The Secondary Headaches: Red Flags

 In many instances, headaches can be epiphenomena of secondary systemic and neurological aberrations that require urgent medical and sometimes surgical interventions. While diagnostic questions and clinical reasoning are the domain and prerogative of the neurologist, patients should make it a point to develop cursory competence in pattern recognition–especially in the context of their personal medical history–as to be able to parse out innocuous from more sinister and life-threatening conditions. The golden rule, as demonstrated by both empirical research and personal intuition, is an early intervention that, in most instances, will reduce both morbidity and mortality and decrease the likelihood of sustaining residual deficits.

              Several qualitative characteristics and symptom clusters should raise red flags when co-occurring with a headache. These are encapsulated by the acronym SNOOP: (1) systemic symptoms like weight loss or fever, or secondary risk factors like immunosuppression due to HIV and malignancy, (2) neurological focal signs like loss of visual acuity or eye pain, and fluctuating conscious awareness, (3) onset of a thunderclap headache, usually described by patients as the “worst headache of my life,” (4) older patient [+50yrs] with a new and progressively worsening headache, and (5) previous headache history: a headache with features and of a severity disproportionate to the headache types usually experienced by a particular individual. Etiologies that require urgent attention and management are discussed below.

              Hematogenous spread of bacteria, usually the streptococcus pneumonia or Neisseria meningitides strains, to the leptomeninges of the brain from remote sites like the ear canal or the sinuses causes bacterial meningitis. Sometimes an infection may be a consequence of neurosurgical operations or mechanical head trauma. Severe holo cephalic headaches are present in roughly 90% of clinical cases. When this headache type manifests in conjunction with a fever, neck stiffness, and other signs of meningismus like photophobia (sensitivity to light) and irritability, and focal neurological anomalies like retroorbital pain exacerbated by ocular movement, one would do well to suspect bacterial meningitis and present to the ED for emergency treatment with antibiotics [usually dexamethasone 10mg IV, before or with 1^st dose of ceftriaxone 2g IV bd or 4mg daily] until proven otherwise. Other phenomena corroborating a diagnosis would be the presence of headache exacerbations when the individual executes sudden movements, the presence of orthopedic inflexibility and an inability to extend a leg when it is flexed at the knee at a 90-degree angle [Kernig’s sign], and presence of involuntary hip and knee flexion when the neck is purposively flexed in the supine position [Brudzinski’s sign]. The latter two are powerful diagnostic markers for this condition when they co-occur, with a specificity of 95%.  

              Bacteria aren’t the only pathogens that cause meningitis; the condition may be spawned by viral agents, fungi, and tuberculosis. There is no pharmacological treatment for viral meningitis which is clinically indistinct from bacterial meningitis but caused by non-polio enteroviruses, herpes viruses, measles, influenza, and arboviruses. Even though early intercession in this disease process will not change the pathological trajectory or influence clinical outcomes, patients must still receive a lumbar puncture. In contradistinction to acute bacterial meningitis, fungal and tubercular meningitis are far more indolent in the course and tend to seethe and percolate for months or even years on end before symptoms balloon and come to the attention of a clinician. Fungal meningitis, sometimes referred to by medical professionals as “meningoencephalitis,” frequently occurs in older patients [+50 yrs] who are immunosuppressed or immunocompromised. The culprit microscopic pathogen is cryptococcus neoformans and its Australian cousin, cryptococcus gattii. Individuals with HIV infection or other malignancies, those who have had organ transplantation, and those who smoke are at a much higher risk of infection. Its hallmark clinical features and chronicity differ substantially from those seen in bacterial meningitis; foremost is a bland headache accompanied by mild alterations in mental status (i.e., increased lethargy and confusion) which progressively worsen as the fungus permeates and invades the meninges and cerebral real estate. The indolent albeit insidious course of fungal meningitis is very, very deceptive–if the mounting CSF pressure is not relieved through sequential lumber punctures/ventriculoperitoneal shunting and homeostasis is not reinstated via dissolution of the fungus mass with antifungal agents like amphotericin B and 5-flucytosine, the individual will become blind, deaf, and eventually die.

              Many viral infections of the CNS cause encephalitis, an inflammatory condition associated with profound and widespread changes in mental status and an acute to subacute evolution. It almost always requires hospitalization and comes hand in hand with a dismal prognosis. Evolving over hours to days, sporadic viral encephalitis is most often caused by the herpesviruses HSV-1 and HSV-2 and the arboviruses (dengue, zika) and infects the temporal limbic regions of the brain with catastrophic consequences. Save for headache which is present in 80% of cases, an encephalitic patient may manifest burning fever and go on to develop memory impairments, hypomania and changes in comportment, disorientation, focal neurological signs like hemiparesis, hemiplegia, and aphasia, focal or generalized seizures, and eventually fluctuations in arousal and loss of consciousness. Damage to the temporal lobes bilaterally may result in devastating residual neurocognitive deficits such as those seen in Kluver-Bucy syndrome where an individual appears inoculated against primary emotions like anger and aggression and abnormally saturated by hyperphagia (compulsive eating), hyperorality (putting things in one’s mouth), docility, and hypersexuality.  Unlike many other viral conditions, there is a treatment available–the antiviral agent acyclovir 10mg/kg IV tds–however efficacy in decreasing mortality and morbidity is strongly determined by the timing of administration. As a general rule of thumb, the earlier the better. 

              Of the secondary causes of headache, the most disconcerting presentation involves complaints of being assailed by excruciating focal head pain which begins instantaneously–literally out of the blue–and reaches peak intensity within seconds, quite like a clap of thunder. Often described as “the worst headache of my life,” the headache is qualitatively different from others the patient has experienced in the past, and the overwhelming intensity and excruciating pain inexplicably associated with it are appreciable in ubiquitous descriptions likening it to being thwacked on the head with a baseball bat or a rock. The focal pain may generalize and involve the neck and back, and signs of meningismus like photophobia, phonophobia, nausea, and vomiting may appear. While this symptom constellation may be caused by multiple vascular or traumatic processes, the most urgent and prognostically time sensitive is a subarachnoid hemorrhage (bleeding in the subarachnoid layer of the meninges of the brain) with or without infiltration of the parenchyma (brain tissue).  

Subsequent imaging of the vascular tree (through CTA or MRA) commonly identifies the rupture of an intracranial aneurysm or an arteriovenous malformation (an anomalous tangle of blood vessels connecting arteries and veins) as the fundamental cause. The former is far more calamitous than the latter, as a patient whose subarachnoid hemorrhage is due to a burst aneurysm will subsequently develop hydrocephalus (buildup of fluid in ventricles of the brain) and deteriorate quickly, with a significant number of patients dying before they reach the ER. Confirmation of a suspected case involves obtaining a non-contrast CT scan to scour for blood in the ventricles and basal cisterns. In more cryptic cases where CT is negative and minimal risk for brain herniation is identified, a lumbar puncture is performed looking for xanthochromia (yellowish tinge denoting existing blood product) in the CSF.  Because meningitis is always a plausible differential in the context of a thunderclap headache and more so when fever is present, CSF may also be scrutinized for elevated opening pressure, decreased glucose level, increased protein, and elevated white blood cells, with neutrophilic preponderance in the case of bacterial meningitis (neutrophils are the white blood cells that attack and kill bacteria).

              Per protocol CT scans that reveal acute blood in the subarachnoid cisterns–seen as a prominent hyperdense signal on the monochrome image–and hence corroborate a diagnosis of subarachnoid hemorrhage require cerebral angiography (CTA, MRA, or digital subtraction) by default to pinpoint the exact cause. An explicit vascular or traumatic etiology is inferred by clinical pattern and context and then prudently confirmed with the appropriate diagnostic test. To give an example, a unilateral headache experienced in concert with neck and face pain and focal neurological signs like miosis (constricted pupil), ptosis (drooping eyelid), and anhidrosis (paucity of sweating) following a serious automobile accident that involved colliding with the windshield is most likely the result of a carotid artery dissection at the cervical level. In this case, the headache would be ipsilateral to the dissection and the angiogram would substantiate this. A thunderclap headache in a pregnant or postpartum female could be due to absent or diminished flow in the cerebral sinuses, a condition called cerebral venous sinus thrombosis. Similarly, a paroxysmal headache amidst a transient sea of confusion, nausea and vomiting, photophobia, and seizures in a 45-year-old male who abuses illicit drugs like cocaine may be reversible cerebral vasoconstriction syndrome (RCVS), a subarachnoid hemorrhage mimic characterized by segmental vasoconstriction (narrowing) and vasodilation (widening) of cerebral arteries. This phenomenon is diagnostically silent and only visible on a CTA if it is performed during the vasoconstriction phase. Sometimes a thunderclap headache is idiopathic, meaning the cause is unknown and too minute to be detected by diagnostic imaging. This is called a primary thunderclap headache.

              While the mere mention of an intracranial tumor sends many people into a frenetic panic, they are quite rare. Space-occupying brain lesions evolve and save for headache, tend to manifest focal neurological signs like papilledema (optic disc swelling due to elevated intracranial pressure) and deficits like hemiparesis (motor weakness), hemianopia (blindness in half the visual field), or ataxia (loss of motor coordination) if eloquent areas of the cortex have been infiltrated. Optic disc swelling is a perturbing sign, and if present diagnostic MRI should be ordered to screen for a structural abnormality. More diffuse infiltrative lesions may signal their presence through global cognitive dysfunction and radical changes in comportment. Seizures tend to be the presenting symptom with a low-grade tumor following an indolent trajectory while headaches predominate when the underlying etiology is a higher-grade malignant and anaplastic one with a high infiltrative rate. Symptoms are commensurate with tumor type and the spatial locations they tend to invade, displace, and destroy; a vestibular schwannoma will cause hearing loss and tinnitus, a pituitary tumor may elicit bitemporal hemianopia (loss of the lateral aspect of the visual hemifield in both eyes), and an olfactory groove meningioma may spur the progressive loss of smell perception and discrimination, known as macrosomia. The majority of brain tumors are metastatic and not primary, having migrated from other areas like the lungs, breast, colon, and skin, and appear on a gadolinium-enhanced MRI as singular or multiple foci of ring-enhancing lesions. A new headache in a patient with a history of cancer is an ominous sign of metastasis.     

              Finally, we come to secondary headaches prevalent in the elderly demographic. A new bilateral or unilateral headache emanating from the temporal regions in an individual over 60yrs replete with focal scalp tenderness and jaw claudication should raise concern for giant cell arteritis, a disease that primarily involves inflammation of medium and large-sized arteries. Sometimes called temporal arteritis, it may involve malaise and fatigue and more than half will develop pain and joint stiffness, otherwise known as polymyalgia rheumatic. It heralds an ominous and insidious course and will cause monocular or binocular blindness [called amaurosis fugax] if not prudently identified and treated. The classic diagnostic hallmark is an elevated erythrocyte sedimentation rate (ESR) indicating inflammation in the body, with prescriptions of high-dose corticosteroids given to confirmed cases to preclude deterioration to permanent blindness.

The other red flag scenario is a diffuse and progressively worsening daily headache in an obese woman of childbearing age, suggesting idiopathic intracranial hypertension which as the name suggests denotes an elevated intracranial pressure of unknown origin. Pseudotumor cerebri is its other moniker, for the patent reason that symptoms will implicate a space-occupying lesion that subsequent diagnostic neuroimaging is unable to find. A vast majority of patients with this condition report that rapid changes in the spatial orientation of the physical body trigger visual obscurations. Diplopia and pulsatile tinnitus may also be omnipresent. Negative findings on structural neuroimaging and raised opening pressure on lumbar puncture substantiate the diagnosis. As with temporal arteritis, a medical professional will prioritize the preservation of vision, with milder cases treated with a prescription of acetazolamide, a carbonic anhydrase inhibitor, and more severe cases requiring urgent surgical intervention in the guise of optic nerve sheath fenestration or ventriculoperitoneal shunting. Both aim to relieve symptoms by reducing intracranial pressure.