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Approach to headache management during COVID-19 pandemic

Juliette Preston, MDAss istant Professor of Neurology

OHSU Headache Center, Director10/03/2020

Overview

• Background/introduction to COVID-19

• Headaches as presenting symptoms

• Pathway to headaches

• Red flags for COVID-19 & headache

• Management of headaches during pandemic in non-COVID patients

• Headache medications and their risks during COVID-19

Background

• In 1912, German veterinarians may have had the first case of coronavirus: feverish cat with swollen belly.

• Chicken could get bronchitis, pigs, dogs and cats could get severe GI diseases.

• In 1960, researchers in the UK and US isolated 2 viruses identified in sick animals. Both had crown-like structure under microscope.

• In 1968, the term coronavirus was coined.

Cyranoski David.Profile of a killer virus. Nature.Vol 581:7 May 2020

Background

• Coronaviruses (CoVs) have an average diameter of 100 nm, and they are spherical or oval.

• They are enveloped, single-stranded RNA virus.• The SARS-related coronaviruses are covered by

spike proteins.• Spike proteins contain a variable receptor-binding

domain (RBD)– which binds to angiotensin converting enzyme-2 (ACE-

2) receptor – found in the heart, lungs, kidneys, and gastrointestinal

tract.

Zhao Y, Zhao Z, Wang Y et al (2020) Single-cell RNA expressionprofiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv, April 2020

Severe Acute Respiratory Syndrome

• SARS-CoV-2, along with SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) are among the seven known coronaviruses that can infect humans.

• The genetic similarity between SARS-CoV-2 and bat coronavirus is 96% while its genetic similarity with SARS-CoV is 79.5%.

Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P et al (2020)Genome composition and divergence of the novel coronavirus(2019-nCoV) originating in China. Cell Host Microbe27(3):325–328

Background• The novel coronavirus most likely originated from

bats and after mutating, it infected other animals and humans.

• Malayan pangolin is considered the intermediate host of SARS-CoV-2.

• Pangolins are the most trafficked mammals in the world.

• In China and Vietnam, pangolins are highly prized by consumers for their meat and their unique scales.

Cyranoski D. Did pangolins spread the China coronavirusto people? Nature 2020.

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Background

• SARS (Severe Acute Respiratory Syndrome)

– SARS coronavirus (SARS-CoV) – virus identified in 2003.

– Animal virus from an animal reservoir, perhaps bats, that spread to other animals (civet cats) and first infected humans in the Guangdong province of southern China in 2002.

– An epidemic of SARS affected 26 countries and resulted in more than 8000 cases in 2003.

https://www.who.int/ith/diseases/sars/en/

Civet cat, wikimedia commons

SARS

• Transmission of SARS-CoV was primarily from person to person.

• Transmission occurred mainly during the second week of illness, which corresponds to the peak of virus excretion in respiratory secretions and stool, and when cases with severe disease start to deteriorate clinically.

Severe Acute Respiratory Syndrome

• Symptoms were influenza-like and included fever, malaise, myalgia, headache, diarrhea, and shivering.

• No individual symptom or cluster of symptoms proved to be specific for a diagnosis of SARS.

• Although fever was the most frequently reported symptom, it was sometimes absent on initial measurement, especially in elderly and immunosuppressed patients.

https://www.who.int/ith/diseases/sars/en/

COVID-19

• In December 2019, the World Health Organization reported cases of pneumonia associated with a new coronavirus, SARS-CoV-2.

• By March 11, 2020, the World Health Organization declared the pandemic status.

Pandemic COVID-19

• The major clinical manifestations of the SARS-Cov-2 infection are due to pulmonary complications.

• Although most have mild symptoms, such as fever, headache, cough, dyspnea,myalgia, and anosmia.

• Other develop acute respiratory distress syndrome (ARDS) that can result in death.

Nath A. Neurologic complications of coronavirus infections. Neurology. 2020.

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Headache and COVID-19

• A meta-analysis inclusive of 61 studies (59,254 patients) reported that headache was present in 12%, representing the fifth clinical feature (after fever, cough, muscle pain and/or fatigue, dyspnea).

• Headache was also reported in the retrospective case series (214 hospitalized patients) from Wuhan with nearly exactly the same prevalence (13%).

Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel coronavirus infection (COVID-19) in humans: a scoping reviewand meta-analysis. J Clin Med. 2020;9(4).Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020.

However..

• A large, multicenter, prospective European study performed on 1,420 patients with mild to moderate COVID-19 reported a higher prevalence of headache(70.3%).– loss of smell (70.2%) – nasal obstruction(67.8%)– cough (63.2%)– Asthenia/lack of energy (63.3%)– myalgia (62.5%)– rhinorrhea (60.1%)– gustatory dysfunction (54.2%)– sore throat (52.9%)– Fever (45.4%)

Lechien JR, Chiesa-Estomba CM, Place S, et al. Clinical and epidemiological characteristics of 1,420 european patients with mild to-moderate coronavirus disease 2019. J Intern Med. 2020.

In healthcare workers

• Netherlands in March 2020, 803 healthcare workers were tested for COVID-10. 90 were positive.

• Most frequent symptoms reported in COVID positive patients: – headache (71%)

– general malaise (63%)

– muscle ache (63%)

– extreme tiredness (57%)

2 Clinical Cases: April 2020

• 38 yo woman with history of migraine with visual aura since age 8 presents with worsening of headaches.

• She used to experience 2-3 severe headaches per month but in the last month, headaches have been daily.

Case #1

• Headaches are described a retroorbital pain associated with nausea and light sensitivity.

• She feels “weak” all over, all of her muscles hurt.

• She barely has the energy to leave her bed.

• She has been on medical leave for the last 2 weeks.

• Her symptoms were preceded by diarrhea for a few days.

Case #1

• Workup done by her internist

– CT brain/CTA- negative

– ESR/CRP- wnl

– CBC/CMP, CK, TSH, ANA, RF, anti-CCP,RPR, HIV,UA-wnl

• Social history: married and works as ambulance driver.

• After the visit: COVID-19: positive

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Case #2: September 2020

• This is a 48 y.o. woman with HTN, HL, DM-2, OSA on CPA, asthma who presents to the Headache Clinic with daily headache.

• Initially, she reports stuffy nose, muscle aches and headaches.

• At first, she thought she had “bad allergies”. She noticed her “breathing was off”.

Case #2

• She called her PCP and reported feeling “short of breath” but denied chest tightness.

• She denied cough or fever.

• Her social history: she is single, lives with her teenage daughter and drives food delivery truck.

• Two days after calling her PCP she had a COVID-19 test which came back positive.

Case 2

• She returned to work after her second test was negative but headaches remained.

• She describes pain as “vise in the neck and around the temple”

• She denies any migraineous features (no light/sound sensitivity or nausea)

Case #2

• She uses Excedrin which helps for a few hours but pain keeps coming back.

• She is upset about her headaches as all of her other symptoms have resolved (dyspnea, nasal congestion and muscle aches).

Overview 2 cases with COVID-19

Case 1

• History of migraine

• Worsening of HA-migraine like

• Diarrhea first symptoms

• Extreme fatigue

• Front line worker

Case 2

• No history of migraine/headache

• New onset HA-tension like

• Dyspnea

• Myalgia

• Essential employee

Headaches have started to respondto Amitriptyline

Patient is not convinced she needsHeadache medications. She has beenseen by 2 other doctors so far.

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Pathway to headaches

• Hypoxia• Dehydration• Systemic inflammation

– Activation of inflammatory mediators:• cytokines• glutamate• NO system • Cyclooxgenase-2/Prostaglandin E2 system

• Metabolic disturbances• Fever• Direct effects of virus-target cells

Pathway to headaches

• SARS-CoV2 binds to angiotension-converting enzyme 2 (ACE2) receptors to enter cells.

• ACE2 receptors are found

– on alveolar epithelial cells

– intestinal enterocytes

– arterial and venous endothelial cells

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution,host–virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11:995-998.Manji H, Carr AS, Brownlee WJ, et al. Neurology in the time of COVID-19. J Neurol NeurosurgPsychiatry. 2020;91:568-570.

Pathway to headaches

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Pathway to headaches

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution,host–virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11:995-998.

• Presence of COVID-19 virus in blood-sluggish flow, facilitate interaction between spike protein and ACE2 receptor on capillary endothelium.

• Budding of viral particle from capillary endothelium can cause endothelial lining damage and allow for viral access to the brain (where it can bind glial cells/neurons).

• Another pathway may be through olfactory epithelium which also express ACE2 receptors. Entry can happy across the cribiform plate of the ethmoid bone.

Other Neurological symptoms?

• Meningitis/encephalitis

• Cerebrovascular disease: hypercoagulablestate, ischemic stroke, cerebral hemorrhage

• Myelitis/rhabdomyolysis

• ADEM(acute disseminated encephalomyelitis),

• Neuropathy including a post-infectious Guillain-Barre syndrome

Red flags to be aware of? Red flags in HA & COVID-19

Mean time between the onset of symptoms and the ED presentation was 8.8 (SD: 6.4) days.In 91/104 (87.5%) patients, the headache was present at the moment of emergency department visit.

Red flags Overview

• Headaches can be a presenting symptoms of COVID-19, generally alongside other symptoms (malaise/fatigue/muscle aches).

• Age older than 50, presence of fever/cough and elevated inflammatory markers are associated with more severe cases of COVID-19.

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Can Personal Protective Equipment cause

headaches?

158 healthcare workers were surveyed in Singapore

Can PPE cause headaches?

Can PPE cause headaches?

• Of the 158 respondents, 128 (81.0%) reported de novo PPE associated headaches.

• Headaches start within 60 minutes of donning either face mask with or without eyewear and resolved within 30 minutes of removing PPE.

• All respondents described the headaches as bilateral in location.

Can PPE cause headaches?

Can PPE cause headaches?

• More likely to develop novo PPE-associated headaches if:

– Pre-existing primary headache diagnosis (OR = 3.44, 95%; CI 1.14-10.32;P = .013)

– Worked in the emergency department (OR = 2.39, 95% CI 1.05-5.47; P = .019)

– Wore combined PPE more than 4 hours per day (OR 3.91, 95% CI 1.35-11.31;P = .012)

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Approach to HA patient

Pandemic

Evaluate risk factors/other symptoms- rule out COVID

PPE not culprit

How to proceed next?

Management during pandemic

• Change in practice: Telemedicine

– less patients contacts (less procedures/less urgent injections)

• Avoidance of Emergency department• Avoidance of hospitalization

Prolonged headache protocol: Pre- COVID

First line:

• Triptans- short acting/long acting, SC vs NS

• Over the counter analgesics

Second line :

• Diclofenac 50 mg /oral Ketorolac 20 mg bid x 3 days

• Or in-office IM Ketorolac 30 mg or 60 mg

• or in-office 25 mg IM Promethazine

Third line:

• Steroid: Medrol dose pack x 6 days or Dexamethasone 2 mg x 3 days

• Ergots- Migranal Nasal Spray (if not cost prohibitive)

• In-office Occipital nerve block

Prolonged headache protocol:

Pre- COVID

First line:

• Triptans

• OTC Analgesics

• Or previous protocol

Second line: Outpatient Infusion Center:

• IV Depakote 1000 mg

• IV Magnesium 2000 mg

• IV Normal Saline 1 L

• +/- IV 10 mg Compazine

Third line: Direct Admission to Neurology Service

• IV DHE 1 mg TID pre-treated with Reglan x 3 days

During pandemic: home treatment for prolonged

headaches

Home regimen: triptans/OTC

-Celexocib 100 mg BID

- Meloxicam 15 mg daily

- Nabumetone 500 mg BID

All for 5-7 days

Quietapine 25-50 mg qhs x 5-7 days

Olanzapine 5 mg qhsor BID x 3-5 days

- Prochlorperazine 10 mg TID or qhs x 3 days

-Promethazine 25-50 mg TID or qhs x 3 days

Valproic Acid 500-1000 mg qhs x 5

days (with confirmed contraceptive)

Methergine (ergots) 0.2 mg PO q6hrs x 3-

5 days

Frist line

Second LineThird line

If frequent calls to office..

Need for preventative agent?

Using abortive at home appropriately:

dose/onset

Frequency of headaches Diary

Yes, >2 HA/w or 4 severe per

month

Already on preventative agent

- Optimize dose

-May need to add another agent or change all together

Not on a preventative agent:

- Time to discuss one or at least

supplement/vitamins

Infrequent headaches

Counsel on lifestyle modification

-caffeine, water intake, regular exercise, regular

healthy meals, sleep hygiene, trigger awareness

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Preventatives and doses

Frist line treatment

• Topiramate 100-150 mg daily

• Sodium Valproate 500- 1500 mg daily

• Amitriptyline 30-75 mg daily

• Propranolol 80-240 mg daily

Second line treatment

• Venlafaxine ER 150-225 mg daily

• Lisinopril 10-40 mg daily

• Candesartan 16-32 mg daily

Third line agents

• Botulinum toxin injection

• CGRP monoclonal antibodies- trial should be at least 3-6 months

** these are not starting doses, but goal doses

COVID-19 and headache medications?

• “Doc should I continue my Lisinopril?”

• Lisinopril is ACE inhibitor

Blocking Angiotensin 1 Receptor may upregulate ACE2 receptors more point of entryfor the virus.

MaassenVanDenBrink et al. The Journal of Headache and Pain (2020) 21:38

Angiotensin II upregulate ADAM 17Which cleaves ACE2 receptor into Soluble ACE2 Virus can no longerEnter once attached to soluble ACE2.

MaassenVanDenBrink et al. The Journal of Headache and Pain (2020) 21:38

ARB/ ACE inhibitors are causing an increase in ACE2 R and a decrease in sACE2 R

However..

• Studies that reports such increase in ACE2 expression are done with high dose ACEi or ARBs or done after lung injury, nephrectomy or myocardial infarction.

• Finding in animal models are inconsistent.

• Human studies does not support increase in ACE2 expression.

• Additionally, upregulation of ACE2 may help with acute lung injury.

Krishna Sriram ,Paul A Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence. Clin Pharmacol Ther. 2020 May 10 : 10.1002.Hisashi Kai, Mamiko KaiInteractions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res. 2020 Apr 27 : 1–7.

For now

• Until further data are available, it is recommended that ARB and ACEI medications be continued for patients with CVD and migraine.

Krishna Sriram ,Paul A Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence. Clin Pharmacol Ther. 2020 May 10 : 10.1002.Hisashi Kai, Mamiko KaiInteractions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res. 2020 Apr 27 : 1–7.Kevin J. Clerkin et al. COVID-19 and Cardiovascular Disease. Circulation Volume 141, Issue 20, 19 May 2020;, Pages 1648-1655

What about NSAIDs and COVID-19?

• One study published in 2015 on diabetic rats showed upregulation of ACE2 receptor after high dose use of Ibuprofen (equivalent to 3000 mg per day in 70 kg adult ).

• One study published in 2006 showed Indomethacin decreased virus replication (> 1000 fold) of canine coronavirus in vitro.

• No conclusive evidence to stop using NSAIDs.

Qiao W et al. Ibuprofen attenuates cardiac fibrosis in streptozotocin induced diabetic rats. Cardiology. 2015 131(2):97–106Amici C, Di Caro A, Ciucci A, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021–1030.

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Conclusion

• Headaches can be a presenting symptoms of COVID-19.• Certain red flags (age, fever, cough) are associated with

more severe disease. • PPE can cause de-novo headache and worsen existing

headache.• Treatment of primary headache still focus on

“prevention” (medications/lifestyle). • Consider home treatment for prolonged headache and

avoid ED/infusion center/inpatient setting. • Reassure patients that it is still ok to use ACEi/ARB and

NSAIDs.

Thank you