm is suspected to be the underlying vascular pathology (102). In a series of 206 patients with cerebral hemorrhage where cerebral angiography was done, the diagnostic yield was higher in younger patients (younger than 45 years of age) and in those with no preexisting hypertension (102).

An electroencephalogram is usually not required as the diagnosis is easy and confirmed by CT. Electroencephalography would show nonspecific slowing in most patients with drowsiness. Alpha-pattern coma has also been described with brainstem hemorrhage (32).

Management

All patients require hospital admission. Blood pressure, cardiac status, and respiratory status require careful monitoring in the early days after the hemorrhage. If there are signs of cerebral edema, the patient may require antiedema measures (eg, steroids, mannitol, or hyperventilation). Although medical treatments are limited, hematoma expansion has been limited in a few cases treated with recombinant factor VIIa, including a pontine hemorrhage (55). Ongoing research in animal models of acute intracerebral hemorrhage may translate into clinical advances in years to come (28).

Surgical intervention has been used (sometimes with dramatic results) in occasional patients. Surgical results are likely multifactorial and dependent on patient-specific variables (101). It can be recommended only for centers with special expertise in this type of surgery. The indications for surgical therapy versus conservative management were compared. In 127 patients with pontine hemorrhage reported until mid-1993, 49 patients were treated surgically. In general, younger patients with slowly progressive disease and normal blood pressure were more often surgically treated. Younger patients harboring more spherical arteriovenous malformations in nontectal regions are excellent candidates for radiosurgery and are associated with higher obliteration rates and lower complication rates (51). Overall, brainstem hemorrhages due to occult vascular lesions have higher complication rates when compared with other lesion sites (71; 21). Smaller subependymal lesions that produce focal lesions with no intraventricular extension of blood may be more amenable to surgery. Surgical approaches are midline, lateral, and through the fourth ventricle. The most common surgical approach is a posterior one through the inferior vermis (49; 31). This exposes the floor of the fourth ventricle and facilitates drainage of the hematoma. Surgery is not indicated in patients with large diffuse hemorrhage or in comatose patients (65). Acquired pendular nystagmus after pontine hemorrhage has been reported to respond favorably to clonazepam (98). Minimally-invasive endoscopic surgery has been used to address brainstem hemorrhage (33).

Special considerations

Pregnancy

Although pregnancy can increase the risk of hemorrhage from an aneurysm or arteriovenous malformation (35), an increased incidence of brainstem hemorrhage has not been reported.

Anesthesia

There is no published information on this subject. Patients with brainstem hemorrhage may have a severe elevation of blood pressure, an unprotected airway, and autonomic instability. This may increase the risk of anesthesia-related complications.

Pediatric age group

Brainstem hemorrhage has been noted in children with traumatic brain injury. Clinical outcomes, however, may include good neurologic outcomes (05).