Veronica Hackethal MD

About 90% of headaches are thought to be primary, the most common of which is tension-type headache. Other primary headache disorders include migraine, trigeminal neuralgias, and other primary headache disorders like cold-stimulus headache, primary exercise headache, and external pressure headache.

Headache Classification Committee of the International Headache Society (IHS). 

The International Classification of Headache Disorders

The SNOOP algorithm has been proposed identify red flags that may differentiate secondary from primary headache. The letters in the algorithm stand for:

S: Systemic symptoms of disease
N: Neurologic symptoms
O: Onset recently or suddenly
O: Older age of onset
P: Pattern change from previous history, including progressive headache with loss of headache free days; precipitated by Valsalva maneuver; postural aggravation; papilledema

Dodick DW. 

The POUND acronym has been proposed to differentiate migraine from underlying intracranial pathology that may require neuroimaging, like tumors, abscesses, aneurysms, or hemorrhages. One study found that meeting 4 of the 5 criteria in the acronym yields a likelihood ratio of definite or possible migraine of 24.

Detsky ME, McDonald DR, Baerlocher MO, et al. 

Does this patient with headache have a migraine or need neuroimaging?

The International Classification of Headache Disorders-3 (ICHD-3) diagnostic criteria for migraine without aura includes the following:
• At least 5 attacks
• Attacks lasting 4 to 72 hours
• Headache with 2 or more of the following: unilateral pain, pulsating quality, moderate/severe pain intensity
• Aggravated by, or causing avoidance of, routine physical activities
• At least one of the following during an attack: nausea and/or vomiting OR photophobia/ phonophobia
• Not better explained by another ICHD-3 diagnosis

The IDMigraine test is a simple, three question screening test that can be used once secondary headache has been ruled out. The test includes three questions covering nausea, photophobia, and headache-related functional disability. A positive screen requires two out of three symptoms to be present. When tested in routine primary care, the IDMigraine showed a sensitivity of 81%, specificity of 75%, and positive predictive value of 93%.

Lipton RB, Dodick D, Sadovsky R, et al. A 

self-administered screener for migraine in primary care: The ID Migraine validation study

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What differentiates migraine from underlying intracranial pathology that may require neuroimaging, like tumors, abscesses, aneurysms, or hemorrhages? Test your skills with this 5-question quiz.

Probing Headaches: A Diagnostic Challenge Quiz

 that normalizing calcium levels inside cells with a compound called cyclopianoic acid (CPA) may be neuroprotective in animal models of Parkinson disease (PD), pointing to a possible therapeutic target for PD and similar neurodegenerative diseases.

A key finding of the study is that levels of calcium inside nerve cells seem to decrease early in PD, and then increase later in the course of the disease.

The study is the first to demonstrate dysregulation of calcium levels inside cells in PD. Results suggest that preventing this dysregulation and keeping calcium levels stable may treat early symptoms of PD and help prevent more disabling symptoms. Treating calcium dysregulation may also benefit patients in later stages of PD.

"Our study points towards the usefulness of treating patients throughout the whole course of the disease, as the calcium pump will otherwise continue to pump and thus contribute to the patient's symptoms. Perhaps the protection of nerve cells can also mean that the damage caused by Parkinson's disease in the brain does not develop as severely as it otherwise would," first author Cristine Betzer, PhD, of the brain research center DANDRITE at Aarhus University, Aarhus, Denmark, said in a press release.

The study also showed that calcium dysregulation appears to be accompanied by a gradual buildup of the protein Î±-synuclein in Lew body inclusions inside neurons, a hallmark of PD pathology. These aggregates can ultimately lead to neuronal damage and death.

The results are in line with recent research suggesting that brain levels of calcium may be lower than normal in patients with PD. These findings are supported by studies suggesting calcium channel antagonists may have a protective role in PD.  Dysregulation of calcium levels may also be involved in other neurodegenerative diseases, like Alzheimer disease and Huntington disease.

To investigate the underlying mechanisms, researchers conducted 

 experiments in three different types of cells, all of which serve as models for cell death which is dependent upon Î±-synuclein aggregation. These experiments showed that calcium levels inside hippocampal neurons decrease by about 20% early in PD, followed by a subsequent increase.

 studies showed that aggregated Î±-synuclein binds to and activates the calcium pump SERCA in the brain tissue of patients with multi-system atrophy and dementia with lewy bodies, but not in healthy controls.

Experiments in worm models showed that using a SERCA inhibitor called CPA normalizes the early reaction in which calcium initially decreases, as well as the later reaction in which calcium increases.

These experiments also showed that CPA protected dopaminergic neurons from death caused by Î±-synuclein aggregation, suggesting that CPA may have potential therapeutic applications.

“In our study, we treated the worms with an inhibitor against the calcium pump and then counted the nerve cells in the worms. And there were many cells left. Which is a sensational and encouraging result,” Dr. Betzer also said in the press release.

She emphasized that the results are not directly applicable to humans.  Further studies in mice and rats are planned. 

Still, the results may hold promise for treating PD in patients with calcium channel regulators that have already been developed for other uses. Already, a clinical study is looking at the calcium channel antagonist isradipine in patients with early PD. “It's possible that the knowledge which already exists about these medications can help us make progress quicker in this new area," Dr Betzer concluded.

• Scientists have shown that regulating calcium levels inside cells may be a possible therapy for PD

• Experiments in cell lines showed calcium levels inside cells initially decline then gradually increase over the course of PD

experiments showed that Î±-synuclein aggregates bind the calcium pump SERCA in diseased human brain cells

• Experiments in worms showed that the SERCA inhibitor CPA normalized calcium levels and protected neurons against Î±-synuclein aggregation-dependent cell death

1. Betzer C, Lassen LB, Olsen A, et al. EMBO Rep. 

Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation

 2018 Mar 29. pii: e44617. doi: 10.15252/embr.201744617. [Epub ahead of print].

Levels of calcium inside nerve cells seem to decrease early in PD, and then increase later on-a finding that stresses the importance of treatment throughout the entire course of the illness.

Normalizing Calcium Levels May Protect Against Neuron Death in PD

Hospitalizations for stroke decreased between 2004 and 2014, in both women and men on anticoagulants for atrial fibrillation (AF). But women still suffer from stroke at higher rates than men, according to a study 

“In this 10-year time period, the addition of female gender in commonly used risk-scoring algorithms and the introduction of DOACs into clinical practice are two important changes that were introduced for stroke prevention among patients with AF. Although a causal inference cannot be drawn, it may be reasonable to hypothesize that the decreasing trend in stroke hospitalizations among anticoagulated patients with AF noted in our analysis may have been at least in part due to these two practice changes,” wrote first author Ghanshyam Palamaner Subash Shantha, MBBS, MPH, of the University of Iowa (Iowa City, IA), and colleagues.

Research suggests that women with AF are at higher risk for stroke than men, even when anticoagulated on warfarin. To account for this risk discrepancy, female gender has been included in the CHA2DS2-VASc score for stroke risk stratification. In 2005, these newer risk scores began to be more widely used in practice. About the same time, direct acting oral anticoagulants (DOACs) became available.

To see whether these changes had an impact on gender differences in stroke burden, researchers undertook a large, nationally representative study. Using data from the Nationwide Inpatient Sample, the largest all-payer database of inpatient hospitalizations in the US, they evaluated gender differences in hospitalization for stroke among patients with AF between 2005 and 2014.

. Women with AF: 18,413,291 hospitalizations; 740,635 with stroke as primary diagnosis

. Men with AF: 18,035,866 hospitalizations; 595,730 with stroke as primary diagnosis

. Age-adjusted stroke hospitalizations significantly increased in both women and men (p

Women: 443 per million in 2005; 495 per million in 2014

Men: 351 per million in 2005; 453 per million in 2014

. Anticoagulation Rates: Significantly increased in both women and men (p

. Stroke hospitalizations involving anticoagulated patients with AF: Significantly decreased in women and men (p

Women: 411 per million in 2005; 347 per million in 2014

Men: 402 per million in 2005; 311 per million in 2014)

The authors noted that the study cohort showed a trend toward increasing comorbidities which are also stroke risk factors, which could explain why stroke hospitalizations increased over this time period. However, the underlying explanation remains unclear.

They also emphasized that women had much more stroke hospitalizations than men. Although the explanation remains unknown, they mentioned biological reasons, such as higher systemic inflammation and higher procoagulant markers in women vs men.  Also, anticoagulation rates may be lower in women. While some studies refute this, results from this study showed that the gender gap in stroke risk narrowed among patients with AF on anticoagulants.

“This alludes to the possibility that effective anticoagulation in women may attenuate the gender gap in stroke risk,” they stressed.

The authors mentioned several limitations, including lack of data on AF type, quality of anticoagulation, and stroke severity. Also, the study could not differentiate stroke precipitated by AF vs other causes, and could not evaluate recurrent strokes.

. Nationally representative study showed that stroke hospitalizations significantly increased in men and women between 2004 and 2015.

. Anticoagulation rates increased and stroke hospitalizations among anticoagulated patients decreased for both women and men over this time period

. Women still had much more stroke hospitalizations than men, but the gender gap narrowed among patients on anticoagulants

. Results suggested more effective anticoagulation among women may help close the gender gap in stroke risk

1. Shantha GPS, Mentias A, Bhise V, et al. 

Gender Differences in the Trends of Hospitalizations for Acute Stroke Among Patients With Atrial Fibrillation in the United States: 2005 to 2014

Researchers evaluated gender differences in hospitalization for stroke among patients with atrial fibrillation. Key results and take-home points here.

Stroke Prevention Over the Last 10 Years: Gender Gap Still Needs Work

For a variety of reasons, the prevalence of stroke is higher in women than it is in men. Globally, the highest burden of stroke lies with women in low- and middle-income countries. A new study in Lancet looked at whether stroke outcomes varied in countries with more or less gender inequality.

1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990â2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117â171.2.Kim YD, Jung YH, Caso V, et al. Countries with women inequalities have higher stroke mortality. Int J Stroke. 2017;12:869-874.https://www.researchgate.net/publication/314026551_Countries_with_women_inequalities_have_higher_stroke_mortality

Veronica Hackethal MD

Articles

Probing Headaches: A Diagnostic Challenge Quiz

Normalizing Calcium Levels May Protect Against Neuron Death in PD

Stroke Prevention Over the Last 10 Years: Gender Gap Still Needs Work

Stroke Deaths and The Link with Gender Inequality