Adult Onset Familial Hemiplegic Migraine

Vijay Rajput, MD, Eric D. Kramer, MD

From Cooper Hospital, University Medical Canter, UMDNJ, Robert Wood Johnson Medical School,Camden, NJ.

Address all correspondence to Dr. Eric D. Kramer, Cooper Hospital/Robert Wood Johnson University, 3Cooper Plaza, Suite 320, Camden, NJ 08103.

Accepted for publication January 29, 1995.

Familial hemiplegic migraine and its associated signs and symptoms have previously been welldescribed. The condition demonstrates autosomal dominant inheritance and has been recently assigned toa locus on chromosome 19. Previous reports of familial hemiplegic migraine have indicated thatexpression always occurs early in life. We describe a patient who presented with multiple episodes ofreversible hemiplegia followed by headache at the age of 75. Seven other family members were found tohave been affected in a similar manner. We believe this case represents a unique description of familialhemiplegic migraine presenting in later life.

Key words: familial hemiplegic migraine, adult onset

Abbreviations: FHM familial hemiplegic migraine; OTC ornithine transcarbamylase; MELAS mitochondrialencephalopathy, lactic acidosis, and stroke-like episodes; CADSIL cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy; MERRFmyoclonic epilepsy with ragged-red fibers; KSS Kearns-Sayre syndrome; IRSC idiopathicrecurring stupor-coma syndrome

(Headache 1995;35:423-427)

Familial hemiplegic migraine (FHM) is a rare, but well-described migraine variant.1 It is an inheritable conditionwith an autosomal dominant pattern. Expression in childhood or adolescence is the rule. Recently, FHM has beenlinked to a locus on chromosome 19.2 Familial hemiplegic migraine should be considered in the diagnosis ofreversible hemiplegia, especially in a young patient with a history of headache.

We describe a patient who presented with symptoms and signs of migraine at the age of 75 years, and apedigree showing seven other affected family members over four generations, each of whom had their onset ofsymptoms after 30 years of age (Figure). We believe that this is FHM presenting later in life. The clinicalmanifestations of this condition and the diagnostic difficulties that can arise are described. The current literature isreviewed.

CASE REPORT

An 80-year-old, right-handed, white woman with a past medical history of hypertension, hyperlipidemia, andcoronary artery disease presented because of somnolence, tremulous and dysarthric speech, and numbness of theleft face, hand, and leg. She had a left parietal pulsatile headache. The patient and her family described previoussimilar episodes that occurred in March 1989, November 1990, March 1993, January 1994, and June 1994. Shehad several previous exhaustive general medical and neurological evaluations. Her serum biochemical andhematologic profile with serum and urine toxicology screening and her chest x-ray, ECG, bilateral carotid Dopplerstudy, echocardiogram, Holter monitor, CT scan of the brain, and EEG did not disclose a cause for her "spells." Ona prior admission to another hospital, she was given a diagnosis of epilepsy and treated with phenytoin.

Her other medications included captopril, ranitidine, ibuprofen, aspirin, and acetaminophen.

The interview and physical examination revealed a mildly confused elderly woman. The neurologicexamination revealed moderate dysarthria and decreased sensation to pin, temperature, vibration, andposition over the left face, torso, and extremities. There were no other abnormalities found on theexamination.

Within 2 hours after presentation, the patient became short of breath and began using accessory musclesfor respiration. Shortly thereafter, she required mechanical ventilation and became unresponsive to deeppainful stimuli.

Not greater than 12 hours after being intubated, the patient improved and was extubated. The neurologicexamination revealed an awake, alert, and comfortable but concerned elderly woman. She was completelyoriented, with intact speech and language function.

She had a left hemianopsia and mild left hemiparesis with an increased biceps tendon reflex on the left.She had an extensor planter response on the left. The neurologic examination returned to normal withinanother 24 hours.

All laboratory examinations were within normal limits. Toxicology screens of the urine and serum werenegative. She had a normal EEG, ECG, chest x-ray, and CT scan of head as well as an echocardiogram andHolter monitor. No basilar artery dissection, thrombosis, or vasculitis were found on angiography. Thediagnostic possibility of hemiplegic migraine with late life onset was considered. Subsequently, when thefamily history became clear, the diagnosis was modified to FHM. She was discharged home on aspirin andpropranolol. Propranolol was not tolerated due to fatigue. She has been headache- and event-free sincestarting valproic acid 250 mg by mouth, twice per day.

COMMENTS

Since FHM was first described by Clarke in 1910, it has been reported in around 40 families.3 Thediagnosis of FHM has remained clinical due to the absence of a pathognomonic finding or diagnostic test.The diagnosis has been based on the detailed description of symptoms by the patient, an extensiveexamination, an appropriate clinical course, and the exclusion of other etiologies. Until recently, there hasbeen marked diagnostic variability between observers due to the lack of an explicit definition and precisecriteria for this disorder. The International Headache Society (IHS) has now categorized FHM as a subtype ofmigraine with aura.4 This classification was based upon the presence of hemiplegia as a silent feature ofaura, the autosomal dominant pattern of inheritance, and the rarity of the condition (Table 1).

Two forms of hemiplegic migraine have been identified-familial and sporadic. Familial hemiplegic migraineaccounts for 4% to 8% of cases of hemiplegic migraine. In hemiplegic migraine, motor impairment - eitherhemiplegia or hemiparesis - usually precedes but may follow the onset of headache. In most cases,symptoms such as paresthesias, aphasia, autoagnosia, visual disturbances, impaired vigilance, and evencoma have accompanied the clinical picture.5 The age of onset has varied from 5 to 30 years with apredominance during youth. Attacks were usually stereotyped throughout the patient's life, tending to occuron one side. Occasional prolonged and severe attacks have occurred which could be separated by manyyears. Attacks have occurred unaccompanied by headache, nausea, or vomiting and have been confusedwith transient ischemia attack or epilepsy.5 Prolonged neurological deficits have been noted to persist fordays.6 Confusion and coma have been an important aspect of the condi-

Table 1.-IHS Diagnostic Criteria of Familial Hemiplegic Migrainea. The aura includes some degree of hemiparesis and may be prolonged.b. At least one first degree relative has identical attacks.c. At least two attacks fulfilling d.d. At least three of the following four characteristics:

(I) One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction.(ii) At least one aura symptom develops gradually over more than 4 minutes or two or more symptoms occur insuccession.(iii) No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, accepted durationis proportionally increased.(iv) Headache follows aura with a free interval of less than 60 minutes. (It may also begin before orsimultaneously with the aura.)

e. At least one of the following:(I) History, physical, and neurological examination do not suggest any organic disorder.(ii) History and/or physical and/or neurological examinations do suggest such disorder, but it is ruled out byappropriate investigations.

tion. The diagnosis of FHM has been made when an appropriate pedigree of affected family members hasindicated an autosomal dominant pattern of inheritance.

Various combinations of neurological deficits have been described in association with FHM: retinitispigmentosa, sensorineural deafness, essential tremor, and disordered ocular smooth pursuit. Most frequenthas been a progressive cerebellar disturbance with dysarthria, horizontal nystagmus, and impaired limbcoordination. These deficits were permanent and not part of the aura.7,8

Meningeal irritation and pyrexia can occur, and patients frequently undergo lumbar puncture in theemergency department to evaluate for meningitis or subarachnoid hemorrhage. The pyrexia and meningealirritation results are thought to be due to disturbances in the microvascular circulation of the meningealvenous sinuses.9-11 Psychosis, aggressive behavior, and florid visual hallucinations have been described.5

Alcohol12 and minor head trauma,1 as well as cerebral angiography13 are well-established precipitatingtrigger factors.

There is no definite diagnostic test for migraine. It is essentially a clinical diagnosis. Thirty-threeangiograms were found to be normal in one series.14 Electroencephalograms (EEG) have shownpolyrhythmic delta (0-4 Hz) distributed either diffusely (largely predominating over the hemispherecontralateral to hemiplegia), or focally in one hemisphere.15 The CSF has been nonspecific with a sterilepleocytosis, modest elevations in protein, and normal glucose determinations.16

Transcranial doppler ultrasonography in FHM has demonstrated vasoconstriction of the proximal largecerebral vessels and also an involvement of the distal vascular bed. This also may occur in other forms ofmigraine.17 The cerebral hemodynamics in FHM has been studied using a xenon-133 inhalation technique.Findings indicated that cerebral perfusion was altered, but not necessarily decreased during attacks of FHM.There was evidence suggesting vasoconstriction of intracerebral arteries in some cases. Whether this wasdue to vasospasm, caused by focal edema affecting the blood vessel wall, or represented a secondaryphenomenon was unclear.18

In making the diagnosis of FHM in this case, more common causes of reversible hemiplegia and comahad to be excluded including brainstem TIA, cardiac arrhythmia, epilepsy, meningitis, encephalitis, cardiacarrhythmia with ischemia, hypoglycemia, hyperglycemic nonketotic state, hypocalcemia, hyponatremia orhypernatremia, renal and hepatic failure, hypercarbia, and drug intoxication. Uncommon diagnoses such aspartial ornithine transcarbamylase deficiency (OTC); mitochondrial myopathy with encephalopathy, lacticacidosis, and stroke-like episodes (MELAS); cerebral autosomal dominant arteriopathy (CADSIL), and arecently described entity termed idiopathic episodic stupor-coma syndrome were also excluded. Thepreviously described evaluation ruled out metabolic, structural, infectious, and toxic causes of reversiblehemiplegia with coma in our patient.

Ornithine transcarbamylase deficiency has been shown to cause reversible hemiplegia of coma in youngwomen. Symptoms usually occur in the first or second decades of life. Partial OTC deficiency can causesimilar problems in the third or fourth decade. Family studies in adult women who are invariably asymptomatichave shown partial OTC deficiency. Headaches have frequently been seen in adult carriers with OTCdeficiency after protein ingestion.19 Delirium, focal neurological deficits, ataxia, encephalopathy, coma, andprogressive mental and physical retardation are the more serious features of heterozygous OTCdeficiency.20 Ornithine transcarbamylase deficiency with symptoms first manifesting in adulthood must beincluded in the differential diagnosis of altered mental status in women. Measurement of plasma ammoniumis a simple but sensitive screen for OTC deficiency in the emergency setting in patients with unexplainedstupor or delirium. If the ammonium level is elevated, measurement of plasma amino acids, particularlycitrulline, followed by measurement of urine orotic acid will secure the correct diagnosis.19

MELAS is one of the three multisystem mitochondrial cytopathies. The other two are myoclonic epilepsywith ragged-red fibers (MERRF) and Kearns-Sayre syndrome (KSS).21 AS this patient had no myoclonicepisodes with myopathy or chronic progressive external ophthalmoplegia, MERRF was excluded. Criteria forthe diagnosis of MELAS include a stroke-like episode before the age of 40 years; encephalopathycharacterized by seizures, dementia, or both; and lactic acidosis, ragged-red fibers, or both.22 This diagnosisis almost always made prior to 15 years of age. The most common features of MELAS are episodicheadache, vomiting, mental retardation, and muscle weakness. Stroke-like episodes most commonly bringthe patient to medical attention. Increased lactate levels in serum and the CSF, focal low density areas in thecerebral cortex, and basal ganglion calcifications can be seen on CT scanning of the brain. These were notpresent in our patient. Some of the patients have respiratory enzyme complex 1 and 4 deficiency.23 A highlevel of concordance between the clinical diagnosis of MELAS and

tRNALeu(UUR) mutation have been identified.24 Concordance between MERRF and tRNALys mutationbetween KSS and mtDNA deletions also can be seen.

The autosomal dominant arteriopathy, CADSIL, (cerebral autosomal dominant arteriopathy withsubcortical infarcts and leukoencephalopathy) is characterized by recurrent small deep infarcts, subcorticaldementia, and leukoencephalopathy. It has been noticed that some patients also experienced recurrentattacks of severe headache with various aura symptoms including transient hemiplegia.25

In some CADSIL patients, neurologic episodes share similarities with the migrainous attacks observed inFHM. The CADSIL gene was recently mapped at chromosome 19q12. Linkage analysis for FHM is ongoingon chromosome 19 at this time. The multipoint linkage data suggest that loci responsible for the two diseasesreside within an interval of about 30 centimorgan on chromosome 19.26 Abnormal regulation or expressionof a common gene or gene product may be responsible for the vascular changes underlying the similarclinical manifestations of these entities. Further analysis of CADSIL and FHM families are needed todetermine the respective locations, and ultimately identify the specific anomalous protein involved.

Idiopathic recurring stupor-coma syndrome (IRSC) is a recently described entity presenting with recurringstuporous state. In one report, an autosomal dominant inheritance pattern was described. The patients hadcharacteristic ictal EEG patterns with diffuse fast (14 to 16 Hz) activity superimposed on a normal frequency,unreactive background.27 Plasma analysis during the attacks revealed an increase in a benzodiazepine-likeagent identified as endozepine-4. The stuporous episodes resolved after the administration of flumazenil, abenzodiazepine receptor antagonist. The authors suggested that IRSC might be due to an unexplainedincrease in the presence of this agent.28 The ictal EEG in our patient did not show this feature.

In this series, the eight patients presented with FHM in middle or later life (range 30 to 75 years). Avariability in the frequency of attacks was reported without a stereotyped clinical presentation of a consistentsided hemiplegia in each family member (Table 2). That there was variablity of the affected side was incontradistinction to prior reports.29 The occurrence of reversible hemiplegia demands an exhaustiveevaluation before migraine can be diagnosed. The treatment of FHM is the same as complicated migraine.The goal is to prevent the migrainous attack. The family has not consented to chromosomal testing so thatthe influence of potential abnormalities on chromosome 19 can not be determined. This is a uniquepresentation of FHM.

Table 2.-Clinical Data in Familial Hemiplegic MigraineFrequency of Side of

Pedigree Age Sex Age at Onset, y Headaches Attacks HemiplegiaI, 1 82@ M 78 Rare 2 Left

II, 2* 80 F 75 Frequent 5 Left,II, 3 82 F 78 Frequent 2 BilateralII, 4 78 F 78 Rare 3 BilateralIII, 5 51 M 41 Rare 12 LeftIll, 6 52 F 40 Frequent 4 BilateralIV, 7 30 M 29 Rare 2 LeftIV, 8 35 M 34 Rare 2 Right

@At death.*Index patient.

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