This document discusses several types of complicated migraine syndromes including hemiplegic migraine, alternating hemiplegia of childhood, migraine with brainstem aura, retinal migraine, ophthalmoplegic migraine, and Alice in Wonderland syndrome. It provides details on symptoms, diagnostic criteria, potential causes or genetic factors, differential diagnoses, and treatment approaches for each type.

1. Complicated Migraine
ADE WIJAYA, MD
SEPTEMBER 2018

2. Outline:
 Hemiplegic Migraine
 Alternating Hemiplegia of Childhood
 Migraine with Brainstem Aura
 Retinal Migraine
 Ophthalmoplegic Migraine
 Alice in Wonderland Syndrome
 Acute Confusional Migraine

3. Hemiplegic
Migraine

4. Hemiplegic Migraine
 A form of migraine with aura that includes motor weakness
 Aura consists of fully reversible motor weakness and visual, sensory, and/or
speech/language symptoms
 “stroke-like”
 The onset of attacks is in the teen years and early twenties
 Beginning with a hemiparesis or motor deficit that precedes the headache and
may persist throughout the duration of the episode
 These neurologic disturbances may occasionally persist for days or weeks after the
conclusion of the headache phase
Davidoff RA: Clinical manifestations of migraine. In: Reinhardt RW, editor. Migraine: Manifestations, pathogenesis, and management. Philadelphia, PA: F.A. Davis Company; 1995; p. 60-6.
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013
Winner P, Rothner AD, Lewis DW: Migraine, migraine variants, and other primary headache syndromes. In: Headache in children and adolescents. Hamilton, Ontario: BC Decker Inc; 2001; p. 60.

5. Familial Hemiplegic Migraine
 Familial hemiplegic migraine (FHM) is an autosomal dominant form of migraine in
which at least one of the patient’s first or second-degree relatives has migraine
aura with motor weakness
 A distinct diagnosis of sporadic hemiplegic migraine (SHM) exists, which is
clinically the same as FHM, but lacks a family history. SHM cases often require
neuroimaging, lumbar puncture and/or additional tests to rule out other potential
causes
Davidoff RA: Clinical manifestations of migraine. In: Reinhardt RW, editor. Migraine: Manifestations, pathogenesis, and management. Philadelphia, PA: F.A. Davis Company; 1995; p. 60-6.
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013

6. Familial Hemiplegic Migraine Type 1
 FHM type 1 (FHM1) is due to a mutation of the CACNA1A gene in the
chromosome 19p32 region and accounts for approximately 50% of all FHM cases
 This missense mutation creates defective neuronal-gated calcium channels
(channelopathy)
 This mutation causes calcium channel opening at a more negative membrane
potential, lowering the channel activation threshold, and delaying its inactivation,
therefore creating cortical and subcortical hyper excitability
Kazemi H, Speckmann EJ, Gorji A: Familial hemiplegic migraine and spreading depression. Iran J Child Neurol 8:6-11, 2014
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013
Winner P, Rothner AD, Lewis DW: Migraine, migraine variants, and other primary headache syndromes. In: Headache in children and adolescents. Hamilton, Ontario: BC Decker Inc; 2001; p. 60.

7. Familial Hemiplegic Migraine Type
2
 FHM Type 2 (FHM2) is secondary to a
mutation on the ATP1A2 gene in the
chromosome 1q23 region, which codes for
a Na/K-ATPase
Familial Hemiplegic Migraine Type
3
 FHM type 3 (FHM3) presents with a
sodium channel defect secondary to
mutation on the SCN1A gene.
Both are associated with recurrent seizures
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013

8. Diagnosis & Treatment
 Diagnosis: MRI/MRA brain & EEG
 Treatment:
- NSAIDS and triptans as abortive therapy
- Verapamil as preventive and abortive therapy
- Other treatments: acetazolamide, intranasal ketamine, ergotamine
Snow V, Weiss K, Wall EM, Mottur-Pilson C, American Academy of Family Physicians, American College of Physicians-American Society of Internal Medicine: Pharmacologic management of acute attacks of migraine and prevention of migraine headache.
Ann Intern Med 137:840-849, 2002
Artto V, Nissila M, Wessman M, et al: Treatment of hemiplegic migraine with triptans. Eur J Neurol 14:1053-1056, 2007
Yu W, Horowitz SH: Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil. Neurology 60:120-121, 2003
Black DF: Sporadic and familial hemiplegic migraine: Diagnosis and treatment. Semin Neurol 26:208-216, 2006
Davidoff RA: Clinical manifestations of migraine. In: Reinhardt RW, editor. Migraine: Manifestations, pathogenesis, and management. Philadelphia, PA: F.A. Davis Company; 1995; p. 60-6.

9. Alternating
Hemiplegia of
Childhood

10. Alternating Hemiplegia of Childhood
 a rare, sporadic neurodevelopmental syndrome with an incidence of 1 in 1,000,000
children
 Recurrent bouts of intermittent, often migratory, alternating hemiplegic episodes
associated with other neurological features such as dystonia, choreoathetosis and
developmental delay
 Onset as early as 3-6 months of age
 The duration of the episodes varies and some may last up to three weeks
 Paroxysmal eye movements, such as nystagmus, are the most frequent and
earliest symptoms.
Sweney MT, Silver K, Gerard-Blanluet M, et al: Alternating hemiplegia of childhood: Early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123:e534-541, 2009
Tenney JR, Schapiro MB: Child neurology: Alternating hemiplegia of childhood. Neurology 74:e57-59, 2010

11. Alternating Hemiplegia of Childhood
 Environmental stress such as temperature extremes and odors, water exposure,
physical activity, lighting and food may be triggering factors, and neurologic
deficits can improve or resolve with sleep
 ATP1A3 mutation
 Associated with epilepsy and cognitive symptoms
Sweney MT, Silver K, Gerard-Blanluet M, et al: Alternating hemiplegia of childhood: Early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123:e534-541, 2009
Tenney JR, Schapiro MB: Child neurology: Alternating hemiplegia of childhood. Neurology 74:e57-59, 2010
Sweney MT, Newcomb TM, Swoboda KJ: The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapidonset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol 52:56-64, 2015
Wagener-Schimmel LJJC, Nicolai J: Child neurology: Benign nocturnal alternating hemiplegia of childhood. Neurology 79:e161-163, 2012
Panagiotakaki E, Gobbi G, Neville B, et al. Evidence of a non-progressive course of alternating hemiplegia of childhood: Study of a large cohort of children and adults. Brain 133:3598-3610, 2010

12. Diagnosis
 Metabolic screening to exclude mitochondrial disorders
 Neuroimaging to rule out stroke and/or vasculopathy
 CSF analysis for neurotransmitters, pterin metabolites and methyltetrahydrofolate
to exclude dopamine biosynthesis disorders
 EEG may be needed to diagnose epilepsy
Sweney MT, Silver K, Gerard-Blanluet M, et al: Alternating hemiplegia of childhood: Early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123:e534-541, 2009

13. Treatment
 Removing inciting triggers and facilitating sleep early on
 Benzodiazepines as abortive therapy
 Flunarizine as prophylactic therapy
Sweney MT, Silver K, Gerard-Blanluet M, et al: Alternating hemiplegia of childhood: Early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123:e534-541, 2009
Tenney JR, Schapiro MB: Child neurology: Alternating hemiplegia of childhood. Neurology 74:e57-59, 2010

14. Migraine with
Brainstem Aura

15. Migraine with Brainstem Aura
 ~ Basilar migraine, Bickerstaff migraine, and/or basilar artery migraine
 Aura symptoms for this disorder are specifically referable to the brainstem, and
are not ischemic in etiology
 This disorder is characterized by fully reversible speech/language, sensory or visual
auras that are not accompanied by retinal or motor symptoms and, by definition,
spread over five or more minutes, last from 5 to 60 minutes, and may be followed
by a headache within one hour
 There must be at least two of the following “brainstem” features present:
dysarthria, vertigo, tinnitus, hypoacusis, diplopia, ataxia, and decreased level of
consciousness
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013

16. Migraine with Brainstem Aura
 This disorder typically involves both the left and right visual fields and may begin
with unilateral or bilateral visual symptoms
 Visual symptoms are typically followed by bilateral paresthesias of arms and legs
and are frequently associated with a combination of the aforementioned
“brainstem” symptoms
 Seizures especially in pediatric population
 Migraine with brainstem aura typically presents in adolescence but may occur at
any age and affects both sexes
 3-19 % of all migraines
Blumenfeld AE, Victorio MC, Berenson FR. Complicated migraines. InSeminars in pediatric neurology 2016 Feb 1 (Vol. 23, No. 1, pp. 18-22). WB Saunders.

17. Differential Diagnosis
 Vertebral dissection or thrombosis
 TIA
 Arteriovenous malformations / cavernous angiomas
 Chiari malformations
 Platybasia
 Basilar impression
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013

18. Retinal Migraine

19. Retinal Migraine
 ~ Ophthalmic, ocular, or anterior visual pathway migraine
 A rare disorder that generally presents with scotoma or visual loss
 1 in 200 migraineurs
 At least two attacks of fully reversible monocular visual disturbance, with either
positive and/or negative visual phenomena. An associated migraine headache
occurs either during or within 60 minutes of onset of the visual phenomena, and
typically lasts for less than 30 minutes
 Normal ophtalmological examination between attacks
 Vascular risk factors need to be evaluated
International Headache Society: Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition (beta version) Cephalalgia 33:629-808, 2013
Troost T, Tomsak R: Opthalmoplegic migraine and retinal migraine. In: Olesen J, Tfelt-Hansen P, Welch K, editors. The headaches. New York: Raven Press; 1993; p. 421.
Carroll D: Retinal migraine. Headache 10:9-13, 1970
Corbett JJ: Neuro-ophthalmic complications of migraine and cluster headaches. Neurol Clin. 1:973-995, 1983

20. Differential Diagnosis
 Transient ischemic attack
 Retinal detachment
 Optic neuropathy
 Amaurosis Fugax (abrupt onset with narrowing retinal vessels)
 Migraine with visual aura (hemifield)
Corbett JJ: Neuro-ophthalmic complications of migraine and cluster headaches. Neurol Clin.1:973-995, 1983
Kline LB, Kelly CL: Ocular migraine in a patient with cluster headaches. Headache 20:253-257, 1980
Killer HE, Forrer A, Flammer J: Retinal vasospasm during an attack of migraine. Retina 23:253-254, 2003
Russell MB, Olesen J: A nosographic analysis of the migraine aura in a general population. Brain 119:355-361, 1996

21. Opthalmoplegic
Migraine

22. Ophtalmoplegic Migraine
 Is a rare condition, occurring in 0.7 of 1 million people and presents as headache
associated with unilateral partial or complete oculomotor palsy
 Cranial neuralgia; often identifiable 2nd cause
 Two attacks of migrainous headaches accompanied or followed by partial or
complete 3rd, 4th, 6th, or occasionally 5th cranial nerve palsies within 4 days of
headache that lack another identifiable etiology
 Onset: children < 10 years old of age, rare in infants
 ~ Tolosa-Hunt syndrome in adults
 Thought to be secondary to ischemic, compressive or inflammatory processes
Blumenfeld AE, Victorio MC, Berenson FR. Complicated migraines. InSeminars in pediatric neurology 2016 Feb 1 (Vol. 23, No. 1, pp. 18-22). WB Saunders.

23. Diagnosis and Treatment
 Diagnosis: MRI brain and orbits with and without contrast
 Treatment: corticosteroids
Ostergaard JR, Moller HU, Christensen T: Recurrent ophthalmoplegia in childhood: Diagnostic and etiologic considerations. Cephalalgia 16:276-279, 1996
Carlow TJ: Oculomotor ophthalmoplegic migraine: Is it really migraine? J Neuroophthalmol 22:215-221, 2002
Prats JM, Mateos B, Garaizar C: Resolution of MRI abnormalities of the oculomotor nerve in childhood ophthalmoplegic migraine. Cephalalgia 19:655-659, 1999
Wong V, Wong WC: Enhancement of oculomotor nerve: A diagnostic criterion for ophthalmoplegic migraine? Pediatr Neurol 17:70-73, 1997

24. Alice in
Wonderland
Syndrome

25. Alice in Wonderland Syndrome
 Altered body perceptions is cortical in nature and characterized by variations in
size and shape and distorted body images
 Patients often describe bizarre visual illusions, spatial distortions, micropsia,
macropsia, metamorphopsia, and teleopsia
 These strange experiences may precede or accompany the headache or may occur
without headache at all
 Not migraine specific and may occur in a variety of disorders including epilepsy,
drug intoxication, delirium of fever, cerebral lesion, schizophrenia, or hypnagogic
states
 The most common etiologies are migraine and Epstein-Barr viral infections
Davidoff RA: Clinical manifestations of migraine. In: Reinhardt RW, editor. Migraine: Manifestations, pathogenesis, and management. Philadelphia, PA: F.A. Davis Company; 1995; p. 60-6.
Winner P, Rothner AD, Lewis DW: Migraine, migraine variants, and other primary headache syndromes. In: Headache in children and adolescents. Hamilton, Ontario: BC Decker Inc; 2001; p. 60.
Todd J. The syndrome of alice in wonderland. Can Med Assoc J 73:701-704, 1955
Losada-Del Pozo R, Cantarin-Extremera V, Garcia-Penas JJ, et al: Characteristics and evolution of patients with alice in wonderland syndrome. Rev Neurol 53:641-648, 2011

26. Acute Confusional
Migraine

27. Acute Confusional Migraine
 A rare condition, first described by Gascon and Barlow
 Acute onset of confusion manifesting as agitation, memory deficit, disorientation,
increased alertness, dysarthria or perceptual disturbance
 Childhood and adolescence
 50 % have migraine attacks; family history
 Headache may occur prior to, during or after the confusional state, may last for
minutes to hours, usually resolves within 24 hours, and may be associated with
retrograde amnesia.
 During the confusional state, the neurological examination is otherwise normal. Mild
trauma appears to be a trigger.
 The pathophysiology is unclear
Blumenfeld AE, Victorio MC, Berenson FR. Complicated migraines. InSeminars in pediatric neurology 2016 Feb 1 (Vol. 23, No. 1, pp. 18-22). WB Saunders.

28. Diagnosis and Treatment
 The diagnosis requires exclusion of encephalitis, seizure, stroke, CNS vasculitis,
metabolic encephalopathy, toxic ingestion, or other causes of acute confusional
state
 During an episode, EEG often shows diffuse slowing and, occasionally, frontal
intermittent rhythmic delta activity (FIRDA)
 Neuroimaging and CSF findings are normal
 Prochlorperazine and intravenous valproate have been reported to be effective
treatments during the episodes.
 Valproate has also been shown to be effective as preventative treatment
Shaabat A: Confusional migraine in childhood. Pediatr Neurol 15:23-25, 1996
Avraham SB, Har-Gil M, Watemberg N:Acute confusional migraine in an adolescent: Response to intravenous valproate. Pediatrics 125:e956-959, 2010
Gantenbein AR, Riederer F, Mathys J, et al: Confusional migraine is an adult as well as a childhood disease. Cephalalgia 31:206-212, 2011
Pietrini V, Terzano MG, D'Andrea G, et al: Acute confusional migraine: Clinical and electroencephalographic aspects. Cephalalgia 7:29-37, 1987
Khatri R, Hershey AD, Wong B: Prochlorperazine--treatment for acute confusional migraine. Headache 49:477-480, 2009
Fujita M, Fujiwara J, Maki T, et al: The efficacy of sodium valproate and a MRA finding in confusional migraine. Brain Dev 29:178-181, 2007

29. Summary
 Complicated migraines present as variable neurological conditions, and must be
carefully differentiated from more serious CNS pathologies
 Careful diagnosis and appropriate treatments