Refractory

Primary
Headache

11-13 ..59 . (13 .)

Diagnosis of headache
a great challenge
Believe it or not? Treatment of Diabetes, HT and DLP
is easier than treating HA

 A patients headache often causes a physician

to develops a headache (and frustration)

Outline
Primary vs. secondary headache
Significance of refractory primary
headache(RH)
Definition & Diagnosis strategy of RH
RH mimickers
Comorbidity hasnt to be ignored
True Primary RH
Conclusion

Diagnostic Alarms (Red flag signs)

Headache begins after 50 yrs. of age
Sudden onset
Accelerating pattern of headache*
Changing pattern of headache**
Headache with systemic illness
Headache which awakes a patient from
a sleep

Diagnostic Alarms (Red flag signs)

Focal neurological signs eg, hemiparesis,
hemi-anesthesia, asymmetrical deep
tendon reflexes and muscular tone
Signs of increased intracranial pressure
Meningeal irritation signs
Suspicious of secondary headache
after appropriate treatment

SNOOP

Adapted from Dodick, D. Seminar Neurol 2010;30:74-81

Warnings of secondary headache

When a secondary cause occurs :
-similar to common primary

headache disorders**
-pattern change: a significant increase in
the number and severity of attacks*
Continuum (Minneap Minn) 2012; 18(4): 783-95.

Warnings of secondary headache

secondary headache - a variation of
primary headache
(lesional vs. non-lesional HA)
pathologic lesion triggers the same
neurophysiologic mechanisms for the
pain in primary headache attacks.
J Headache Pain 2012; 13(4): 263-70.

Defining the
Refractory Primary Headache

Term of use
Chronic Daily Headache(CDH)
15 days a month, > 3 months

Chronic Migraine (CM)

Refractory Headache/
Migraine?

Migraine headache > 15, > 3 months, No medication overused

Transform Migraine (TM)

More frequent migraine over months to years
Less photo-/phonophobia, nausea/vomiting
Less headache severity
Tend to bilateral, and constant

Silberstein SD. Headache 1994;34:1-7

Olesen J et al. Cephalalgia 2006;26:742-746

Why a definition for RH/RM Is Necessary

Triage patients to appropriate levels of care.
IdentifyBestPractices.
Serve as the criteria for inclusion in studies of novel
pharmacological approaches.
Better characterize the disorder.
Identify risk factors for progression of migraine into the
refractory type.
Serve as a paradigm for treating physicians
Improve the understanding of the pathophysiology of
migraine

Born of RHSIS
2000: IHS formed
The Refractory Headache Special Interest Section of the American
Headache Society (RHSIS)

Schulman EA, et al. Refractory migraine 2010: 6

Schulman EA, et al. Headache 2009: 49(4):509-18

Refractory headache
Primary
Type of headache
Secondary

Type of therapy

Refractory
migraine
TTH
CH
Other primary headache
e.g.
Post traumatic headache
(PTH), intracranial hypo/
hypertension, MOH,
neuralgia

Refractory of acute therapy

Refractory of preventive therapy

True RM: Diagnostic strategy

(3)

(2)
Exclude chronic
headache other than
migraine

Chronic
daily
headache
(CDH)
Exclude
secondary CDH

(1)

Primary
CDH

Already modify
triggers/life style
modification

Chronic
migraine
(CM)

Failed adequate trials of

preventive medication
(3/4 drug classes) with
adequate dose & trial (2
months)

(4)
(5)

without
MOH

Significant
disability
(MIDAS > 11)

True Refractory migraine

Term of use

Pharmacologic
refractoriness

The Definition of RM
- Diagnosed migraine
- Still having headache even if they avoided trigger, and
modified life style
- No response to...
: 3/4 of preventive migraine drug class (beta-blocker, antidepressant, TCAs, CCB)
: NSAIDs, combined analgesics, triptans
- No Medication overused headache

Case example
A 45 years-old with history of episodic migraine
characterized by alternate side throbbing headache
with triggered by hot weather and associated with
photo-/phonophobia
6 months, the headache has become constant diffuse
and dull aching pain with photophobia, and nausea
without vomiting
The neurologist diagnosed as transform migraine

What would you like to do next?

Eye ground : papilledema both side

1. Headache attributed to idiopathic intracranial hypertension

2. Migraine without aura

RH mimics
Physician may mis-diagnose when refractory
headache has normal neuro-imaging and no
obvious neurological symptoms

Secondary headache with normal neuro-imaging

Secondary headache

Headache attributed to trauma or injury to the head and neck

Headache attributed to cranial or cervical vascular disorder

arteritis

cervical carotid or vertebral artery dissection

reversible vasoconstriction syndrome (RCVS)

Headache attributed to non-vascular intracranial disorder

idiopathic intracranial hypertension (IIH)

spontaneous intracranial hypotension (SIH)

non-infectious inflammatory disease

headache attributed to epileptic seizure

Secondary headache(cont)

Headache attributed to infection

meningitis, systemic infection

Headache attributed to a substance or its withdrawal

Headache attributed to disorder of homostasis

hypoxia/hypercapnia, aeroplane travel, sleep apnea headache, arterial

hypertension, hypothyroidism, fasting

Headache or facial pain attributed to disorder of the cranium, neck, eyes,

ears, nose, sinuses, teeth, mouth or other facial or cervical structure

cervicogenic headache, retropharyngeal tendinitis, craniocervical

dystonia

Temporomandibular disorder (TMD)

Headache attributed to psychiatric disorder

Primary headache: Great migraine mimicker !

Hemicrania continua (HC)
1. Persistent, strictly unilateral headache
2. + ipsilateral cranial autonomic symptoms (conjunctival
injection, lacrimation, nasal congestion, rhinorrhoea, forehead
and facial sweating, miosis, ptosis and/or eyelid oedema)
3. +/- restlessness or agitation
4. Absolutely sensitive to indomethacin.

Peres MFP et al. Cephalalgia 2006; 26, 917-919

Life style modification and avoid

trigger factors: how do you
advice your patients?

Baldacci F, Vedovello M, et al. Headache 2013

104 Migraine patients

Each patient was first asked to report
spontaneously any migraine trigger
then directed to make a selection from a list of the
most common triggers reported in the literature

72% of pts report at least 1 trigger, and 100% reported at least 1 trigger
after shown a specific list of triggers

Number of spontaneously identified triggers (%) vs number of total triggers

identified in migraine patients

Daily life
style

Daily
triggers

Daily
headache

Headache follow up form - with trigger identification

The mechanism of photophobia and light

trigger migraine
Photophobia and Light trigger headache

Migraines are correlated with higher

levels of nitrate-, nitrite-, and nitric
oxide-reducing oral microbes in the
American Gut Project Cohort
172 oral samples

Non-Migraine

Migraine

salivary nitrate-nitrite-nitric oxide pathway

Gonzalez A, et al. 2016. mSystems 1(5):e00105-16

Co morbidity hasnt to be ignored!

22 . .
5
dyspepsia and GERDs, insomnia,
rhinitis and asthma
- 2

20 /
-

MRI & MRA brain were NORMAL

medication:

- Naproxen 250 1x2,

- tramadol 1 tab prn 6 hrs,
- nortriptyline 10 1 hs
( all medicines had been used continuously for 2 mo )
---------------------------------------------------------
- Tramadol >> dizziness and nausea
switch to Ibuprofen + paracetamol each
1 tab every 6 hrs.
- Naproxen >> gastritis
switch to Meloxicam, omeprazole
(further Rx for 1.5 mo) > no achievement of Rx goal !

2nd MRI was done > Normal

Review Hx Chronic Daily Headache :CTTH
& Reassess Medication overuse headache (MOH)

Rx:
: Reassurance / detailed clarification of
symptoms and its pathogenic mechanism
: nortriptyline 10 1hs
# Clinical improve 50 %after long term use of TCA
( 1.5 mo)
Rx: nortriptyline 10 1 hs. Continue till 3 mo

Co-morbidity of Migraine

Cardiac
Mitral valve prolapse
Myocardial infarction
Patent foramen ovale
Immunologic
Allergies
Neurologic
Essential tremor
Positional vertigo
Seizure disorder

Psychologic
Anxiety disorder
Depression
Manic disorder
Panic disorder
Pulmonary
Asthma
Vascular
Hypertension
Stroke
Other
Fibromyalgia syndrome
Irritable bowel syndrome
Raynauds phenomenon

True RPH: true but difficult to manage

Refractory migraine
Refractory TTH
Refractory CH
Refractory other primary headache
Headache triggered by certain activity (sleep,
cough, exercise, sexual activity) - usually non-
refractory, and self limited
New daily persistent headache (NDPH)
Nummular headache - refractory

Case example
A woman with persistent headache for 3 years
She remember the onset of headache exactly
MRI + MRA brain - normal, complete
neurological exam, LP-normal
No headache progression, but still there
High disability
Not response to any medication

Headache diary

Refractory primary headache: NDPH

New daily persistent

headache (NDPH)

daily unremitting headache from onset without

precipitating factor or headache history

typical bilateral, continuous, and associated with photo/

phonophobia, N/V

most striking feature: spontaneous, rapid develop,

persistent from onset or within 3 days of onset

82% can identify exact day of onset

2 subtypes: self-limited form , refractory form

Rx: no medication work well

Rx of refractory primary headache

RPH type
Refractory migraine

Refractory CH

Treatment option
Combination, Other
preventive medication,
Inpatient infusion therapy,
Botulinum toxin injection,
ONS
DHE infusion therapy, ONS

Refractory TTH

Multimodal therapy

Refractory other primary

headache

Depended on specific type

of headache, limited data

True refractory migraine

Fail 3/4
preventive
therapies

(All also need

multimodal
therapy)

Try combination therapy

(OPD) headache intervention
- Botulinum toxin
- Nerve block +/- trigger point
injection
(Inpatient) Infusion therapy
(Inpatient) Neurostimulation

Botulinum toxin injecfon for

Chronic Migraine
Paradigm Injecfon Sites

155 U

Frontalis:
4 x 5 U

Procerus: 1 x 5 U

Temporalis:
8 x 5 U*
Occipitalis:
6 x 5 U*

Corrugator:
2 x 5 U

Cervical
paraspinals:
4 x 5 U

*Additional Units of BOTOX can be administered per physicians discretion.

Up to an additional two doses (2 x 5 Units).
Up to an additional 4 doses (4 x 5 Units).

Trapezius:
6 x 5 U*

PREEMPT 2 study result

PREEMPT 2 primary endpoint: mean change from baseline in

headache day frequency

New study showed 195 u > 155 u for CM with MOH

Dodick et al. Cephalalgia 2010; 30(7) 804814

Combination therapy

Parenteral Regimen
Dihydroergotamine (0.251 mg IV or IM, t.i.d.)
Diphenhydramine (2550 mg IV or IM, t.i.d.)
Various neuroleptics (e.g., chlorpromazine 2.510
mg IV, t.i.d.)
Ketorolac (10 mg IV, t.i.d.; 30 mg IM, t.i.d.)
Valproic acid (250750 mg IV, t.i.d.)
Magnesium sulfate (1 gram IV, b.i.d.)
Intravenous (IV) steroids
(LOS > 3 days; mean of
international centre = 13 day)

Occipital Nerve Stimulation: CCH, CRM

Occipital nerve stimulation

for the treatment of
intractable chronic migraine
headache: ONSTIM
feasibility study

ONSTIM study for CRM

Joel R Saper et al. Cephalalgia 2010 31(3) 271285

Conclusion

Why to set up a Dx. of RH

How to Dx
DDx from Mimickers
Therapy modalities (RH & comorbidity)
Preventable or not and how?

Diagnostic strategy
Exclude chronic
headache other than
migraine

Chronic
daily
headache
(CDH)
Exclude
secondary CDH

Primary
CDH

Already modify
triggers/life style
modification

Chronic
migraine
(CM)

without
MOH

Failed adequate trials of

preventive medication
(3/4 drug classes) with
adequate dose & trial (2
months)

Significant
disability
(MIDAS > 11

Refractory migraine

Treatments of RH: principles

Headache type-specific Rx.

-medication (adq. abortive & prophylaxis Rx)
-intervention: ONB - ONS, BTx injection
-neuro-modulation
Comorbidity: Do not be ignored!
Holistic and team-based approach
(Bio-psycho-social approach)

Bio-psycho-social model of
Primary headaches
Gene

Env. factors

CHANGES

Headache syndromes

co-morbidity

(Psych and systemic)

Thank you for your attention