The skull is a fixed volume container. The Monro-Kellie hypothesis[42
] states that the sum of the volumes of the normal intracranial contents (blood, CSF and brain) and any additional component (hematoma, tumor) is constant. An increase in the volume of any of the components must be compensated for by a reduction in one or more of the other components or the ICP will rise. The intracranial blood volume and CSF are the two components that can compensate for an increase in volume of another component, for example, an expanding brain tumor. Once the compensatory mechanisms are exhausted, there is a rapid rise in ICP. The rate at which the volume changes, determines the ability of the compensatory mechanisms to cope. A slow growing meningioma  may achieve a considerable size before causing symptoms, and is more likely to present with a seizure or focal signs, whereas a fast-growing glioblastoma  will often present with features of raised ICP.
ICP can rise for a number of reasons . There may be a new “space-occupying lesion” such as a primary or secondary tumour , hematoma or abscess ; an area of swelling, e.g., in encephalitis, after a large ischemic stroke or venous infarction in venous sinus thrombosis; or elevation in CSF pressure . Elevated CSF pressure may be focal as in obstructive hydrocephalus due to aqueduct stenosis or diffuse as in communicating hydrocephalus or intracranial hypertension. An LP is safe and can be therapeutic in communicating hydrocephalus and intracranial hypertension, but is potentially dangerous where there is focal raised pressure such as in obstructive hydrocephalus or a “space-occupying lesion.” If there is focal raised pressure, removal of CSF may decompensate the intracranial compensation mechanisms, leading to shift and transtentorial herniation: “coning.”
Symptoms suggestive of raised intracranial pressure
In an audit of patients with intracerebral tumors, headache was the commonest first symptom (23.5%) and was present in almost half by the time of presentation (46.5%).[43
] However, it was rarely the only symptom, and at presentation most patients (86%) had focal symptoms or signs (hemiparesis, hemisensory disturbance, diplopia) and/or more non-focal symptoms (confusion, personality change). Only 6 out of 310 patients (1.9%) had isolated headache with a normal examination and no clinical pointer to an underlying lesion. Headache due to a focal lesion causing raised ICP almost invariably causes a progressive headache with associated features. Isolated headache and longstanding headache are rarely due to an underlying focal lesion, and an isolated seizure is much more likely to have a sinister underlying pathology (positive predictive value 1.2% for first seizure compared with 0.09% for isolated headache).[44
Classically, raised ICP headache is worse in the morning. This is attributed to a rise in ICP due to lying flat overnight.[42
] However, not all morning headache is due to raised ICP. Migraineurs commonly waken with headache, which then gets worse, and patients with medication overuse headache commonly waken with headache, which then improves on taking the overused medication.[45
] Morning headache due to raised ICP will “waken the patient up” and then gets better once the patient is up and has assumed an upright posture. Nocturnal hypoventilation, due to respiratory muscle weakness or obstructive sleep apnea, is also important to consider in patients with morning headache.[46
When there is a long history of isolated episodic morning headache, the most likely diagnosis is migraine and investigation is not required unless there are “red flags.”[8
] Medication overuse (a complication of the treatment of primary headache) is the single commonest cause of secondary headache. If there is evidence of medication overuse, and there are no “red flags” then it is reasonable to withdraw medication without investigating. In a patient with a progressive history, usually over a short period of time, with new focal or non-focal symptoms, new focal signs, or if there is a history of cancer or immunosupression, then imaging is required to look for an underlying lesion.[9
] CT brain scan is the initial imaging modality of choice due to its accessibility in most patients. If there is a significant suspicion of a neoplastic lesion, then the CT should be contrast enhanced. MRI should be considered if the CT is normal or may be required to give further information on the lesion found on CT. In patients with headache precipitated by valsalva (coughing, sneezing, straining, stooping, exertion) MRI is required to exclude an Arnold Chiari malformation or a posterior fossa lesion.[47
Normal neuroimaging does not exclude raised ICP. Headache due to raised CSF pressure is usually episodic to begin with and gradually progresses to become daily over weeks.[48
] It has the typical features of raised ICP (worse in the morning, with exercise and valsalva) and commonly has features attributable to raised CSF pressure (pulsatile tinnitus [perception of a whooshing noise], transient visual obscurations [transient visual disturbance, ranging from slight blurring to total loss of light perception, on change in posture or valsalva maneuver], diplopia and visual blurring). Papilledema is typical and is usually bilateral; however, cases are reported without papilledema: so-called idiopathic intracranial hypertension without papilledema (IIHWOP).[49
] Other common findings on neurological examination include visual field defects, enlarged blind spots and sixth nerve palsies (unilateral or bilateral).[48
Idiopathic intracranial hypertension (IIH) is most commonly seen in obese women of childbearing age. It is a diagnosis of exclusion and all patients require adequate investigation to exclude a secondary cause. By definition, neuroimaging is normal in IIH and there are no imaging findings that can be used to give a positive diagnosis. Slit-like ventricles may be seen on CT and MRI, and a partially empty sella, flattening of the posterior sclera, or gadolinium enhancement of the optic disk may be seen on MRI.[50
] A lumbar puncture demonstrates an elevated opening pressure with normal CSF constituents. A CSF opening pressure >25 cm CSF is considered to be abnormal, although in some patients an opening pressure of up to 28 cm CSF may be normal.[51
] CSF should be sent for microscopy, culture and sensitivity, protein and glucose and cytology to exclude a secondary cause.
Venous sinus thrombosis must be excluded either by CTV or MRV. Other secondary causes to consider include medications (most commonly tetracyclines), infective or inflammatory meningitis, malignant meningitis (carcinoma, lymphoma or leukemia) and carbon dioxide retention due to obstructive sleep apnea or other respiratory disease.[48
The hallmark of intracranial hypotension is orthostatic headache (headache on assuming an upright posture). Intracranial hypotension is due to CSF leak, either following a diagnostic LP[52
] or occurring spontaneously.[53
] Not all orthostatic headache is due to CSF leak. It has also been associated with postural tachycardia syndrome,[54
] and with metastasis to the skull base[55
] and cervical spine.[56
The cause of spontaneous CSF leaks is unknown. Orthostatic headache starts or worsens after assuming an upright posture and improves or resolves after lying down. The headache follows a new daily persistent pattern, with the patient waking up headache free followed by gradual onset headache. Usually, the headache develops within 15 minutes of assuming an upright posture and resolves within 15–30 minutes of lying down.[53
] Occasionally the headache takes hours to develop “second-half day headache” or the onset can be sudden, mimicking a SAH.[57
] The orthostatic component may disappear with time and in any patient with a new persistent headache, it is important to establish if the headache was orthostatic at the outset.
Post-LP headache usually settles with conservative management and if the onset and symptoms are typical, then investigation is usually not required.[52
] MRI is the investigation of choice for spontaneous intracranial hypotension. Subdural fluid collections, enhancement of the pachymeninges , and sagging of the brain are typical findings. Sagging of the brain can result in crowding of the posterior fossa and cerebellar tonsillar descent, which is presumably why some patients also describe valsalva-induced headache. Engorgement of venous structures and pituitary hyperemia may also be seen, and in up to 20% of patients there may be no abnormal findings on MRI scanning. While not diagnostic, CT may show bilateral subdural collections, providing a clue to the diagnosis. If an LP is performed, the opening pressure should be less than 6 cm CSF, although normal CSF opening pressures are reported.[53
] With a typical history and MRI findings, an LP is not required, particularly as it may aggravate the patient's symptoms. It is important to try and identify the location of the CSF leak. Spinal MRI and CT myelography are most commonly used.
MRI showing pachymeningitis due to low CSF pressure
Giant Cell Arteritis
Giant Cell Arteritis (GCA) should be considered in any patient over the age of 50 who presents with new headache.[9
] The incidence increases significantly with age and patients are often much older. GCA is recognized to occur in individuals younger than 50, but this is vanishingly rare. GCA is an important diagnosis to consider because of the risk of visual loss and stroke. Some patients only have headache and there should be a low index of suspicion in patients over 50. In patients less than 50, the diagnosis should only be considered if characteristic features are present.
The headache has no specific features; it may be diffuse or localized, and is often bi-temporal. The two commonest presentations are with headache or with visual symptoms. Associated symptoms include scalp tenderness, fever, other constitutional symptoms, and symptoms of polymyalgia rheumatica. Jaw claudication (jaw and temple pain brought on by chewing, particularly vigorous chewing, that settles following stopping chewing) is very specific but poorly sensitive. Its presence is useful diagnostically, but its absence does not exclude GCA. Scalp tenderness has low specificity. The most useful sign is temporal artery beading, prominence or enlargement.[58
An erythrocyte sedimentation rate (ESR) is the best screening investigation. In a systematic review,[58
] the mean ESR in patients with biopsy-proven GCA was 88 mmHg. An ESR of less than 50 mmHg substantially reduces the likelihood of the diagnosis being GCA and a normal ESR makes it unlikely, but does not exclude it. A full blood count (FBC) looking for anemia and raised platelet count, and C-reactive protein (CRP) are useful additional blood tests.[9
If GCA is considered likely, steroids should be started immediately. It is important to confirm the diagnosis and a temporal artery biopsy should be performed as soon as possible. There is controversy about how long after initiation of steroids it is still useful to perform a biopsy. Convention suggests that a biopsy should be performed within 2 weeks. However, in a small prospective study,[59
] 6 out of 7 biopsies obtained between 4 and 6 weeks after starting steroids were positive. It is, therefore, still worth performing a temporal artery biopsy regardless of the duration of steroid treatment.[59
] Focal areas of arteritis may result in “skip lesions” and a negative biopsy with a good clinical history does not exclude GCA. However, a negative biopsy should always prompt adequate consideration of an alternative diagnosis.[60
Is investigation required in primary headache?
By definition, there is no secondary underlying pathology in primary headache, such as TTH, migraine, and cluster headache. Neuroimaging is required in selected patients with “red flags” to screen for secondary causes of headache . The chance of finding a significant underlying abnormality in patients with a stable headache pattern and a normal neurological examination in migraine is vanishingly small. A meta-analysis of neuroimaging studies[61
] estimated a 0.2% prevalence of significant intracranial abnormality. No abnormalities were found on neuroimaging in two small studies on TTH. In patients whose headaches could not be adequately classified, the risk of a significant abnormality was variable and in one study cited was as high as 6.7%. Evidence for the Trigeminal autonomic cephalalgias (TACs: cluster headache, paroxysmal hemicrania and SUNCT syndrome) is restricted to case reports. A literature review of symptomatic cases published between 1975 and 2007[62
] revealed 40 cases. These were associated with atypical phenotypes, abnormal examination, and poor treatment response though a significant minority had a typical presentation. A relatively high proportion were associated with pituitary tumors.
There is therefore good evidence that neuroimaging is not required in stable migraine, and should be restricted to patients with “red flags.” There is insufficient evidence to make recommendations in TTH or TACs. By extrapolation, it seems reasonable to not to image patients with TTH unless there are “red flags.” Imaging should be considered in patients with TACs, particularly those with an atypical phenotype, abnormal examination, or poor treatment response. There should be a lower threshold for neuroimaging in patients whose headaches cannot be classified.
In 350 consecutive patients scanned with CT regardless of the need for imaging, incidental findings were found in 7%.[63
] Relevant abnormalities were only found in patients where it was expected (abnormal neurological examination or warning symptoms). In two large studies performed on asymptomatic general populations with normal neurological examinations, MRI revealed incidental findings in 7% of healthy young men applying for military flying duties in the German Air Force (mean age 20)[64
] and 12% of a healthy older population in Rotterdam (mean age 63).[65
] A meta-analysis[10
] estimated that the overall prevalence of incidental findings on brain MRI was 2.7% or the “number of patients needed to scan” to get an incidental finding was 37. The commonest incidental findings were benign neoplasms and vascular abnormalities. Silent infarcts and white matter intensities were excluded from this calculation. They were common and their prevalence increased with age. White matter intensities occurred in more than 15% of the 70–89 age group.
CT Verses MRI in primary headache
MRI is more sensitive than CT,[66
] but in migraine is more likely to pick up incidental findings and not more likely to pick up clinically relevant findings.[9
] CT is therefore adequate in most patients, with MRI reserved for selected patients where the clinical history suggests MRI may be more useful, e.g., in patients with brainstem symptoms or with associated valsalva headache. In patients with TACs MRI is recommended.[9
Should patients be imaged for reassurance?
Patients increasingly expect a scan when they attend for assessment, particularly in secondary care. Explanation may suffice, but in some patients neuroimaging is required for reassurance. This has to be balanced against the risk of incidental findings and all patients should be counseled about the risk of finding an incidental abnormality before neuroimaging is organized.[10
] In a prospective randomized controlled trial of 150 patients with chronic daily headache and no “red flag” features,[67
] patients were randomized to receive no imaging or an MRI brain scan. Those randomized to a scan had significantly lower anxiety levels at 3 months, but this was not maintained and anxiety levels had returned to baseline at 1 year. There was, however, a significant reduction in healthcare costs in patients with psychiatric co-morbidity who were scanned compared to those who were not, presumably by altering the referral patterns of their primary care physicians. Anxiety levels were not increased in either the control or scan groups.
- Most patients presenting with headache have primary headache
- Most patients do not require investigation
- Medication overuse headache (a complication of the management of primary headache) is the most common secondary headache
- “Red flags” can help target those patients who require investigation
- Thundercalp headache should be assumed to be SAH until excluded with urgent CT +/- LP
- A lumbar puncture should be performed without delay in patients with suspected meningitis
- Raised ICP headache usually presents with new persistent headache with progressive focal or non-focal symptoms and an abnormal neurological examination (Headache +)
- Low-pressure headache should be considered in patients with orthostatic headache. The orthostatic component may disappear with time
- Giant cell arteritis should be considered in any patient presenting with new headache over the age of 50 years
- Investigation of patients with headache should be balanced against the risk of incidental findings, particularly where investigation is being preformed primarily for reassurance.