Continuing Education Activity

Brainstem stroke is the most lethal form of all strokes. Both hemorrhagic and ischemic brainstem strokes account for a significant cause of morbidity and mortality on the global front. An ischemic form has a higher incidence compared to its hemorrhagic brainstem counterpart. Knowledge pertaining to brainstem stroke syndromes is prudent for early diagnosis and timely management to ensure better clinical outcomes. An adequate understanding of anatomy, physical exams, radio imaging, and pathophysiology are pivotal during the evaluation and management of the disease. This activity reviews the evaluation and treatment of brainstem infarction and highlights the role of the interprofessional team in assessing and treating patients with this condition.

Objectives:

• Summarize the etiology of the brainstem strokes.
• Outline the evaluation of the brainstem strokes.
• Review the management options available for brainstem strokes.
• Outline common complications and foster the need for a multidisciplinary approach to prevent mortality, limit neurological deficits, and promote functional gain through effective and continuum rehabilitative strategies.

Introduction

Brainstem stroke is the most lethal form of all strokes. Both hemorrhagic and ischemic brainstem strokes account for a significant cause of morbidity and mortality on the global front. An ischemic form has a higher incidence compared to its hemorrhagic brainstem counterpart.[1] Knowledge pertaining to brainstem stroke syndromes is prudent for early diagnosis and timely management to ensure better clinical outcomes.

The brainstem is composed of the midbrain, the pons, and the medulla oblongata, situated in the posterior part of the brain. It is a connection between the cerebrum, the cerebellum, and the spinal cord. Embryologically, it develops from the mesencephalon and part of the rhombencephalon, all originating from the neural ectoderm. The brainstem is organized internally in three laminae: tectum, tegmentum, and basis. Gray matter in the brainstem is found in clusters all along the brainstem forming mostly the cranial nerve nuclei, the pontine nuclei, and the reticular formation. White matter in the form of various ascending and descending tracts can be found mainly in the basis lamina, which is the most anterior part.[2] The brainstem is responsible for multiple critical functions, including respiration, cardiac rhythm, blood pressure control, consciousness, and the sleep-wake cycle. The cranial nerve nuclei in the brainstem have a crucial role in vision, balance, hearing, swallowing, taste, speech, motor, and sensory supply to the face. The white matter of the brainstem carries most of the signals between the brain and the spinal cord and helps with its relay and processing. 

The vascular territories of the brainstem have been categorized as:

Medulla oblongata (4 arterial territories):

• Anteromedial -from the anterior spinal artery (ASA) and the vertebral artery (VA)
• Anterolateral-from the ASA and VA
• Lateral - from the posterior inferior cerebellar artery (PICA), and
• Posterior -from the posterior spinal artery (PSA).

Pons (3 arterial territories):

• Anteromedial-from perforating arteries of the basilar artery (BA)
• Anterolateral-from the anterior inferior cerebellar artery (AICA)
• Lateral zone -from lateral pontine perforators of the BA, AICA, or from the superior cerebellar artery (SCA).

Midbrain (4 arterial territories):

• Anteromedial-from the posterior cerebral artery (PCA)
• Anterolateral -from the PCA or a branch of the anterior choroidal artery
• Lateral group -from the collicular, choroidal, and posterior cerebellar arteries
• Posterior group -from the superior cerebellar, collicular and posteromedial choroidal artery.[3]

Brainstem infarction is an area of tissue death resulting from a lack of oxygen supply to any part of the brainstem. The knowledge of anatomy, vascular supply, and physical examination can be life-saving in the setting of an acute infarct and provide precise diagnosis and management. Time becomes an essential factor in management. Early intervention has shown dramatically reduced morbidity and mortality.[4] Brainstem, accounting for almost one-third of all ischemic strokes, leads to high morbidity and mortality on the global front. The pons is predominantly affected.[3] Medullary infarction accounts for 7% of all ischemic brainstem strokes with lateral subtypes being the most common. There is a male preponderance (3:1). Atherosclerosis and VA dissections are the most common causes.[3]The pontine infarction can present as isolated or as a subset of a larger posterior circulation infarction. Ventral infarcts are the most common subtype. Atherosclerosis of the perforating arteries and occlusion of the BA are the most common causes. This can present as a lacunar variant presenting ubiquitously as pure motor, dysarthria-clumsy hand, ataxic hemiparesis syndrome, and pure sensory stroke patterns.[3] Isolated midbrain infarctions are rare and most commonly present with concurrent involvement of the cerebellum, pons, or thalamus.[3]

Dorsal Pontine involvement is the most common anatomical site for the location of brainstem hemorrhagic stroke.

Etiology

Brainstem infarction refers to the sequelae of ischemia to any part of the brainstem, due to the loss of blood supply or bleeding. Occlusion and stenosis of the posterior circulation cause significant hypoperfusion in the brainstem. The most common etiologies for brainstem infarction are atherosclerosis, thromboembolism, lipohylanosis, tumor, arterial dissection, and trauma. In medulla oblongata infarcts, 73% are due to stenosis of the vertebral artery, 26% are due to arterial dissection, and the rest are caused by other causes like cardioembolic.[5] However, the number of infarcts due to cardioembolic etiology increased to 8% in pontine infarcts and 20% to 46% in midbrain infarcts.[6] 

Risk factors for stroke, in general, include hypertension, diabetes mellitus, metabolic syndromes, hyperlipidemia, tobacco use, obesity, history of ischemic heart disease, atrial fibrillation, sleep apnea, lack of physical activity, use of oral contraceptives, fibromuscular dysplasia, trauma, and spinal manipulation.[3][7][8]

Risk variables for ischemic brainstem strokes include:

• Atherosclerosis
• Hypertension
• Diabetes
• Smoking
• Atrial fibrillation
• Hyperlipidemia
• Ischemic heart disease
• Embolism, and
• Dissections.[3]

Large vessel atherothrombosis is the predominant cause of all ischemic strokes in all anatomical locations. Cardioembolic events are more common in mesencephalic infarcts whereas dissections are common for medullary infarctions.[3]

25%of ischemic strokes occur within the posterior circulation (60% in the brainstem and 40% occur in the cerebellum).[3]

As per the TOAST classification system, large artery atherothrombosis accounts for the largest cause of these strokes in all arterial territories (63% overall and 74% in pons). Cardioembolism accounts for 15%–30% of the same. Cardioembolic etiology is involved in 26% of the midbrain and 31.5% of multiple concurrent multiple infarctions. Dissection is more commonly involved in the lateral medulla supplied by vertebral arteries.[9]

Etiology for hemorrhagic brainstem strokes:

• Hypertension (almost 90% of cases)
• Anticoagulant therapy (around 7%)
• Arteriovenous malformations
• Occult vascular malformations –cavernomas and capillary telangiectasia, and
• Amyloid angiopathy.[3][10]

Epidemiology

Globally, there is a rise in lifestyle diseases like cardiovascular disease, stroke, and diabetes mellitus, both in developed and developing nations. The global burden of stroke can be measured at 122 million disease-adjusted life years.[11] In the US, a stroke is reported every 40 seconds.[12] It has been estimated that the brainstem accounts for 10% to 15% of all strokes.[7] The lifetime (age 25 and onwards) risk of stroke in males is between 23.3 to 26.0%, and in females is between 23.7% to 26.5%. There is variation between regions with Eastern Sub-Saharan Africa with the lowest lifetime risk of 11.8% to East Asia, with the highest risk of 38.8%. China has the most significant lifetime estimated risk of 39.3%.[13]

Pontine is the most prevalent site of brainstem strokes (60% of infarction).[14] Ischemic vertebrobasilar strokes account for 23% whereas ischemic brainstem infarcts comprise 11% of all ischemic strokes. Approximately, 27%, 14%, and 7% of them involve the pons, medulla, and midbrain respectively. The cerebellar is involved in 7%, PCA territory in 36%, and concurrent multiple sites involved in 9%. Isolated pons infarcts were observed in 3% of all ischemic strokes. Lateral medullar infarcts are almost 5 times more common than medial infarcts. In the overall assessment, the lateral midbrain is the least involved anatomical region.[14] The anteromedial (AnM), Anterolateral (AnL), and lateral (L) territories have similar incidences with posterior infarcts being the least common subtype. AnM variant is frequently involved in the midbrain, AnM, and AnL in the pons, and L in the medulla respectively.[14]

Primary brainstem hemorrhage (PBH) constitutes 10% of all intracerebral hemorrhages (ICH). This has an annual incidence of roughly 2-4/100,000 per year.[15] Pons is most commonly involved (60-80%).[15] Age groups of 40-60 years are predominantly involved with male preponderance.[15] This has male preponderance with women showing better survival.[15]

Wallenberg’s syndrome, also known as ‘posterior cerebellar artery syndrome’ or ‘lateral medullary syndrome’, is the commonest of brain stem strokes.  Anterior inferior cerebellar artery syndrome (lateral pontine syndrome) AICAS is the second most common brain stem stroke.[14]

Pathophysiology

The pathophysiology of all infarcts is the lack of oxygen in the tissue, leading to its death. The human brain requires 20% of oxygen consumption even though it accounts for only 2% of the body by weight.[16] The cerebral blood flow is autoregulated to maintain a constant level of perfusion and adequate venous drainage to deal with all its needs. The cerebrum is also unique as it has little to no energy stores and uses glucose as its primary energy source, with distally produced ketone bodies being used only in starvation.[17] Dependence on aerobic respiration and low respiratory reserve makes the brain susceptible to ischemia and eventually causes irreversible tissue death. The cellular cascade of events is as follows:

• Depletion of ATP due to lack of aerobic respiration in the mitochondria.
• Loss of function of membrane ion pumps and impaired voltage gradient across membranes, leading to cellular edema.
• Excitotoxicity of the neurons due to the release of glutamate and synaptosomal-associated protein 25, causes further deterioration of energy levels and membrane ion potentials. Production of reactive oxygen species and free radicals leads to cell death.[18] 

While the above apoptotic/ necrotic pathway is in process, specific protective pathways are triggered: 

• Expression of heat shock protein 70, B-cell lymphoma 2 gene family, and prion protein to prevent activation of the apoptotic cascade.
• Release of Neurotrophin-3, interleukin-10, and granulocyte-colony stimulating factor, helping in the activation of survival pathways and reduction of proinflammatory cytokine activities.

The cellular cascade is potentially reversible, which can lead to vasogenic edema over the next few hours. Vasogenic edema causes an increase in pressure in the surrounding tissue, leading to mass effect, and worsening the situation.[19] The eventual release of matrix metalloproteinases causes loss of structural integrity and the dissolution of the blood-brain barrier.[20]

In the case of hemorrhagic etiology, the rupture of blood vessels causes hypoxia, pressure effects, and chemical irritation of brain tissue due to the disruption of the blood-brain barrier.

Animal models for PBSH are mainly obtained through stereotactic injection of collagenase or autologous blood.[15]The pathogenesis observed in animal models showed erythrocyte lysis, expression of heme oxygenase (HO-1), iron deposition, and release of reactive oxygen species (ROS) generation involved in the pathogenesis.[21]

Anterior territory involvement is more common with stroke in the mesencephalon and pons, whereas posterior and lateral anatomical involvement occurs more frequently in strokes involving the medulla.[9]

History and Physical

A loss of about 1.9 million neurons in the brain happens each minute in an untreated stroke.[22] Hence a targeted approach must be followed with clear objectives. Assessment of airway, breathing, and circulation, and its stabilization as a patient with brainstem stroke can present with trauma, altered mental status, altered respiratory drive, hypoxia, vomiting, and or mechanical airway obstruction.

Establishing the time of insult is critical. Patients, family members, attenders, co-workers, first responders, or any reliable witness can determine the time the patient was last known normal. If in the case of deficits arising in one's sleep, the last known normal is the time the patient went to bed. A clinician needs to distinguish between stroke and its differential diagnosis, causing various neurological deficits. Reliable information about the patient's current medication, especially with regard to oral hypoglycemic, insulin, anti-epileptics, neurological or psychological drugs, anti-platelets or blood thinners, drug abuse or overdose, and sleep apnea must be established. Co-morbidities and risk factors need to be assessed. Evaluation of signs and symptoms of hemorrhagic stroke is life-saving. Any history of uncontrolled hypertension, sudden onset of headache, vomiting, and signs of raised intracranial pressure must raise high suspicion of hemorrhage and warrants an immediate non-contrast computed tomographic (CT) scan of the head.

Brainstem lesions can be divided into three broad categories to identify the affected region or function of the brainstem.[3][23]

• Ascending and descending pathways: Weakness, loss of pain and temperature sensation, ataxia, Horner syndrome, loss of position and vibration sensation, gaze palsy
• Nuclei and cranial nerves: Ocular and extraocular muscle weakness, loss of sensation over the face, autonomic dysregulation, dysphagia, dysarthria, dysphonia, vertigo, alteration in taste and hearing
• Integrative and other functions: Choreoathetosis, tremors, ataxia, central dysautonomia, gaze paresis, lethargy, and locked-in syndrome.

A concise physical examination should evaluate any signs suggestive of trauma, meningeal irritation, or neurological deficits. Neurological examination of a brainstem stroke must include the following assessment:

• Levels of consciousness and higher mental function
• Complete evaluation of cranial nerves and their functions
• Motor and sensory system examination, including reflexes, neglect, speech, and language
• Cerebellar signs, coordination, and gait
• Autonomic system.

The 4 medial (towards Midline) structures within the brainstem:

• Motor tract (corticospinal tract)
• Medial Lemniscus
• Medial longitudinal fasciculus, and
• Motor nucleus of cranial nerve 3, 4, 6, and 12.

The 4 lateral (towards Sidelines) structures within the brainstem:

• Spinocerebellar tract
• Spinothalamic tract
• Sensory nucleus of the trigeminal nerve, and
• Sympathetic tract.[24]

This can help in the anatomical localization of the brainstem stroke.

Evaluation

The initial evaluation of patients presenting with a suspected stroke of the brainstem includes vital signs, oxygen saturation, blood pressure, pulse rate, respiratory rate, fingerstick blood glucose levels, and non-contrast CT scan of the head or brain magnetic resonance imaging (MRI). Non-contrast CT scan of the head is a quick and widely available imaging modality, and it is highly sensitive for acute hemorrhage. On a head CT scan, blood can be seen as a hyper-dense lesion. Infarction of brain tissue can be detected by brain MRI diffusion-weighted images and fluid-attenuated inversion recovery images, which are highly sensitive in the hyper-acute setting.[25]

Blood workup should include complete blood count, coagulation profile, serum electrolytes, renal function, lipid panel, hemoglobin-A1c level, thyroid function, vitamin B12 level, and vitamin D levels. Other blood investigations for hypercoagulability states, autoimmune conditions, liver pathologies, and genetic tests can be obtained. A cardiovascular workup for atrial fibrillation with either an electrocardiogram or Holter monitor, echocardiogram, cardiac enzyme levels, and chest X-ray should be obtained. A multi-phase CT angiography can establish the state of vertebral and carotid arteries, along with assessment for any endovascular management. Sleep study or polysomnography is diagnostic for various sleep disorders and must be suspected in stroke cases with unknown etiologies. Evaluation of both modifiable and non-modifiable risk factors for cardiovascular disease must be done.

Due to the high density of nuclei and fibers running through the brainstem, the lesion in various structures gives rise to different signs and symptoms. Variously named stroke and stroke syndromes have been described in the literature.

• The 'top-of-the-basilar' syndrome: Also known as the rostral brainstem infarction. It results in alternating disorientation, hypersomnolence, unresponsiveness, hallucination, and behavioral abnormalities along with visual, and oculomotor deficits, and cortical blindness. Occurs due to occlusion of the distal basilar artery and its perforators.[26]
• Ondine's syndrome: Affects the brainstem response centers for automatic breathing. It results in complete breathing failure during sleep but normal ventilation when awake. The blood supply affected is the pontine perforating arteries, branches of the basilar artery, anterior inferior cerebellar artery, or the superior cerebellar artery.[26] 
• One-and-a-half syndrome: Affects the paramedian pontine reticular formation and medial longitudinal fasciculus. It results in ipsilateral conjugate gaze palsy and internuclear ophthalmoplegia. The blood supply affected is the pontine perforating arteries and branches of the basilar artery.[27]  

Brainstem stroke syndromes include:

Midbrain syndromes

• Claude syndrome: Affects the fibers from CN III, the rubrodentate fibers, corticospinal tract fibers, and corticobulbar fibers. It results in ipsilateral CN III palsy, contralateral hemiplegia of lower facial muscles, tongue, shoulder, upper and lower limb along with contralateral ataxia. The blood supply involved is from the posterior cerebral artery.
• Dorsal midbrain syndrome (Benedikt): Also known as paramedian midbrain syndrome, affects the fibers from CN III and the red nucleus. It results in ipsilateral CN III palsy, contralateral choreoathetosis, tremor, and ataxia. The blood supply involved comes from the posterior cerebral artery and paramedian branches of the basilar artery.
• Nothnagel syndrome: Affects the fibers from CN III and the superior cerebellar peduncle. It results in ipsilateral CN III palsy and ipsilateral limb ataxia. It can be due to quadrigeminal neoplasms and is often bilateral.
• Ventral midbrain syndrome (Weber): Affects the fibers from CN III, cerebral peduncle (corticospinal and corticobulbar tract), and substantia nigra. It results in ipsilateral CN III palsy, contralateral hemiplegia of lower facial muscles, tongue, shoulder, and upper and lower limbs. The involvement of substantial nigra is present can result in a contralateral movement disorder. The blood supply affected is the paramedian branches of the posterior cerebral artery.[28][29][30][31][32]

Pontine syndromes

• Brissaud-Sicard syndrome: Affects the CN VII nucleus and corticospinal tract. It results in ipsilateral facial cramps and contralateral upper and lower limb hemiparesis. The blood supply affected is the posterior circulation. Rarely, the syndrome can arise due to brainstem glioma.
• Facial colliculus syndrome: Affects the CN VI nucleus, the CN VII nucleus, fibers, and the medial longitudinal fasciculus. It results in lower motor neuron CN VII palsy, diplopia, and horizontal conjugate. It can occur due to neoplasm, multiple sclerosis, or viral infection.
• Gasperini syndrome: Affects the nuclei of CN V, VI, VII, VIII, and the spinothalamic tract. It results in ipsilateral facial sensory loss, ipsilateral impaired eye abduction, ipsilateral impaired eye abduction, ipsilateral nystagmus, vertigo, and contralateral hemi-sensory impairment. The blood supply involved derives from the pontine branches of the basilar artery and the long circumferential artery of the anterior inferior cerebellar artery.
• Gellé syndrome: Affects the CN VII, VIII, and corticospinal tract. It results in ipsilateral facial palsy, ipsilateral hearing loss, and contralateral hemiparesis.
• Grenet syndrome: Affects CN V lemniscus, CN VII fibers, and spinothalamic tract. It results in altered sensation in the ipsilateral face, contralateral upper, and contralateral lower limbs. It can arise due to neoplasm. 
• Inferior medial pontine syndrome (Foville syndrome): Also known as the lower dorsal pontine syndrome, affects the corticospinal tract, medial lemniscus, middle cerebellar peduncle, and the nucleus of CN VI and VII. It results in contralateral hemiparesis, contralateral loss of proprioception & vibration, ipsilateral ataxia, ipsilateral facial palsy, lateral gaze paralysis, and diplopia. The blood supply affected is from branches of the basilar artery.
• Lateral pontine syndrome (Marie-Foix syndrome): Affects the nuclei of CN VII, & VIII, corticospinal tract, spinothalamic tract, and cerebellar tracts. It results in contralateral hemiparesis, contralateral loss of proprioception & vibration, ipsilateral limb ataxia, ipsilateral facial palsy, lateral hearing loss, vertigo, and nystagmus. The blood supply affected is the perforating branches of the basilar artery and the anterior inferior cerebellar artery.
• Locked-in syndrome: Affects upper ventral pons, including corticospinal tract, corticobulbar tract, and CN VI nuclei. It results in quadriplegia, bilateral facial palsy, and horizontal eye palsy. The patient can move the eyes vertically, blink, and has intact consciousness. The blood supply affected is the middle and proximal segments of the basilar artery.
• Raymond syndrome: Affects the CN VI fibers, corticospinal tract, and corticofacial fibers. It results in an ipsilateral lateral gaze palsy, contralateral hemiparesis, and facial palsy. The blood supply involved is from the branches of the basilar artery.
• Upper dorsal pontine syndrome (Raymond-Cestan): Affects the longitudinal medial fasciculus, medial lemniscus, spinothalamic tract, CN V fibers and nuclei, and superior and middle cerebellar peduncle. It results in ipsilateral ataxia, coarse intension tremors, sensory loss in the face, weakness of mastication, and contralateral loss of all sensory modalities. The blood supply involved is from the circumferential branches of the basilar artery.
• Ventral pontine syndrome (Millard-Gubler): Affects the CN VI & VII and corticospinal tract. It results in ipsilateral lateral rectus palsy, diplopia, ipsilateral facial palsy, and contralateral hemiparesis of the upper and lower limbs. The blood supply involved derives from the branches of the basilar artery.[28][29][31][33][34][35][36][37][38]

Medulla oblongata

• Avellis syndrome: Affects the pyramidal tract and nucleus ambiguus. It results in ipsilateral palatopharyngeal palsy, contralateral hemiparesis, and contralateral hemi-sensory impairment. The blood supply affected is the vertebral arteries. 
• Babinski-Nageotte syndrome: Also known as the Wallenberg with hemiparesis, affects the spinal fiber and nucleus of CN V, nucleus ambiguus, lateral spinothalamic tract, sympathetic fibers, afferent spinocerebellar tracts, and corticospinal tract. It results in ipsilateral facial loss of pain & temperature, ipsilateral palsy of the soft palate, larynx &  pharynx, ipsilateral Horner syndrome, ipsilateral cerebellar hemi-ataxia, contralateral hemiparesis, and contralateral loss of body pain and temperature. The blood supply involved is from the intracranial portion of the vertebral artery and branches from the posterior inferior cerebellar artery.
• Cestan-Chenais syndrome: It affects the spinal fiber and nucleus of CN V, nucleus ambiguus, lateral spinothalamic tract, sympathetic fibers, and corticospinal tract. It results in ipsilateral facial loss of pain and temperature, ipsilateral palsy of the soft palate, larynx & pharynx, ipsilateral Horner's syndrome, contralateral hemiparesis, contralateral loss of body pain & temperature, and contralateral tactile hypesthesia. The blood supply affected is the intracranial portion of the vertebral artery and branches from the posterior inferior cerebellar artery.
• Hemimedullary syndrome (Reinhold syndrome): Affects the nucleus & fiber of CN V, CN XII nucleus ambiguus, lateral spinothalamic tract, sympathetic fibers, afferent spinocerebellar tracts, corticospinal tract, and medial lemniscus. It results in ipsilateral Horner's syndrome, ipsilateral facial loss of pain & temperature, ipsilateral palsy of soft palate, larynx & pharynx, ipsilateral tongue weakness, ipsilateral cerebellar hemi-ataxia, contralateral hemiparesis, and contralateral face sparing hemihypesthesia. The blood supply involved is from the ipsilateral vertebral artery, the posterior inferior cerebellar artery, and branches from the anterior spinal artery. 
• Jackson syndrome: Affects CN XII and pyramidal tract. It results in ipsilateral palsy of the tongue and contralateral hemiparesis. The blood supply involved is from the branches of the anterior spinal artery.
• Lateral medullary syndrome (Wallenberg syndrome): Affects the spinal nucleus & fiber of CN V, nucleus ambiguus, lateral spinothalamic tract, sympathetic fibers, inferior cerebellar peduncle, and vestibular nuclei. It results in ipsilateral Horner's syndrome, ipsilateral facial loss of pain & temperature, ipsilateral palsy of soft palate, larynx & pharynx, ipsilateral cerebellar hemi-ataxia, contralateral loss of body pain & temperature, nystagmus, dysarthria, dysphagia, and hyperacusis. The blood supply affected is the vertebral artery and branches from the posterior inferior cerebellar artery.
• Medial medullary syndrome (Dejerine syndrome): Affects the fibers of CN XII, corticospinal tract, and medial lemniscus spinal. Results in ipsilateral tongue weakness, ipsilateral loss of proprioception & vibration, contralateral hemiparesis, and contralateral face-sparing hemihypesthesia. The blood supply affected is the branches from the vertebral artery and the anterior spinal artery.
• Schmidt syndrome: Affects the fibers and nuclei of CN IX, X, XI, and pyramidal system. It results in ipsilateral palsy of the vocal cords, soft palate, trapezius, & sternocleidomastoid muscle, and contralateral spastic hemiparesis. The blood supply involved involves branches from the vertebral artery, the posterior inferior cerebellar artery the anterior spinal artery.
• Spiller syndrome: Affects the fibers and nucleus of CN XII, corticospinal tract, and medial lemniscus spinal along with medial hemi-medulla. Results in ipsilateral tongue weakness, ipsilateral loss of proprioception & vibration, contralateral hemiparesis, and contralateral face-sparing hemihypesthesia. The blood supply involved is from the branches of the vertebral artery and the anterior spinal artery.
• Tapia syndrome: Affects the nucleus ambiguus, CN XII, and pyramidal tract. It results in ipsilateral palsy of the trapezius, sternocleidomastoid muscle, & half of the tongue, dysphagia, dysphonia, and contralateral spasmodic hemiparesis. The blood supply involved is from the branches of the vertebral artery, the posterior inferior cerebellar artery the anterior spinal artery.
• Vernet syndrome: Affects the CN IX, X, and XI. It occurs due to compression in the jugular foramen.[28][29][39][40][41][42][43]

Brainstem stroke subgroups differ significantly only in the incidence of hemiparesis (74% in pontine but 30% with medullary or cerebellar strokes) and ataxia (97% and 95% of cerebellar and medullary but 74% in pontine) strokes.[14] Convulsive-like movements have been observed in pontine strokes due to ischemia of the corticospinal tracts.[44] Restless leg syndrome (RLS) has been observed in anteromedial pontine infarction.[45]

Radiological imaging:

CT scanning is the method of preference for radio imaging owing to its general availability. CT findings also closely correlate with prognosis in PBSH.[46] Computed tomography (CT) may paradoxically appear normal in the early course of the stroke. The ‘hyperdense BA’ sign may be observed. CT shows a non-enhancing high attenuated lesion. 1/2ABC is the most frequent method to calculate the volume of ICH. 2/3SH was more accurate than 1/2ABC, S is the area of the largest axial hemorrhagic slice and H represents the height of the hematoma.[46] CT angiography (CTA) helps to locate the level of occlusion as well as delineate the size of the infarct. The ‘spot sign’ is not significantly related to hematoma expansion.[47] CT perfusion (CTP) delineates the ‘core’ and ‘penumbra’ zones.[3]

MRI helps to accurately depict the location and extension of the stroke.[3] Diffusion-weighted (DW) MR sequence is the recommended modality to visualize the irreversibly infarcted regions and also has rapid acquisition. MR perfusion images are paramount in evaluating the penumbra zone.[3] Hemosiderin deposition on T2-weighted (T2W) and gradient-echo MR images alongside characteristic ‘popcorn’’ appearance are radiological hallmarks for cavernomas.[3]

Anatomical classification of PBSH:

Chung and Park classified pontine hemorrhage into:

• Dorsal –involving unilateral or bilateral tegmentum
• A ventral group involving the ventral basis pontis, and
• Massive-involving both the basis pontis and tegmentum with extension into the midbrain.[3]

Kase and Caplan classified pontine hemorrhages into:

• Large paramedian
• Unilateral basal or basotegmental, and
• Lateral tegmental.[3]

TOAST classification system for the etiology of the stroke:

• Large arterial atherothrombosis->50% narrowing in CTA/MRA
• Cardioembolic-AF in ECG, paroxysmal AF in Holter monitoring, akinetic segments or thrombus in TTE/TEE, history of rheumatic valve disease or prosthetic valves, monitoring, myocardial infarction (MI) within a month, or the presence of patent foramen ovale seen in TEE or Bubble test
• Small vessel disease- of <2 cm presenting as pure motor, pure sensory, ataxic, and dysarthria with clumsy hand patterns
• Rare causes-vasculitis, dissection, para-neoplastic syndrome
• Rest is classified as a stroke of unknown cause.[3]

Original and modified intracerebral hemorrhage (ICH) scores may not apply well to primary pontine hemorrhage (PPH). Only 10% of PBSH was included in the ICH score.[47] The PPH score also lacks external validation and failure to take into consideration early do not resuscitate orders (DNRs) was the major flaw of the same.[47]

Treatment / Management

After the patient's airway, breathing and circulation have been stabilized, a timeframe of the patient's symptoms is obtained. Vitals and fluid status must be stabilized. Hypo or hyperglycemia must be corrected. Fever, if present, should be managed accordingly. Blood pressure must not be aggressively controlled to allow permissive hypertension only in the case of ischemic injury. Patients with last known normal within 4.5 hours can be considered as candidates for thrombolysis, whereas a 24-hour last known normal can be a candidate for mechanical thrombectomy. If it is a case presenting earlier than 4.5 hours of onset, thrombolysis with intravenous recombinant tissue plasminogen activator (tPA) significantly improves the clinical outcome.[48]

Inclusion criteria for tPA:

• Clinical diagnosis of ischemic stroke
• <4.5 hours of the onset of symptoms
• Age >18 and <80 years
• Symptoms of stroke presenting for more than 30 minutes.[48][49]

Excision criteria for tPA:

• Unknown timeline of onset of patient symptoms
• Intracranial hemorrhage or any active bleeding
• Persistently elevated blood pressure ≥ 185 mmHg systolic and ≥ 110 mmHg diastolic
• Low platelets <100,000/mm3, altered INR >1.7, PT >15 sec or aPTT >40sec
• Current use of anti-coagulant
• Severe hypoglycemia <50mg/dL
• History of previous intracranial hemorrhage
• History of gastrointestinal bleeding in the past 21 days
• History of intracranial or intraspinal surgery in the past 90 days
• History of intra-axial intracranial neoplasm or gastrointestinal malignancy.[49][50]

Intravenous alteplase (recombinant tissue plasminogen activator) should be given at the dose of 0.9 mg/kg (maximum dose of 90 mg/kg) with 10% as the loading dose in the first minute. The patient must be under continuous observation. Anti-platelet therapy must be withheld for at least 24 hours post-thrombolysis and restarted after a head CT scan without evidence of bleeding. The time window for thrombolytic therapy in brainstem ischemic strokes has not been well defined.[51]

Mechanical endovascular thrombectomy in patients with large anterior circulation occlusion is well documented; however, most strokes affecting the brainstem arise from posterior circulation perforating branches. For those cases where the occlusion is at the main vertebral or basilar artery, endovascular thrombectomy is recommended for successful revascularization and favorable outcome.[51][52][53][54][55][56][57][58] Other studies have shown no evidence of a difference in favorable outcomes between endovascular therapy when compared to standard medical therapy alone.[59][60]

Antiplatelet therapy: The usage of acetylsalicylic acid as monotherapy or dual therapy along with clopidogrel within 24 – 48 hours after the onset of symptoms significantly improved patient outcomes.[47]

The surgical treatment of PBSH is controversial. Brainstem hemorrhage has been excluded from previous intracerebral hemorrhage (ICH) trials such as the Surgical trial in lobar intracerebral hemorrhage (STICH) and Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE).[47] The management of PBSH primarily involves conservative treatment and surgery is generally not recommended.[46]

Conservative treatment of PBSH is generally recommended for:

• Smaller hematoma ->5 ml and <10 ml
• GCS score ->6 and <8
• Age <65 years
• A unilateral tegmental variant, and
• No extra-pontine extension.[47]

Surgery not advocated for patients with:

• Hematoma less than 3 mL and more than 15 ml
• No evidence of ventricular dilatation and altered level of consciousness
• Severe irreversible brain damage, and
• Extreme hemodynamic instability.[47]

Surgical options for PBSH include:

• Craniotomy and microsurgical evacuation
• Stereotactic hematoma puncture and drainage
• Endoscopic hematoma removal such as Endoscopic endonasal transclival approach (EETA), and
• External ventricular drainage.[46][47]

Takahama et al. performed stereotactic puncture and drainage in 1989. There is a comparatively decreased mortality rate in the aspiration group compared to the microscopic surgery group (24.4% versus 31.6%). The ‘precision’ is the key and can be assisted with the application of newer armamentariums such as Stereotaxy, 3D printing, Robotics, and virtual and augmented reality are new armamentariums.[47] Intraoperative neurophysiological monitoring is another helpful adjunct.[47]Hematoma aspiration is justifiable in older fragile patients.[47] Minimally invasive microsurgery is a very rapid, effective, and safe modality with hematoma volume <10 ml.[47]

In 1998, Hong et al. first performed craniotomy for evacuation of BSH (1998). The advantages of microscopic craniotomy include:

• Maximum hematoma clearance under direct vision
• Better hemostasis, and
• Concurrent removal of the ventricular bleed to avoid secondary hydrocephalus can be undertaken.[47] 

The surgical group has a two-fold lower risk of mortality and a higher odds of recovery. However, there is a two-fold risk of being in a vegetative state or harbingering moderate to severe disabilities.[47] Early microsurgical clearance reduces mortality and improves prognosis.[47] This however requires high surgical skills and precise anatomical knowledge pertaining to safe entry zones within the brainstem.[61][62]Animal studies have shown brain edema and arterial necrosis occurring mostly after  6 hours of PBSH. Therefore, in theory, surgery within a 6-hour window appears to be the most logistic approach.[47]

Takimoto et al. first performed Neuroendoscopy in 2003. This is ideally suited for ventral hematomas. This approach utilized natural surgical corridors with the advantage of minimal brain retraction and direct visualization of the lesion. A longer learning curve is the main limitation of this modality.[47]

Chinese clinical nerve repair guidelines for surgical intervention for PBH include:

• 6-24 hours of ictus
• Hematoma volume- more than 5 mL or
• Hematoma diameter- more than 2 cm.[47]

Chinese surgeons are however compelled to operate even on moribund patients owing to the sociological issue of ‘filial piety’.[47] Most of the included studies are however of low-moderate quality with minimal follow-up strategies. Moreover, almost 7% of these patients lacked integration of angiographic studies despite being normotensive.[47] None of the studies incorporated any anatomical classification system as well.[47] 

Intraventricular hemorrhage (IVH) occurs in almost 40% of PBSH patients so EVD can effectively prevent the hazards of acute hydrocephalus.[47] CLEAR III trial has however shown no significant advantage of ventricular irrigation with alteplase in IVH.[47]

Class 1 evidence for nursing care and management includes:

• Should be highly trained in stroke care.
• Need for frequent thorough neurological assessments.
• The patient’s head should be in neutral alignment with the body.
• Only non-dextrose and normotonic intravenous fluids (normal saline) should be given.
• Intravenous rtPA should be administered without delay to all eligible candidates.
• Avoid temperatures >99.6°F, serum glucose concentration >140 mg/dL, infections, seizures, and constipation.
• Frequent hemodynamic and hydration assessment.
• Measures aimed to prevent aspiration pneumonia, falls, pressure sores, and DVT need to be emphasized.
• Nurses should be familiar with bedside swallow assessment and a swallow screening ideally needs to be performed by the speech-language pathologist.[63]

Discharge disposition should encompass:

• Use of statins
• Dysphagia screening
• Stroke education
• Smoking cessation advice and counseling
• Assessment for rehabilitation.[63]

Management of risk factors like hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, thyroid abnormalities, sleep apnea, malignancies, and hypercoagulable states should be treated accordingly.  Dietary and lifestyle modification must be explained and discussed. Supplementation with vitamin B12 and vitamin D3 should also be considered. Physiotherapy and rehabilitative strategies must start at the earliest and must be aggressively pursued as the brain losses its plasticity within 90 days.

The vascular causes for the brainstem hemorrhages such as cavernomas also need to be properly addressed.[10] Nanoparticle and stem cell combined therapy are recent advances in the management of brainstem strokes.[64][65]

Differential Diagnosis

1. Neoplastic and metastatic lesions
2. Central pontine myelinolysis
3. Acute disseminated encephalomyelitis
4. Multiple sclerosis
5. Diffuse axonal injury (DAI)
6. Stroke mimics:

• Transient ischemic attack (TIA)

• Subarachnoid hemorrhage (SAH)

• Seizures

• Basilar migraine

• Basilar meningitis

• Hypoglycemia

• Electrolyte imbalance

• Conversion disorder.[47]

Pertinent Studies and Ongoing Trials

The ongoing 'Safety and Efficacy of Surgical Treatment in Severe Primary Pontine Hemorrhage Evacuation' (STIPE) trial should provide newer insights into the role of surgical treatment of PBSH.[46] The inclusion criteria of the trial include:

• GCS <8
• Hematoma volume ≥5 ml
• New PPH score of 2-4 points.[46]

Prognosis

Stroke is the primary cause of disability and a leading cause of mortality worldwide. Stroke has a burden of 122 million disease-adjusted life years, with gradually increasing incidences.[11] Early diagnosis and management have a lower chance of permanent morbidity. The risk of stroke recurrence is 10 to 15%; hence regular follow-up is advised. Early initiation of rehabilitative care is also recommended. Patients with significant neurological deficits have a worse prognosis. The final prognosis depends on various factors including, age, the severity of the stroke, etiology of the stroke, location, structures involved, associated risk factors, co-morbidities, and management.

Variables prognosticating poor outcomes in brainstem strokes include:

• Old age
• Tachycardia (>110 beats/min)
• Systolic blood pressure <100 mmHg
• Absence of a pupillary light reflex
• Pupillary abnormalities
• Low Glasgow coma scale
• Large hematoma volume
• Central hyperthermia
• A need for mechanical ventilation
• History of diabetes mellitus
• Elevated platelet-to-lymphocyte ratio, and
• An Elevated Neutrophil-to-lymphocyte ratio.[46]

Conventional treatment of symptomatic basilar artery occlusion has poor results in almost 80% of cohorts.[66] Death and dependency were observed in almost 95%. Both vertebral artery occlusion (mostly due to atherosclerosis) and basilar artery occlusion (mostly due to cardio-embolic) have poor outcomes.[67] Time to therapy is better in the intravenous thrombolysis (IVT) group.[67] IVT is safer in posterior circulation ischemic strokes (PCIS) than in anterior circulation ischemic strokes (ACIS).[68] This can be considered even in borderline cases even after 4.5 hours of ictus. Time to IVT in PCIS seems to be a less crucial factor than in ACIS.[68] Reportedly 38–49% have a favorable outcome after IVT. [68] The mortality rate following IVT is not significant between PCIS and ACIS.[68] Moreover, there are no significant differences while comparing time to treatment, mortality, and favorable outcomes between intra-arterial thrombolysis (IAT) and endovascular thrombectomy (EVT), probably owing to collateral flow from posterior communicating arteries towards the posterior circulation.[67]

Recanalization confers a two-fold decrement in mortality and a 1.5-fold decrease in the futile outcome rates.[67] Better recanalization and improved clinical outcomes in acute basilar occlusion are observed with endovascular thrombectomy compared to thrombolytic therapy (no difference in stent-retrievers and thrombo-aspiration approaches).[67] Significant improvement in the functional outcome and functional independence following thrombectomy, when compared to the best medical therapy alone, was observed. The mortality rate was significantly lower in the intervention group (RR 0.76).[69]

A comparative study between different management modalities revealed the following outcomes:

• Mortality-34.5%, 9.9%, and 28.9% in the mechanical thrombectomy (MT), percutaneous transluminal angioplasty and stenting (PTAS), and MT+PTAS
• Arterial dissection-3.6% in the MT, 3.1% in the PTAS, and 16.7% in the MT+PTAS  
• Distal embolization-3.4%, 5.8%, and 9.5% in the MT, PTAS, and MT+PTAS
• Favorable outcomes-42.8% of the MT+PTAS group, 64.7% of the PTAS, and 39.2% of the MT
• Intracranial hemorrhage-5.2%, 4.5%, and 15.3% in the MT, PTAS, MT + PTAS, and
• Successful recanalization-85.3% in the MT, 99.4% in the PTAS, and 92.7% in the MT+PTAS.

PTAS was therefore the most effective intervention for vertebrobasilar artery occlusion (VBAO) and was also associated with a lower rate of mortality compared to mechanical thrombectomy alone.[70]

Almost 30% of these cohorts still possess some disabilities even at 1-year post-stroke. Multiple infarctions and omissions in the use of statins have been associated with poor outcomes at 1 year.[71]

A worse prognosis is observed among patients with primary brainstem hemorrhage (PBSH) having dysarthria, pupillary abnormalities, lower cranial nerve involvement, and diminished consciousness on admission.[11]The prognosis for brainstem hemorrhage is worse than ischemic stroke. Primary brainstem hemorrhage (PBSH) is the most fatal form of ICH.[46]The mortality rate can be as high as 30%-88%.[72] In a study comprising 1437 pontine hemorrhages, the overall mortality observed was 48.1%.[73] Massive subtype with ventral or paramedian locations of involvement has a poor prognosis (survival rate of only 7.1%). The unilateral tegmental subtype has comparatively more favorable outcomes with basotegmental variants showing intermediate prognosis (94.1% versus 18.2%).[46][47][72] The bilateral, ventral, and massive hematomas encompass the worst prognosis.[47]The medulla oblongata is the most serious subtype type harbingering the risk of rapid death following the ataxic pattern of respiration.[46][47] Predominant and consistent variables prognosticating outcomes include the presenting GCS, location, and volume of the hematoma.[1][74]Low Glasgow Coma Scale at presentation, hematoma (more than 4 ml and 2cm diameter), ventral subtype, and need for mechanical ventilation indicate the poor outcome.[1][46][75] A scoring system by Huang et al. incorporating hematoma volume and GCS is the best and the largest population-based and best evidence score in predicting mortality.[47] Almost 90% of patients eventually develop hydrocephalus causing 100% mortality in the CM group. Early intervention for the same markedly improves the clinical outcome.[72] Age and intraventricular extension, though important predictive variables are not independent determinants of early death in PBSH.[46][73] The Surgical evacuation (SE) group has a mortality of 27.6% compared to 60.6% in the conservative management (CM) group.[72] Early tracheostomy (≤ 7 days after admission) has a favorable 30-day functional outcome.[46] Quantitative electroencephalography (EEG) and neuro-physiological monitoring like brainstem auditory evoked potential (BAEPs), somatosensory evoked potentials (SEPs), and motor evoked potentials (MEPs) are reliable predictors for recovery and mortality in PBSH patients.[47]

Complications

• Neurological deficits-presenting characteristically as 'crossed signs' as in various brainstem stroke syndromes
• Dysautonomia- due to involvement of the sympathetic tract
• Altered level of awareness and coma- due to involvement of the Reticular activating system (RAS) as in the ‘locked-in’ syndrome and the ‘top-of-the-basilar’ syndrome
• Dysregulation of the respiratory control mechanism- due to the involvement of the dorsal and ventral respiratory group of neurons (DRG, VRG), pneumotaxic and apnuestic respiratory centers and can present as Central hypoventilation syndrome or Ondine’s curse syndrome.
• Dysregulation of the blood pressure control mechanism- due to the involvement of the Nucleus of tractus solitarius and neurons in the ventrolateral medulla
• Acute hydrocephalus
• Dysphagia
• Dysarthria
• Ataxia
• Central pain syndrome- in 25% of cases of Wallenberg’s syndrome
• Restless leg syndrome
• Post-stroke fatigue
• Depression
• Pulmonary aspiration-Patients with medullary and cerebellar strokes have a high risk of severe aspiration. 
• Deep vein thrombosis and pulmonary embolism
• Bed sores
• Contractures
• Sepsis, and
• Mortality.[14][26][76][77]

Postoperative and Rehabilitation Care

In a cohort study pertaining to a rehabilitation unit, ataxia (68%), hemiplegia (70%), and dysphagia (40%) were the most common neurological deficits. However, significant functional gains in all these domains were observed. Aspiration pneumonia and urinary tract infection was observed in 15% and 25% of patients respectively. 96% were ultimately discharged home.[78]

Functional recovery and long-term survival with brainstem stroke have been better than that observed in hemispheric stroke.[79] 35% of brainstem infarction survivors returned to living independently within the first year post-stroke (compared to only 22% with hemispheric stroke survivors).[79]

Dysphagia

• Seen in 47%.
• Best evaluated by videofluoroscopic modified barium-swallowing (VMBS).
• Proper swallowing instructions need to be done.
• Initially managed by nasogastric (NG) tube feeding.
• Gastrostomy and jejunostomy feeding tubes are required in 20%.
• ‘Oral and pharyngeal postures’ and biofeedback techniques are essential.
• Integration of speech-language pathologists is recommended.
• The long-term result is favorable.

Ataxia

• Seen in 86%.
• Gait initiation and patterning are governed by the pons and medulla
• Gait training is promoted through the ‘use it to improve it ’ technique.
• Can be managed by postural training as well as motor learning, control, and strengthening exercises.
• Bobath treatment approach is also effective.

Dysarthria

• Seen in 49% to 89%.
• Regaining tone and strength of facial and buccal muscles.
• Reducing the rate of speech, pausing, deep breathing and over-articulating can also help.
• Palatal lift and palatal augmentation have been effective.

Paresis

• Observed in 94%.
• Can be managed by task-related motor training and restorative approaches.

Diplopia

• Seen in 38%.
• Use of diachronic mirrors or integration of fogging, occlusion, and suppression techniques are applied.
• Surgical procedures only if rehabilitation has failed, usually 6 months post-stroke.[79]

Deterrence and Patient Education

ACT FAST is an acronym suggested by the American Stroke Association to recognize the early symptoms of a stroke. It has the following components:

• F-Face drooping
• A-Arm Weakness
• S-Speech, and
• T-Time to call 9-1-1.

Along with the above symptoms, if the patient experiences any of the following, emergency medical services must be activated

• Sudden confusion
• Sudden trouble seeing
• Sudden numbness
• Sudden trouble walking, and
• Sudden severe headache.

Control of risk factors can significantly reduce future strokes:

• Smoking cessation
• Alcohol use
• Drug addiction and abuse
• Hypertension and diabetes control
• Obesity and a sedentary lifestyle
• Sleep apnea.[80]

Pearls and Other Issues

Here are some important considerations:

• Early identification of stroke and its management: 'Time is brain'.
• Avoiding pitfalls of stroke-like syndrome/'stroke mimics': Migraine headache, seizure disorder, transient ischemic attack, and vertigo.
• Permissive hypertension to improve perfusion in ischemic stroke.
• Patient education with the 'FAST' acronym.

Enhancing Healthcare Team Outcomes

The diagnosis and management of brainstem stroke bring a considerable burden to the healthcare system, the patient, the family members, and society at large. The slow increase in global burden of stroke has been steadily increasing.

The enhancement must start with proper patient education about the risk factors and how they can be modified. A simple community educational approach about smoking cessation, a healthy diet, an active lifestyle, regular health screening for diabetes mellitus and hypertension, drug addiction cessation, and rehabilitation can be undertaken. A decentralized model where a community-level assessment of primary and secondary prevention of non-communicable disease can result in a reduction in the incidence of stroke.

Acute management of stroke in a peripheral setting must be managed with skilled individuals; however, a complete and robust interdisciplinary team of neurologists, physicians, psychiatrists, nurses, physiotherapists, and other paramedical staff is necessary for the best patient outcome. A trained first responder who can immediately stabilize the patient and prevent deterioration is critical. Usage of the National Institutes of Health Stroke Scale or the Modified Rankin Scale or other standardized models and scales help clinicians with their decision.[81]

Constant root-cause analysis, frequent updates to local hospital protocol, and continued medical education should be implemented. The usage of telemedicine, teleradiology, and a rapid communication system can allow various interprofessional to deploy rapidly and prevent long-term complications. Examination of the patient must be done as a team, where each member can be delegated certain aspects of evaluation and management. A multi-disciplinary approach has been shown to prevent at least 80% of subsequent strokes.[80] [Level I, II]

Post-stroke rehabilitation care must include inputs from clinicians, nurses, and pharmacists, to obtain the best outcome for the patient. A healthy support system of dieticians and therapists, along with adequate domiciliary support, must be provided.

Proper coordination and communication among the Occupational therapist (OT), attending nurses, and the clinician are pivotal. OT helps to address limitations in activities of daily living (ADLs) by appropriately addressing pertinent impairments.