Keywords

1 Introduction

Brain metastases can result in a large variety of focal and nonfocal neurological symptoms. The clinical presentation of brain metastases is affected by the location, size and growth rate of the tumour. Any new neurological symptom or change in behaviour or cognition in a patient with cancer warrants further investigations for brain metastases. Focal neurological symptoms, like hemiparesis and dysphasia, can be caused by a direct effect of the brain metastasis or the surrounding oedema on the brain tissue or other neural structures. Most of these neurological symptoms occur within days to weeks, although an intratumoural haemorrhage can result in an acute onset of symptoms. Epileptic seizures occur in 10–20% of patients with brain metastases.

Nonfocal symptoms, like headache, nausea and disturbance of consciousness, can arise from increased intracranial pressure. When the tumour obstructs the flow of the cerebrospinal fluid (CSF), a hydrocephalus can develop, resulting in headache, nausea, sleepiness and an unsteady gate. The mass effect of brain metastases can lead to cerebral herniation. This may result in reduced consciousness and ultimately to death due to brainstem compression, unless high doses of Dexamethasone for surrounding oedema are given.

2 Focal Neurological Deficits

The presentation of patients with brain metastases varies widely, and symptoms can be either focal or nonfocal. There is a large variety in symptoms based on the location of the brain metastases. Most patients present with neurological symptoms with a subacute onset within days to weeks due to an increasing mass effect of the tumour on the brain and the surrounding oedema. An intratumoural haemorrhage can result in a sudden onset of headache, nausea, focal neurological symptoms and sometimes decreased consciousness. Melanoma, choriocarcinoma, thyroid and renal carcinoma brain metastases have a relatively high bleeding risk [1]. Furthermore, patients with brain metastases have a slightly increased risk of stroke due to vascular compromise by the tumour, venous sinus thrombosis and the hypercoagulable state of patients with a metastatic tumour.

Supratentorial brain metastases can result in motor, sensory, language or visual impairments depending on the size and location of the tumour. Hemiparesis results from a tumour in the motor cortex, internal capsule, corona radiata or brainstem. Tumours in the sensory cortex and thalamus usually give rise to sensory disturbances. Tumours in the dominant frontal and temporal lobe can cause aphasia. Compression of the midbrain by a metastasis can result in the Parinaud syndrome with an impaired upward gaze, light-near dissociation, convergence nystagmus and eyelid retraction. Common focal and nonfocal presenting neurological symptoms are shown in Table 8.1 [2]. Unfortunately, neither absence of focal symptoms nor a normal neurological examination does rule out brain metastases.

Table 8.1 Presenting clinical features in 1013 patients with brain metastases
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3 Nonfocal Symptoms

3.1 Symptoms of Increased Intracranial Pressure

Brain metastases can give rise to an increased intracranial pressure in various ways. Often mass effect on the brain is caused by the tumour itself and its surrounding vasogenic oedema. In addition, obstruction of the CSF flow, for example, due to mass effect of the brain metastasis on the third or fourth ventricle, can lead to hydrocephalus. Brain metastases can cause cerebral herniation, which is the shift of cerebral tissue from its normal location into an adjacent intracranial space as a result of mass effect. This displacement may result in reduced consciousness by direct or indirect pressure of the brainstem.

Patients with an increased intracranial pressure usually have symptoms of headache, vomiting, decreased vision due to papillary oedema and sometimes reduced consciousness due to compression on the brainstem or both hemispheres. When the intracranial pressure is very high, patients can experience ‘plateau waves’, a sudden rise in intracranial pressure that leads to headache or an altered consciousness for 5–20 min.

3.1.1 Headaches

Headaches in patients with systemic cancer can be caused by the antitumour treatment (e.g. hormone therapy), psychological factors, a pre-existing headache syndrome (tension type headache or migraine) or can be due to cerebral or leptomeningeal metastases. Approximately 30% of patients with cerebral metastases present with headache. Tumours located in the posterior fossa and in the midline are more often associated with headache, probably partly due to the disturbance of the CSF flow. Other factors that are associated with tumour-related headache are the size of the tumour and the extent of cerebral oedema [1].

Classically, headaches associated with brain metastases are described as occurring at night or early in the morning, and pain tends to increase after Valsalva manoeuvres, such as sneezing or coughing. Headache can be positional with an increase in headache while bending over or standing up. Unfortunately, the majority of patients with brain metastases does not present with these classical headache symptoms, and often it is not possible to differentiate between tension-type headache, migraine or brain metastases based on the clinical characteristics of the headache in patients with systemic cancer.

In patients with brain metastases, headaches are often accompanied by other symptoms, in particular nausea and vomiting. In a prospective study of 68 patients with systemic cancer without known brain metastases, evaluation for headache showed brain metastases in 32% of patients. Headache duration <10 weeks, emesis and pain not compatible with the tension-type all significantly predicted the presence of brain metastases [3]. In a more recent prospective study, 54 patients with systemic cancer with new headache or a change in pattern of an existing headache were evaluated; 54% were found to have brain metastases. Clinical predictors of brain metastases were emesis, gait instability and extensor plantar response at neurological examination [4].

3.1.2 Vomiting

Vomiting is most frequent in tumours of the posterior fossa, especially when there is extension in or compression of the fourth ventricle. Some patients may experience unexpected vomiting without preceding nausea, ‘projectile vomiting’. In case of increased intracranial pressure due to brain metastases, vomiting often occurs in the morning.

3.1.3 Visual Symptoms

Patient can present with different visual symptoms due to the increased intracranial pressure. Papillary oedema can lead to complaints of reduced vision in one or both eyes. In case of high intracranial pressure from brain metastases, diplopia can result from compression on the third, fourth or sixth cranial nerve. Due to its length, the sixth cranial nerve is most often affected.

3.1.4 Reduced Consciousness

Reduced consciousness in brain tumour patients is mostly caused by obstructive hydrocephalus and cerebral herniation.

An obstructive or noncommunicating hydrocephalus in patients with brain metastases is caused by obstruction of the CSF flow in the ventricles from the mass effect of the tumour and surrounding oedema. Common places for obstruction of CSF flow in patients with brain metastases are obstruction of the fourth ventricle from mass effect in the posterior fossa and obstruction of the Sylvian aqueduct from supratentorial mass effect. The presentation of patients will depend on the speed of onset of the obstruction of the CSF. In an acute obstruction resulting from an intratumoural haemorrhage or rapidly growing metastasis, patients may present with subacute headache, nausea, blurred vision from papillary oedema and reduced consciousness. In a gradually progressive hydrocephalus, symptoms may be mild, including mild cognitive complaints and ataxia, while imaging shows a clear dilatation of the ventricles.

A communicating hydrocephalus is caused by obstruction of CSF flow through the subarachnoid spaces or impaired absorption at the arachnoid granules. In patients with brain metastases, a communicating hydrocephalus is mainly seen in patients with altered CSF composition by malignant cells or/and high protein content. This is mostly caused by concomitant leptomeningeal metastases or an intraventricular haemorrhage from brain metastases adjoining the ependyma. Figure 8.1 shows examples of (non) communicating hydrocephalus in patients with metastases of the central nervous system.

Fig. 8.1
figure 1

Examples of (non)communicating hydrocephalus in patients with central nervous system metastases: noncommunicating hydrocephalus due to compression of the fourth ventricle caused by cerebellar metastases (a), noncommunicating hydrocephalus due to compression of the fourth ventricle caused by a brain metastasis in the mesencephalon (b) and communicating hydrocephalus in patient with both brain metastases (not shown on MRI) and cytology proven leptomeningeal metastases (c)

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Cerebral herniation is the shift or herniation of brain tissue from one dural compartment in an adjacent compartment due to an increased pressure from a space-occupying mass (Fig. 8.2). Four well-known forms of herniation are subfalcine, transtentorial, central and tonsillar herniation. In subfalcine herniation, the cingulate gyrus is pushed under the falx. This is a common form of herniation that usually does not directly give rise to neurological symptoms. Seldom a frontal lobe infarction is seen due to the occlusion of the anterior cerebral artery that runs in close proximity to the falx. Transtentorial, or uncal herniation, leads to the displacement of the uncus, the mesial temporal lobe, over the tentorial edge. Patients with transtentorial herniation may present with a fixed and dilated ipsilateral pupil due to ipsilateral oculomotor nerve compression. Herniation of the uncus into the posterior fossa and the midbrain can result in impaired consciousness and contralateral hemiparesis by compression on the corticospinal tract. Compression on the posterior cerebral artery from transtentorial herniation can cause a cerebral infarction in the occipital lobe. In central transtentorial herniation, the entire midbrain is herniated downwards due to generalized cerebral mass effect. Cerebellar-foramen magnum herniation, or tonsillar herniation, is the downwards displacement of the cerebellar hemispheres through the foramen magnum leading to compression on the caudal medulla. Clinical manifestations can be episodic tonic extension and arching of the neck, respiratory disturbances, cardiac irregularity and impaired consciousness and ultimately death.

Fig. 8.2
figure 2

Different forms of herniation caused by a brain tumour and surrounding oedema: subfalcine herniation of the cingulate gyrus under the falx (a), central herniation (tumour not visible on MRI shown, only cerebral oedema) (b), transtentorial herniation of the uncus of the temporal lobe over the tentorial edge, central herniation (tumour not visible on MRI shown, only cerebral oedema (c) and tonsillar herniation of cerebellar hemispheres through the foramen magnum (d)

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3.2 Cognitive Symptoms

Cognitive symptoms and mental status change are common presenting symptoms in patients with brain metastases and are mainly depending on the location and size of the brain metastases [5]. The volume of brain metastases is stronger correlated with cognitive dysfunction than the number of brain metastases [6].

Cognitive dysfunction, including memory problems and mood or personality changes, is found in 65–90% of patients with brain metastases [7,8,9]. Most often multiple cognitive domains are affected, particularly in larger tumours affecting multiple brain regions.

Cognitive symptoms in patients with brain metastases are generally in line with the traditional understanding of functional neuroanatomy of the brain. Tumours in the frontal lobe may cause executive function disorders, resulting in difficulties in planning, inappropriate behaviour and affect. Patients with tumours in the dominant posterior frontal lobe can have an expressive aphasia due to involvement of the Broca area. Tumours in the dominant temporal lobe can result in different language problems, including word-finding difficulties and understanding of speech and written text. Temporal lobe tumours in the non-dominant hemisphere can lead to problems in intonation and perceiving and expressing emotion in speech. Apraxia, dyscalculia and dyslexia can occur in patients with tumours in the parietal lobe. These patients can also have spatial orientation problems. Patients with tumours in the occipital lobe, especially in the non-primary visual cortex, may show difficulties in visual perception and memory of objects. Cerebellar tumours might also cause the so-called cerebellar cognitive affective syndrome, with disturbances in executive functioning, language deficits and personality changes.

4 Epilepsy

An epileptic seizure is among the most common presenting symptoms of brain metastases and has a significant impact on quality of life. Around 10–20% of patients with brain metastases present with an epileptic seizure [10,11,12,13]. Up to 35% of patients with brain metastases experience at least one epileptic seizure during the course of their disease [14]. The incidence of epilepsy in patients with brain metastases is lower than in patients with a primary brain tumour, probably due to the less-infiltrative growth of brain metastases and the inability to influence neuronal excitability biochemically [15]. Patients with brain metastases and an epileptic seizure have a high risk of recurrence. Therefore, start of anti-epileptic drugs is advocated after a first epileptic seizure [15, 16]. Prophylactic use of anti-epileptic drugs in patients with brain metastases who never had an epileptic seizure is not recommended.

Epilepsy mainly results from supratentorial brain metastases, with the highest risk of epilepsy in cortical metastases. Patients with metastases in the frontal lobe, temporal lobe or insula have a higher risk of epilepsy than patients with metastases in other brain regions [17]. Incidence of epilepsy seems to vary by the underlying primary tumour, with the highest incidence in melanoma patients (67%) and lung cancer patients (29%) [18]. Induction of epilepsy is thought to result from tissue damage in brain metastases, such as necrosis and deposition of haemosiderin [19]. New-onset seizures in patients with known brain metastases may indicate progression of tumour or associated oedema or an intratumoural haemorrhage.

In patients with brain metastases, almost all epileptic seizures are symptomatic, and the ictal signs depend on the location of the metastasis. Most generalized tonic clonic seizures are secondary seizures with a focal onset.