Headache is one of the commonest medical problems. Studies indicate a one-year prevalence of 90% and a life-time prevalence of almost 99%. Essential in the work-up of headache is the history: length of headache history, frequency of recurrence, duration, site (unilateral or bilateral, localized or diffuse), quality (throbbing or tightness or heaviness), severity (interfering with activities of daily living), time of onset, premonitory symptoms (mood change, hunger or yawning), aura, associated features (nausea, vomiting, diarrhea, photophobia, phonophobia, red watering eye, stuffy nostril), precipitating factors, relieving factors, past health, family and social history.
Acute new-onset headache
Acute severe headache associated with neck stiffness raises concern about SAH, meningitis or systemic infections. Hence clinical findings in addition to brain CT scan (preferable MRI) and LP may be diagnostic.
Subarachnoidal hemorrhage (SAH): A large majority of SAH is caused by ruptured intracranial aneurysm (Berry aneurysm = saccular aneurysm). The prevalence of intracranial saccular aneurysms is around 2%. The mean age of rupture is around 50 years of age. About 85% of aneurysms are located in the anterior circulation. Risk factors for rupture include history of prior SAH, smoking, AHT, alcohol abuse, cocaine use, obesity, pregnancy and positive family history. Besides a positive family history which increases the chances 4x, hereditary diseases are associated with increased risk of aneurysms (e.g. polycystic kidney disease, Ehlers-Danlos syndrome type IV, NF-1, and Marfan syndrome). Most commonly rupture occurs in the morning and the evening. Headache (acute, explosive, severe and continuous) is the most typical manifestation associated with nausea, vomiting, meningismus, focal neurological findings and loss of consciousness. Neck rigidity occurs in 75% of cases during the first 24 hours. About 50% of patients may have a presentation mimicking meningitis. A sentinel headache (or warning leak) occurs in 50% of patients before a major rupture of a saccular aneurysm. These headaches present in the same way as the SAH itself. Accurate diagnosis of a sentinel headache can be lifesaving since the mortality of SAH is between 50 - 70%. Fever in SAH is associated with vasospasm (and subsequently stroke, which appears between 3 to 12 days after rupture) and poor outcome independently of hemorrhage severity or presence of infection. Transcranial doppler is preferred above angiography to verify the diagnosis of vasospasm. Hydrocephalus (e.g. increasing confusion or stupor) may develop acutely or may appear after 2 - 4 weeks.
The first day of SAH, CT scan is able to detect 95% of cases and precludes the need for LP. This figure gradually reduces to 30% after 2 weeks. MRI (FLAIR) is more sensitive than CT scan. LP should be done on all patients suspected of SAH but with normal CT scans or MRI. MRI gradient echo has a sensitivity of 94% in early stage and 100% sensitivity after 4 days. In contrast to bloody tap, the CSF is under increased pressure (up to 500 mmH2O) at least during the first day after the event. The blood WBC/RBC ratio (1:1000) is a good indicator of SAH, but leucocytosis up to 18,000 cells/mm3 (with normal ESR) may be found in the early days. Similarly, CSF RBC hemolysis may alter the WBC/RBC ratio, resulting in higher relative WBC count. It is worth mentioning that this procedure may precipitate rebleeding from a ruptured aneurysm. Arteriogram (four vessel angiography) does not reveal the cause of bleeding in 15% of cases (probably due to vasospasm and may require second angiogram in several weeks). In cases with negative angiogram the risk of rebleeding is 4%. Survival rate after 20 years is 69%. To reduce the risk of rebleeding with its high mortality and prevent stroke from vasospasm, Hunt & Hess grade I and II patients should have surgery done within 36 hours after the ictus. Those cases can be related to occult aneurysm, dural or spinal AVM, mycotic aneurysm, sickle cell disease, coagulation disorders, drug abuse (ecstasy, cocaine abuse), intracranial or cervical tumors and HSE. Systemic complications related to SAH, are myocardial ischemia, hyponatremia (SIADH) and leucocytosis (with normal ESR). The patient's state of consciousness (Hunt & Hess grade) at the time of angiography appears to be the best indicator of prognosis. Health outcomes for survivors 1 year after the onset of SAH: 56% are alive after 1 year; 46% recover incompletely (memory impairment (50%)), mood problems (39%), speech problems (14%) and self care (10%). Seizures at onset (observed in 4-16% of patients) are a predictor of poor outcome. Perimesencephalic hemorrhage has a favorable outcome. Headache is mild and vasospasm rarely develops. The aneurysm at the top of the basilar artery is seldom visualized and may be of venous origin.
Carotid and vertebral artery dissections: Occurs in 2.5% of patients with a first stroke. One fifth of the dissections are bilateral. Risk and predisposing factors for spontaneous dissections include: migraine, AHT, oral contraceptives, fibromuscular dysplasia, temporal arteritis, PAN, meningovascular syphilis, Ehlers-Danlos syndrome (type IV), Marfan syndrome, cystic medial necrosis and Moyamoya disease (Japanese for “haze of smoke”). Traumatic dissections have been associated with a variety of causes going from cough, exercise-induced to massages (shiatsu). Focal cerebral ischemia occurs in 60% of patients and may follow the headache by up to 4 weeks, or may precede it. Incomplete Horner syndrome (ptosis with miosis but without anhidrosis) is present in 50% of patients with internal carotid artery dissection. The pupil will not dilate in response to hydroxyamphetamine. Headache (and neck pain) is the most common symptom of vertebral artery dissection. Diagnosis of internal carotid artery and vertebral artery artery dissection can be reliably made by MRA. Intracranial arterial dissections are less common. Treatment in general is with anticoagulation (heparin 100 U/kg iv bolus followed by 1000 U/h as continuous infusion increase by 5 U/kg/h q4h prn depending on aPTT while warfarin is instituted) and follow-up angiogram several months later. Steroids may rapidly relieve the pain and can serve as a diagnostic feature.
Cerebral venous thrombosis (CVT): Predisposing factors include: local infectious causes (direct septic trauma, intracranial infections (including syphilis), systemic infections (endocarditis; viral infections e.g. herpes, CMV and HIV; parasitic infections e.g. malaria, trichinosis; and mucor and aspergillosis) and regional infections. Noninfectious causes include: local pathology such as head injury, neurosurgery, cerebral infarcts, tumors etc. There are numerous medical associations, including severe dehydration, cardiac disease, fever, malignancies (usually hematologic malignancies), hematologic disorders (sickle cell disease, polycythemia, thrombocythemia), coagulopathy (antithrombin III deficiency, protein C and S deficiency, activated protein C resistance, DIC, and APLS), inflammatory states (ulcerative colitis and Crohn disease, Behçet disease, Wegener granulomatosis, PAN, SLE, sarcoidosis), nephrotic syndrome, venous thromboembolic disease, homocystinuria, pregnancy, young women in the puerperium or in association with recent use of contraceptives and thyrotoxicosis. Androgen therapy, “ectstasy” and L-asparaginase are some of the drugs which can cause CVT. Diffuse progressive headache is the initial manifestation in 80% of cases. Seizures, focal signs and papilledema generally follow headache. Therefore the triad of progressive headache, somnolence and papilledema is considered as pathognomonic. Deep CVT should be suspected if the patient is a young female presenting headache, w/ or w/o signs of ICHT or diencephalic involvement but radiological uni- or bilateral infarction in the thalamus or basal ganglia. The “empty delta sign” of the superior sagittal sinus on an enhanced brain CT scan is found in 35% of cases. Preferably phase-contrast MRA or MRV should be used for diagnosing CVT. Serum D-dimer (positive if the value is > 500 ng/ml; sensitivity 83% and negative predictive value 95%) may be useful in the diagnosis of CVT. LP should be avoided but could be justified to help exclude infectious or leptomeningeal malignancy. It is noteworthy that up to 10% of patients with chronic daily headache have "isolated ICHT w/o papilledema" and suffer from CVT particularly of the transverse sinus on MRV. In deep CVT the MRI lesions in the thalamus (uni- or bilateral) may be confused with an abscess or tumor, and do not necessarily have a hemorrhagic component. CVT needs to be differentiated from SAH, subdural hematoma, brain abscess, mucormycosis, HSE, cerebral vasculitis and chronic meningitis.
Pituitary apoplexy: Acute hemorrhagic infarction of a pituitary adenoma may result in a dramatic syndrome of pituitary apoplexy, which includes severe headache, nausea, vomiting and lethargy. Ophthalmoplegia, visual and pupillary disturbances, and meningismus may be present.
Migraine: Using the International Headache Society criteria the prevalence of migraine is about 13% of the adult population with female preponderance (75:25). Common provoking factors are: menstruation, oral contraceptive, hormonal replacement therapy, alcohol, monosodium glutamate, missed meal, stress and post stress period, anxiety, odors, visual triggers, high altitude, lack of sleep or excessive sleep, physical exertion, fatigue, vasodilating drugs. There is a strong genetic factor with about 70% of migraineurs having a positive family history. Rare disorders of which migraine can be a feature are familial hemiplegic migraine (autosomal dominant), retinal migraine, basilar migraine, MELAS, APLS, CADASIL, Osler-Rendu-Weber syndrome (hereditary hemorrhagic telangiectasia). Migraine with prolonged atypical aura and white matter abnormalities should suspect CADASIL. The latter has been mapped to chromosome 19. In the presence of complex history, poor response to treatment, or neurologic abnormalities, neuroimaging studies should be obtained.
With aura (classic migraine): Aura followed after a free interval (< 1 hour) by unilateral throbbing pain of moderate to severe intensity lasting 4-72 hours and frontal, periorbital or temporal in location. Usually migraine is gradual in onset. Associated with nausea, vomiting and photophobia and phonophobia. Movement exacerbates headache (exertional headache). Aura can be visual, sensory or motor (weakness) in nature. Abrupt-onset migraine resembles thunderclap headache but lack of periodicity and normal neurological investigation facilitates the diagnosis of migraine.
Without aura (common migraine): similar to migraine with aura. The absence of an aura makes the differential diagnosis with tension headache more difficult.
Familial hemiplegic migraine (FHM): Familial hemiplegic migraine is linked to chromosome 19p and is herited in a dominant mode. Hemiplegia with or without aphasia (lasting hours to weeks) associated with alteration in consciousness ranging from confusion to coma may be the presenting manifestation. Headache may be absent or can be ipsilateral to the paresis.
Sporadic hemiplegic migraine (SHM): This form of migraine is always associated with an aura, either motor, sensory, visual or aphasic in nature. It occurs generally before the age of 45 years. It needs to be differentiated form TIA, Todd phenomenon, focal deficits associated with hypercapnia, hyponatremia, hypocalcemia, hepatic failure and renal failure, meningitis/encephalitis, carotid dissection, APLS, SLE and OTCD.
Ophthalmoplegic migraine: Patients presenting with migraine headache and diplopia (paresis of one or more cranial nerves, but mostly the 3rd cranial nerve), the latter usually presenting when the headache subsides. Recovery of the oculomotor paresis may occur in 1 to 6 weeks. The diagnosis is made by exclusion (Tolosa-Hunt syndrome, parasellar lesions, diabetic cranial neuropathy, collagen vascular disease, and orbital pseudotumors). MRI with MRA will be essential.
Abdominal migraine: The criteria for this migraine variant include: (1) cyclic vomiting, (2) family history of migraine, (3) a history of migraine with or without aura, (4) recurrent identical attacks of abdominal pain, (5) no abdominal symptoms between attacks, (6) onset of attacks of abdominal pain in early childhood or early adult life, (7) episodes lasting from 1 to several hours, (8) and pain usually located in the upper abdomen. The diagnosis is made by excluding OTC deficiency, urogenital disorders, peptic ulcer, and other gastrointestinal disorders.
Episodic Tension-type headache (ETTH): ETTH is by far the most common form of headache. The life-time prevalence of ETTH is in the order of 78% with female preponderance (60:40). The one-year prevalence of ETTH in the adult population is around 40-74% with a slight female preponderance. The highest rate of occurrence is the 4th decade. The diagnosis of ETTH requires a history of > 10 previous headache episodes with a total of less than 15 days/month (less than 180 days/year). The headache is diffuse, bilateral (more frontotemporal) and mild to moderate in severity and dull (tightness, heaviness, pressure-like) in nature. The duration varies between ½ hours to 7 days. Essential is that there is no aura, no associated nausea or vomiting and the pain is not aggravated by physical activity. Similar to migraine however, ETTH can be triggered by lack of sleep, stress, anxiety or depression. Tension-type of headache seen in migraineurs behaves different from ETTH since they are often associated with migraine symptoms such as photophobia, phonophobia and nausea.
Cluster headache: This form of headache is more common in males than females (>2.5:1) and is prevalent between the ages of 20 and 40 years. Severe strictly unilateral excruciating periorbital, retroorbital or temporal stabbing sharp or boring pain (“the eye being pull out”) lasting 15-180 minutes. Several attacks per day can occur. The attacks are often nocturnal (shortly after falling asleep). Autonomic features such as ipsilateral lacrimation (91%), injection of conjunctiva (77%), nasal congestion (75%), Horner syndrome (74%) or rhinorrhea (72%) are common. Migrainous features (e.g. nausea and photophobia/phonophobia) are observed in half of the cases. There is a characteristic periodicity of 2 to 3 months and a remission for a year. Alcohol is a precipitating factor (63%). The diagnosis is primarily clinical, but it is essential to perform MRI of the brain or contrast enhanced CT to rule out symptomatic cluster headache (nasopharyngeal carcinoma, pituitary and parasellar tumors, clivus tumors, vertebral artery aneurysms, large hemispheric AVM, upper cervical meningioma). The results of neuroimaging studies in cluster headache are normal. Abortive measures are triptans and 100% oxygen. Prophylactically, verapamil, methysergide, lithium and prednisolone has been used.
Paroxysmal hemicrania: This is a rare benign form of unilateral shortlasting headache with clinical resemblance to cluster headache but not responsive to standard anticluster therapy. Female preponderance (2:1). Severe, throbbing, boring or stabbing orbitotemporal pain lasting anything between 1 and 30 minutes with 3-30 attacks per day. Often nocturnal, precipitated by alcohol and responsive to indomethacin but response may take up to 2 weeks. Migrainous features and ipsilateral autonomic features can be observed and the pain can irradiate to the shoulder and arm.
Short-lasting Unilateral Neuralgiform Pain with Conjunctival injection and Tearing (SUNCT): SUNCT is a benign form of headache with autonomic features (prominent conjunctival injection and lacrimation) with male preponderance. Stabbing, burning or sharp periorbitotemporal pain and, in contrast with paroxysmal hemicrania, the attacks are diurnal and last only seconds but very frequently (up to 30/hour). It can be precipitated by alcohol. There are no migrainous features. Lamotrigine has been used successfully as prophylactic therapy.
Icepick headache: Severe stabbing pain which can occur at any location. The attacks last only seconds or less with variable frequency during the day. The pain is responsive to indomethacin.
Cough, Exertional, and sexual headaches: These forms of headache usually appear in the 3rd to 6th decades of life and are more prominent in men. Benign cough headache is precipitated by cough, sneezing, weightlifting, bending, stooping or straining with bowel movements and usually lasts less than one minute. Posterior fossa tumors, Arnold-Chiari type I malformations, Dandy-Walker syndrome, platybasia and basilar impression, and syrinx may be causes of symptomatic cough and exertional headache hence they need to be ruled out by neuroimaging. They generally present with occipital headache, neck pain and cranial nerve dysfunction or unsteadiness. Cerebellar ataxia and progressive spastic quadriparesis is found in severe cases. Benign exertional headache is induced by physical exercise and can last anything between 5 minutes to 24 hours. The headache is often throbbing in nature and precipitating factors are hot climate and high altitude. Symptomatic forms need to be excluded (SAH, cerebral artery dissection and pheochromocytoma). Sexual-induced headache can either be dull, explosive or postural and is related to sexual excitement. The headache usually lasts minutes to hours. In all cases of sexual headache, SAH and pheochromocytoma needs to be ruled out. It is noteworthy that Viagra® can induce headache in 10% of users. Sexual headaches are characterized by a mean age at onset of 40, male predominance, bilateral and occipital distribution of the pain, and a high comorbidity with other primary headaches.
Headache associated with hyperadrenergic states: This includes essential hypertension, anxiety attacks, hyperthyroidism, intracranial lesions, diencephalic seizures, sympathomimetic drug abuse (e.g. cocaine and amphetamine), and pheochromocytoma.
Brain tumors: The prevalence of adults with brain tumors who complain of headache at the time of diagnosis varies between 30 - 70%. The median duration of headache at the time of diagnosis varies from 3 weeks to 15 months. The incidence of metastatic brain tumors is almost 10 times higher than that of primary brain tumors. The latter include: glioma (45%) including glioblastoma multiforme (20%) and astrocytoma (10%); meningioma (15%); and pituitary adenoma (7%). Pituitary adenoma (macroadenoma if serum prolactin > 300 U/L) can cause bitemporal hemianopsia in addition to amenorrhea and infertility. Pilocytic astrocytoma and germ cell tumors develop in the 2nd and 3rd decade of life, astrocytoma and oligodendroglioma in the 3rd and 4th decade while malignant glioma (>75% of these are of astrocytic origin) and primary CNS lymphoma in the >40 age range. Metastases account for 45% of all intracranial tumors. Metastatic lesions generally occur following the diagnosis of the primary tumor and are single in up to 40% of cases. The primary site are in order of occurrence lung (64%), breast (14%), unknown primary (8%), melanoma (4%) and colorectal (3%). The average interval between the diagnosis of the primary tumor and the development of brain metastasis is about 4 months for lung cancer and up to 3 years for breast cancer. Less then 10% of patients with headaches and brain tumors have normal neurological examination. Papilledema is by far the most common finding (40%). Bifrontal and nuchal headaches are often indicative especially when related to exertion, coughing, sneezing, vomiting, straining or sudden changes in posture or related to time of day-related. 6% of glioblastoma multiforma survive 2 years, while 46% of astocytoma survive. Microadenoma of the pituitary gland should be diagnosed by 3 mm T1 spin-echo sections in coronal and sagittal plane.
Carcinomatous meningitis: Meninges are involved in 5-15% of all patients with solid or hematological tumors: leukemia (40%), breast (34%), lymphoma (30%), lung (26%), melanoma (25%) and gastrointestinal (9%). About one third of patients with meningeal carcinomatosis have cranial nerve involvement, but less than 50% of patients have nuchal rigidity, headache or vomiting. MRI reveals diffuse dural meningeal enhancement (50-90%) and CSF in over 50% of cases elevated protein and reveals aseptic meningitis. CSF cytology is positive in only 50% of cases. Useful tumor makers in CSF are CEA (breast, lung, gastrointestinal tumors), epithelial membrane antigen, β-glucuronidase, β2-microglobulin, and lactate dehydrogenase.
Colloid cyst of the third ventricle: This tumor usually becomes symptomatic in the 3rd and 5th decades of life. Episodic positional headaches or paroxysmal severe headaches with signs of intracranial hypertension are typical features. Because of the risk of sudden death (5%) surgery is recommended even in asymptomatic individuals.
Cystic lesions of the basilar cisterns: These may be due to neurocysticercosis, colloidal cysts, arachnoid cysts, cholesterol cysts (are usually seen in young and middle-aged patients, are located in the skull base and do not show enhancement), and pyogenic or TB abscesses.
Idiopathic intracranial hypertension (IICHT) or pseudotumor cerebri: This disorder is almost exclusively found in young obese women (>90% of patients are obese women). The female-to-male ratio of this disorder is 8:1. The mean age at the time of diagnosis is around 30 years. Pregnancy and menstrual irregularities are risk factors for developing IICHT.
The diagnosis of IICHT is based on the following criteria: 1) signs and symptoms of increased intracranial pressure (headaches with nausea or vomiting and a normal neurological examination with the exception of papilledema (95%)), visual loss from optic atrophy (30%), cranial nerve palsy (unilateral or bilateral VI nerve palsy) (25%) or tinnitus; 2) increased CSF pressure (>20 cm H2O in non-obese and >25 cm H2O in obese) with no cytological or chemical abnormalities (occasionally slightly low protein content); and 4) normal to small symmetric ventricles or empty sella syndrome (70%), dilation of the optic nerve sheaths, and elevation of the optic disc. With respect to vision, visual field testing is the most sensitive method for detecting visual loss in these patients, and the most common abnormalities are blind spot enlargement, generalized constriction of isopters, and inferior nasal field loss.
Conditions that may result in IICHT: CVT, SLE, Addison disease, hypoparathyroidism, chronic obstructive pulmonary disease, right heart failure with pulmonary hypertension, sleep apnea, renal failure, severe iron deficiency anemia. Certain drugs are known to be a risk factor for inducing IICHT e.g. nalidixic acid, vitamin A, lithium, minocycline, oral contraceptives, thyroid hormone replacement, anabolic steroids and corticosteroids withdrawal. Since 30% of patients with CVT may present with "isolated intracranial hypertension without papilledema" gadoliunium-enhanced MRV should be considered systematically in these patients. This indicates that CVT is probably underdiagnosed. Furthermore 10% of patients who present with CDH have CVT and almost 50% of these patients have "isolated ICHT without papilledema". Furthermore, all individuals (obese or non-obese) with a CSF pressure > 20 cm H2O should undergo MRV. Angioplasty or thrombolytic therapy improves the outlet obstruction but not the clinical picture of IICHT.
Immediate treatment of the elevated intracranial pressure per se is unneccessary and, in general, these patients are not at risk for transtentorial or uncal herniation. Treatment modalities which are no longer routinely recommended include subtemporal decompression, chronic corticosteroids, and serial lumbar punctures. It is impossible for serial LP's alone to removed enough fluid to relieve elevated intracranial pressure, as CSF is produced at a rate of 0.35 mL/min, allowing the entire CSF circulation to be replenished in just 2 hours!! Therefore current management of pseudotumor cerebri should be based upon the level of visual loss, as additional therapeutic strategies should be guided by visual fields and visual acuity. If no visual loss, headache may be treated with medications commonly used for vascular headaches such as acetaminophen, nonsteroidal anti-inflammatory agents, tricyclic antidepressants, or beta-blockers. Acetazolamide may be used in these instances as well but may not be necessary. If mild to moderate visual loss (visual deficits include enlarged blind spots, arcuate defects, mild peripheral constriction, and visual acuity is 20/30 or better) acetazolamide is the first-line drug (500 mg bid or tid as a starting dose, and will increase the total dosage to 3 g if necessary). The major side effects include paresthesias of the lips, fingers, and toes (which most patients tolerate), nausea, vomiting, malaise, sedation, renal calculi, metabolic acidosis, and rarely, aplastic anemia. The dose can be lowered in individuals not tolerating the drug. The drug should not be given to those with sulfa allergies because of cross reactivity. Most individuals with mild to moderate visual loss will do extremely well with acetazolamide, with resolution of the field defects and papilledema within 3 to 6 months, after which the medication can be tapered. When acetazolamide is not tolerated, switching to furosemide (orally, 20-100 mg) is recommended and monitor the serum potassium carefully. Major side effects of furosemide include hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia, and ototoxicity. Treatment of severe IICHT or progressive visual loss despite medical management consists of optic nerve sheath fenestration surgery. Other indications for optic nerve surgery are severe visual loss at presentation, inability to comply with medications, poor follow-up, or inability to cooperate with visual field testing. If the severe visual loss is sudden, if central visual loss is caused by macular edema, or if optic nerve sheath fenestration is not immediately available, then high-dose iv steroids (methylprednisolone, 250 mg four times per day for 5 days) combined with acetazolamide (500 mg three times per day) is another treatment option. Lack of immediate improvement is an indication for optic nerve sheath decompression. The iv steroids are followed by 80 mg prednisone orally, tapered over four to eight weeks in order to avoid the side effects of chronic use, and the acetazolamide is continued until the disc swelling resolves. Lumboperitoneal shunting should be reserved for patients in whom headache is the major problem or in whom visual loss progresses despite optic nerve sheath fenestration. Women who are pregnant and develop pseudotumor cerebri can be treated with acetazolamide except in the first trimester.
Intracranial hypotension headaches (IHH): These are most commonly induced post-LP, or occur spontaneous, or in CSF shunt overdrainage or following trauma or surgery. The orthostatic headache is typical and relieved by recumbency. Post-LP headache is found in up to 40% of patients after diagnostic LP. The headache begins within 72 hours or can be delayed for as long as 14 days and persists for about 5 days. Nausea and neck stiffness, interscapular pain, changes in hearing, upper limb radicular symptoms are common associated findings. Cranial nerve palsies (abducens palsy) have been reported and tend to occur between 4 to 14 days after the procedure and resolve in 4 to 6 weeks. There is a clear relationship between the diameter of the needle used and the incidence of post-LP headache. In case of IHH not caused by LP, chronic postural headache may develop and the diagnosis is based besides the clinical findings on LP (with CSF analysis) and MRI. The opening pressure at LP is either normal or <60 mmH2O (normal 60-200 mmH2O). CSF analysis can be normal or demonstrate lymphocytic pleocytosis with elevated protein. Brain and spine MRI findings include diffuse symmetric dural gadolinium meningeal enhancement also called pachymeningitis (dural vasodilatation), subdural hematomas and hygromas (70%) and acquired Arnold-Chiari type I malformation (62%) can sometimes be found. Indium-labelled albumin injected into lumbar CSF with isotopic scan of the spinal canal taken 24-48 hours later may also be diagnostic. Differential diagnosis for isolated orthostatic headaches includes spontaneous intracranial hypotension, colloid cyst of the third ventricle and post-lumbar puncture headache.
Takayasu disease: Nicknamed “pulseless disease or temporal arteritis of the young” affects the aorta, subclavian and left carotid arteries. The disease commonly presents before the age of 40 years and affects female 10x more than male. A triad consisting of subacute headache, often unilateral (42%), highly elevated ESR (72%) and signs of arterial insufficiency (e.g. carotid bruit, brachial blood-pressure asymmetry, or claudication) in a young patient is diagnostic. There is weight loss and the patient is subfebrile. Depending on the extent and level of the arteritis several types of clinical presentations may emerge going from hypoglossal nerve paralysis to “temporal arteritis”. The diagnosis can be made by angiogram of the thoracic aorta and (affected) branches which shows focal, tapered narrowing or stenosis of the artery. CT scan shows mural thickening resulting from inflammation of the media and adventitia. In contrast to temporal arteritis, no remission can be achieved with corticosteroids, sometimes resulting in the use of methotrexate or azathioprine. Important differential diagnosis are carotid artery dissection (Marfan syndrome and Ehlers-Danlos syndrome) and endocarditis. Other diseases affecting the thoracic aorta include ankylosing spondylitis, inflammatory bowel disease, Behçet syndrome, relapsing polychondritis, thrombangiitis obliterans, Cogan syndrome, RA, SLE, sarcoidosis and retroperitoneal fibrosis.
Headache, eye, ear, nose, throat disorders (HEENT):
Eyes: The diagnosis of orbital pseudotumor, which may cause optic neuropathy, and Tolosa-Hunt syndrome (recurrent granulomatous inflammation in the cavernous sinus and superior orbital fissure) is one of exclusion using MRI of brain and orbit. The syndrome is a complex of peri- or retro-orbital or hemicranial boring, lancinating, stabbing, quite severe pain associated with ipsilateral ophthalmoplegia, oculosympathetic dysfunction, and sensory loss in the 1st division of the trigeminal nerve. The age of onset varies from 3.5 to 75 years, with a peak in the 5th decade. Hematologic screens may show a mild leukocytosis or elevated ESR. Some patients may demonstrate elevated ANA or RF titers. CSF analysis may show a mild protein elevation or slight pleocytosis. Neuroimaging studies may be normal, but frequently show abnormal enhancing lesions in the cavernous sinus on MRI examination. Carotid angiography may show irregular narrowing of the carotid artery. In the absence of an identifiable cause and a classic presentation of retro-orbital pain and cavernous sinus involvement in an otherwise healthy appearing patient, the diagnosis of Tolosa-Hunt syndrome should be made. The syndrome is treated with a 5 day course of iv methylprednisolone followed by a tapering dose of oral prednisone. Spontaneous remissions occur, sometimes with residual neurological deficits, but attacks may recur at intervals of months or years. Differential diagnosis may include carotid artery pathology, neoplasms, inflammation/infections (sinusitis, herpes zoster, mucormycosis, syphilis, TB, sarcoidosis, Wegener granulomatosis), diabetes and migraine.
ENT: About 50% of patients presenting to ENT specialists with symptoms of sinusitis complain of severe headaches. Radiographic evidence of sinusitis is present in up to 40% of adults without symptoms as an incidental finding. Fever is present in 50% of patients with acute sinusitis. In contrast to acute frontal sinusitis, the pain in acute maxillary sinusitis is improved when supine and worse when the head is upright. Frontal sinusitis can result in brain abscess, meningitis, subdural and epidural abscess, osteomyelitis and orbital inflammation and infection. Acute sphenoiditis is responsible for 3% of all cases of acute sinusitis. The headache is always present, may aggravate with exertion, postural changes and coughing, and is often associated with nausea and vomiting. Sphenoidal sinusitis may result in meningitis, cavernous sinus thrombosis, subdural abscess, pituitary insufficiency. Headaches associated with chronic sinusitis are usually low grade and diffuse, and often increase during the day. MRI is the investigation of choice for the evaluation of headache in sinusitis.
Infection and headache: Systemic infections (pyelonephritis, biliary sepsis) and intracranial infections may cause headache.
Acute meningitis and encephalitis: S. pneumoniae and Gram negative bacilli are the most common cause of acute bacterial meningitis in the Western world. Enteroviruses (echo and Coxsackie), followed by mumps, HSV-2, lymphocytic choriomeningitis (hamster, mice) and adenoviruses are the most common viruses causing aseptic meningitis. Many of them occur more often in childhood. Polio is one of the most common forms of viral meningitis in underdeveloped countries. Viral encephalitis can be caused by enteroviruses, arboviruses, flavivirus (Japanese encephalitis), HSV-2, Epstein-Barr virus, measles, influenza virus, West Nile fever virus, St. Louis encephalitis and varicella zoster virus. Acute aseptic (lymphocytic) or chronic meningitis, and acute encephalitis or meningoencephalitis are common clinical presentations. In addition to fever, meningismus, pain with eye movement, and altered mental status with meningeal signs, headache, in viral meningitis, is typically severe and of sudden-onset headache. In elderly however headache is less common. Often other systemic manifestations inherent to the viral infection are observed. CT scan or MRI followed by CSF analysis is an essential procedure. Blood cultures, CIE and latex agglutination test of the CSF to test for bacterial antigens, PCR for herpes simplex virus encephalitis has supplanted the need for brain biopsy. The latter may however be negative if treatment with acyclovir has been initiated.
Several opportunistic infections may cause chronic meningitis resulting in chronic headache: cryptococcal, TB, syphilis, toxoplasmosis, PMFLE, candida, CMV and HSE.
Viral meningitis is characterized by predominantly lymphocytic pleocytosis with normal CSF glucose and small and variable increase in protein. An excpetion to this rule are viral infections with HSV-2, lymphocytic choriomeningitis (often also associated with 1000s of lymphocytes) and VZV, which may occassionally display CSF glucose levels between 25 and 40 mg/dl. The diagnosis of viral meningitis is finally based on complement fixation or ELISA techniques by showing a 4x increase in titer from acute to convalescent serum drawn at least with 10 days interval. In contrast, low CSF glucose levels are usually observed in TB (lymphocytic pleocytosis + cranial polyneuropathy + low CSF glucose + fever) and fungal meningitis (particularly in later stages of the disease), neoplastic disease (metastatic carcinoma, lymphoma, meningeal carcinomatosis)(lymphocytic pleocytosis + cranial polyneuropathy + normal or slightly decreased CSF glucose + afebrile) and sarcoidosis of the meninges. Mycoplasma infections, cat-scratch fever and Q fever may also result in aseptic meningitis. HIV meningitis may often be associated with cauda equina neuritis.
Aspergilosis meningitis: The lungs are the usual site of primary infection or alternatively direct extension from an area anatomically adjacent to the brain (paranasal sinuses). In most cases patients are neutropenic with underlying hematologic malignancy, intravenous drug users, HIV-1 infection, sarcoidosis, organ transplantation, diabetes mellitus, chronic hepatic failure and patients on corticosteroids. However some patients do not have any risk factor at all. Brain abscess is the most common clinical manifestation with stroke-like presentation. Headache, encephalopathy, fever and seizures may also occur. Meningeal irritation is rare. CSF is usually abnormal but nonspecific. Neuroimaging shows often signs of infarction which later develop into abscesses (often frontal or temporal and cerebellum). Biopsy is diagnostic. Any patient with cerebral infarct and risk factors for invasive aspergillosis should be suspected for aspergillosis.
Rhinocerebral mucormycosis: This fungal infection is one of the most acute, fulminant fungal infections known. Predisposing conditions are diabetes mellitus often in association with ketoacidosis, acidemia from profound systemic illness (sepsis, sever dehydration, chronic renal failure), hematologic malignancies, organ transplantation, injection drug use, and deferoxamine use. However < 5% of patients do not have any risk factor at all. Patients with rhinocerebral mucormycosis may initially present with ophthalmologic (diplopia, proptosis) or ENT manifestations. Cranial nerve abnormalities are common. Thrombosis is a striking feature of this infection hence focal neurologic deficits are very common suggesting far-advanced disease. Involvement of the carotid arteries is common in this infection. MRI may show sinus opacification, erosion of bone, cavernous sinus involvement, and obliteration of deep fascial planes. In intravenous drug users basal ganglia are the most common site of CNS disease (bilateral infarction). Biopsy is diagnostic. Treatment with intravenous amphotericin B is essential.
Drug-induced aseptic meningitis: The clinical presentation of drug-induced meningitis is similar to viral meningitis and can be caused by several classes of drugs either after oral or inthrathecal administration including: NSAIDs, antibiotics, antimitotic agents, intravenous immune globulin etc.
In any case of aseptic chronic persistent and recurrent meningitis TB, neoplastic disease, cryptococcal infection, HIV, Behçet disease, neurosyphilis, sarcoidosis or borreliosis should be considered.
Inflammatory disorders and headache: Vasculitis (occurring in PAN, SLE, Wegener granulomatosis, Behçet disease, Churg-Strauss syndrome, Sjögren syndrome and PACNS may present as subacute/chronic headache in addition to multiple strokes in different vascular territories, memory difficulties, behavioral changes, and CSF pleocytosis (aseptic meningitis).
Hyperviscosity syndrome: Patients with multiple myeloma may have headaches as a result from hyperviscosity syndrome.
Chronic daily headache
New daily persistent headache (NDPH): This form of chronic headache is characterized by rapid onset of persistent headache that continues on a daily basis. Although the headache can persist for a long time, the disorder is usually self-limiting.
Analgesic rebound headache: Agents commonly associated with rebound headache or barbiturates, caffeine containing-analgesics, opioids, and ergotamines. The clinical characteristics include: daily headaches in a patient with a primary headache disorder who uses immediate-relief medications frequently or in excessive quantities. The headache is often provoked by physical or intellectual effort and is accompanied by asthenia, nausea, restlessness and irritability. There is a clear drug-dependent rhythmicity with early morning headaches being commonest. Withdrawal symptoms develop when patients are taken off medication abruptly.
Chronic-tension type headache (CTTH): The prevalence of CTTH in the general population is around 2.3%. The diagnosis is based on the presence of pressing or tightening-like headache, mild to moderate with bilateral location not aggravated by physical activity and present for at least 15 days/month (180 days/year for more than 6 months) in the absence of any organic or structural cause of headache.
Transformed migraine (TM): The prevalence of CTTH in the general population is around 2.4%. Often the patient develops interparoxysmal tension-type headache leading to daily or near-daily headache. The diagnostic criteria consist of headache more than 15 days/month for more than 1 month, with an average duration of >4 hours/day with a history of distinct migraine attacks usually starting in 2nd or 3rd decades of life. Organic causes of headache needed to be excluded. Family history is generally present and response to antimigrainous therapy is preserved.
It is important to emphasize that 10% of patients with CDH have a syndrome of intracranial hypertension without papilledema but with increased CSF pressure and abnormalities on MRV consistent with CVT particularly of the transverse sinuses.
Hemicrania continua: This type of chronic headache is more common in female (2:1) and is characterized by continuous (for 1 month), strictly unilateral, headache is continuous (dull, pressure, throbbing) but fluctuating in intensity without disappearing completely. Severe bouts (stabbing, throbbing, pressure) occur. The associated symptoms of hemicrania continua can be divided into three categories: autonomic features (conjunctival injection, rhinorrhea, eyelid edema, ptosis, miosis, tearing, and sweating), stabbing sharp pain lasting shorter than 1 minute ("jabs and jolts") and has migrainous features (photophobia, phonophobia, nausea and disability). No precipitating mechanism can be identifies and no history of migraine is present. There is absolute response to indomethacin (on average 150 mg for 3 to 4 days).
Headache in the elderly
The prevalence of headache decreases with age. A large majority (66%) of headaches in the elderly are of the primary type.
Episodic Tension-type headache in elderly (ETTH): TTH constitutes about 43% of new onset headache cases over the age of 65. About 10% of TTH sufferers develop TTH after the age of 50. TTH can be classified as episodic or chronic (see criteria). The diagnosis is based on exclusion.
Migraine in elderly: The prevalence of new onset migraine after the age of 50 is less than 2%. Late-life migraine accompaniments (aura-like phenomenon) can be part of the migraine, however headache is associated in only 50% of cases or may be mild. Migraine needs to be differentiated from TIAs. The diagnostic work-up includes brain CT scan or MRI, MRA of the brain, carotid ultrasound, EEG, cardiac evaluation and biochemical and hematological studies. MRI may show white matter hyperintensities.
Cluster headache in elderly: Very rare after the age of 50. The rarity of this disorder should prompt a complete work up as for migraine.
Hypnic headache: Although rare, it occurs typical between the age of 40 and 80 (mean 63 year) and predominantly in female. The headache occurs only during sleep when the patient is awakened at a consistent time each night (frequency needs to be >15/month). The headache is mostly bilateral, frontotemporal or diffuse, throbbing or dull pain, and mild to severe in intensity, lasts between 15 minutes and 3 hours (average 1 hour) and can be associated with nausea. Hypnic headache is not associated with autonomic features. Often responsive to caffeine at bedtime. Other effective regimens include lithium. The diagnosis is based on exclusion of other forms of nocturnal headache in the elderly: drug withdrawal, migraine, cluster and chronic paroxysmal hemicrania, temporal arteritis, oxygen desaturation, pheochromocytoma, primary and secondary neoplasm, hydrocephalus, subdural hematoma and vascular lesions. The headache responds promptly to an evening dose of lithium carbonate 300 mg or verapamil 120 mg nocte.
Temporal arteritis: About 18 in 100,000 people older than 50 years develop temporal arteritis. In about half of the cases associated with polymyalgia rheumatica (morning aches and stiffness in back and proximal muscles in shoulder and hip joints), while only 15% of polymyalgia rheumatica patients have co-existing temporal arteritis. The sex ratio is 3:1 (F:M). The diagnostic criteria for TA are: age > 50, new onset of localized headache, temporal artery tenderness, or decrease pulse, ESR > 50 mm/h, positive histology. Three of these criteria suffice to satisfy the diagnosis (sensitivity 93.5% and specificity 91.2%). The diagnosis is based on clinical suspicion. However, sometimes the presentation can be very atypical e.g. like an “occipital neuralgia” with normal ESR, fever of unknown origin, cough (10%) or amaurosis fugax (12%), cognitive deficit (10%), mononeuritis multiplex (14%), weight loss, jaw claudication, malaise, myalgia, depression or scalp tenderness. The most relevant tests are ESR (normal in up to one third of patients), CRP (in combination with ESR specificity of 97%) and temporal artery biopsy (false negative can range from 5 – 44%). Other indirect diagnostic tests are plasma viscosity (same sensitivity and specificity as ESR), CBC (normochromic normocytic anemia), biochemical analysis (elevation alkaline phosphatase and aminotransferase), and decreased α2-globulin levels. 5% have associated hypothyroidism. Color duplex echography of the superficial temporal arteries can be useful. Pathologic evidence of temporal artery biopsy persists for up to two weeks after the start of corticosteroid treatment. In case of normal ESR with negative biopsy, contralateral biopsy could be considered. Prednisone gives headache relief within 24 hours. Wegener granulomatosis and Churg-Strauss syndrome may also have positive temporal artery biopsies. When temporal headache is associated with swelling of the temporalis muscle, eosinophilic fasciitis should be suspected. Eosinophilic cationic protein is elevated (normal range 2-16 μg/L) but peripheral eosinophil count may be normal.
Subdural and epidural hematoma: These forms of secondary headache should be suspected after head injury or in patients taking anticoagulants. Subdural hematoma is more common than epidural ones. After mild head injury, subdural hematoma occurs in about 1% of patients. Brain CT scan (in emergency setting) and/or preferably MRI (isodense hematoma) are mandatory in the diagnostic evaluation. Epidural hematoma are typically associated with skull fractures. Approximately 40% of patients with epidural hematoma lose consciousness at the time of impact, but recover for a "lucid" interval progressing to coma.
Postherpetic neuralgia: Occurs in 10 - 15% of patients with VZV infections, and even in over 40% of zoster patients older than 60 years. But the incidence increases dramatically with age (80% of those older than 80 years of age). Can present as Ramsay-Hunt syndrome (vesicles in auditory canal and facial nerve palsy). Occasionally pain without rash (zoster sine herpete) can occur. Oral famcyclovir 500 mg tid for 7 days decreases the duration of the postherpetic neuralgia.
Systemic disease: This includes a variety of disorders such as infections, acute hypertension, hypoxia, hypercapnea, hypercalcemia, severe anemia, hyponatremia and chronic renal failure.
Diseases of the cranium, neck, eyes, ears and nose: This includes cervicogenic headache, glaucoma, otitis, sinusitis and dental infections.
Headache associated with muscle rigidity: Sometimes observed in IPD.
Exertional headache: In patients with cardiac ischemia, exercise can occasionally induce headache which is relieved by rest.