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Patients with mitochondrial disease experience a variety of headache types, including migraine. Other than pain, symptoms include nausea, sometimes severe vomiting (enough to cause dehydration), photophobia and phonophobia, and occasionally an aura. Patients may have lower trigger thresholds and require more aggressive treatment than routine headache-sufferers. Common triggering agents include excessive activity and exhaustion, dehydration or underhydration, and undernutrition with poor calorie intake, or any combination of the above. Patients with energy disorders are at risk for developing obstructive and central sleep apnea; each can reduce the quality of sleep, leaving patients with significant day-time fatigue and at risk for developing headaches.

Patients with mitochondrial disease may have significant autonomic dysfunction (Zelnik, 1996; Axelrod, 2006)including vascular dysautonomia characterized by tachy- and bradycardia, dizziness, and orthostatic changes in heart rate and blood pressure. Those factors that aggravate autonomic dysfunction can precipitate headaches and significant fatigue. Other signs of autonomic dysfunction include heat or cold intolerance, diminished sweating, spontaneous pallor/flushing/mottling without cause, or abnormal gut motility or bladder function. See AUTONOMIC DYSREGULATION.

Local infections (e.g., otitis or sinusitis) can cause headaches. Some patients have associated immune dysfunction which may predispose them to infections that cause headaches.

Complicated migraine can be associated with symptoms that include unilateral weakness, anisocoria, abnormal sensations, and/or confusion. These can mimic or be interpreted as stroke-like episodes. See ACUTE NEUROLOGIC DETERIORATION.


Mitochondrial Differential Diagnosis

1. Inadequate hydration

2. Inadequate calorie intake

3. Inadequate sleep

4. Autonomic dysfunction, specifically vascular dysautonomia

5. Infections (e.g., systemic, otitis, sinusitis)

6. Local effect (e.g., contact lenses)

7. Migraine as a complication of mitochondrial disease

Assessment and Recommendations:


  • Determine what symptoms are associated with the headaches and whether or not there are any trigger factors.
  • Have the patient/parents keep a headache diary noting onset, duration, severity, location, associated symptoms, and suspected triggers.

1. Inadequate hydration and calorie intake:

a. Determine the patient's hydration history and status.

b. Assess the patient's nutrition, specifically calorie intake.



1. If fluid or calorie intake is low, encourage fluids and/or calories. Remember that patients may tolerate only small amounts or volumes at one time. A trial of IV fluids might improve symptoms and support an autonomic etiology. See FEVER AND INFECTIONS.

2. Inadequate sleep:

a. What is the patient's best time of day... after waking up in the morning? If not, could there be an issue with obstructive sleep apnea? Ask about snoring or restlessness during sleep, morning exhaustion, or day-time napping.


1. If activity or exhaustion are trigger factors, encourage a schedule in which there are frequent resting periods and adequate sleep.

2. If the quality of sleep is a concern, a sleep study may be informative.

3. Autonomic dysfunction, specifically vascular dysautonomia:

a. Assess for autonomic dysfunction and those factors that can cause autonomic dysfunction: temperature dysregulation, abnormal (usually low) basal body temperature, heat and cold intolerance, abnormal sweating patterns, tachy- and bradycardia, dizziness, and bladder dysfunction.


1. Evaluate for vascular dysautonomia, and look for orthostatic changes in heart rate and blood pressure which can cause fatigue and dizziness.

2. If fluid or calorie intake is low, encourage fluids and/or calories. A trial of IV fluids might improve symptoms and support an autonomic etiology.


4. Infections (especially systemic, otitis, sinusitis):

a. History of recent infection or infectious symptoms?

b. Is there a history of recurring infections?


1. Assess for infection, including otitis and sinusitis.

2. CBC and WBC differential count, cultures, as appropriate.

3. Treat infections aggressively. See INFECTIONS.

5. Local effect (e.g., contact lenses):

a. Does the patient wear contact lenses?


1. The wearing of contact lenses may be associated with ocular migraine (_____).

6. Migraine as a complication of mitochondrial disease:

a. Is there a past or family history of migraine? Are episodes associated with headache or sensitivity to light or noise, or aura prior to symptoms?


1. If causes of migraine have been considered and treated without adequate benefit, consider treating the pain, or refer to a neurologist.

2. Riboflavin in high doses may be an effective anti-migraine agent (children - 5-10 mg/kg/day divided BID; adults - 200-300 mg BID) (Schoenen, 1988; Yee, 1999; Wyderski, 2002);


7. Management of pain:

a. Support for living with chronic pain include a psychologist or counselor, attention to pacing one's lifestyle, and establishing priorities for quality of life

b. Strategies for living with chronic pain include physical therapy, biofeedback, acupuncture, massage, physical therapy, and relaxation techniques



Axelrod FB, Chelimsky G, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics 2006;118:309-21.

Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1988;50(2):466.

Wyderski RJ. Treatment of migraine. New Engl J Med 2002;347(10):764.

Yee AJ. Effectiveness of high-dose riboflavin in migraine prophylaxis. Neurology 1999;52(2):431.

Zelnik N, Axelrod FB, Leschinsky E, et al. Mitochondrial encephalomyopathies presenting with features of autonomic and visceral dysfunction. Pediatr Neurol 1996;14:251-4.

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