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25-Year-Old Man With Recurring Headache and Confusion
FATTA B. NAHAB, MD*; GREGORY A. WORRELL, MD, PHD†; AND BRIAN G. WEINSHENKER, MD‡

A

25-year-old right-handed man was brought to our
emergency department because of confusion and
right arm and right leg weakness. Two days earlier, during
an evening meal, he developed a severe left-sided headache
that lasted several hours and forced him to bed; he was
afebrile and had no other neurologic symptoms. He had
“migraines” in the past that occurred only once a year. He
also had frequent, less severe headaches that were controlled with aspirin. He suspected that the current headache
was a migraine. On the evening of onset of the headache, he
was examined at his local emergency department; he was
afebrile and had no focal neurologic findings. Findings on a
computed tomographic (CT) scan without contrast were
normal. He was treated with ketorolac methamine, hydroxyzine, and sumatriptan and discharged.
The next morning, the patient’s headache had not resolved. His temperature was 38.6°C, and his physician
prescribed ceftriaxone. Throughout the rest of the day, his
headache did not improve. Family members noted that the
patient appeared “confused.” The next morning, 2 days
after onset of the headache, the patient’s family brought
him to our emergency department because of worsening
confusion, disorientation, and unsteadiness when walking.
A general examination revealed an athletic man in no
acute distress. He was afebrile, and vital signs were normal.
He was drowsy and inattentive; neglect of his right
hemispace was apparent. He had nonfluent aphasia with
poor naming and repetition and followed only simple 1step commands. The patient was able to move all 4 extremities spontaneously, although he moved his right arm
and leg less than his left arm and leg. A pronation drift of
the outstretched right upper extremity was evident. Reflexes were symmetrical, and the plantar responses were
flexor. No nuchal rigidity was noted. A complete blood cell
count was unremarkable, and no leukocytosis was present.

1. Which one of the following diagnoses is most likely in
this patient?
a. Encephalitis
b. Subarachnoid hemorrhage (SAH)
c. Meningitis
d. Migraine with prolonged aura
e. Seizure
Headache, altered level of consciousness, and confusion
are consistent with each of these diagnoses. Encephalitis,
specifically herpes simplex encephalitis, seems most likely
considering the sequence: headache followed by fever and
confusion accompanied by focal neurologic findings.
However, our patient did not have a fever at the earliest
presentation, and 92% of patients with confirmed herpes
encephalitis have fever on presentation.1
Subarachnoid hemorrhage usually presents with a sudden, severe “thunderclap” headache, often accompanied by
vomiting, altered consciousness, and focal neurologic deficits. Our patient had some of these symptoms, but the
temporal course of the headache, which developed over
several hours, makes SAH less likely. Furthermore, no
meningism was evident. The normal findings on a CT scan
make SAH less likely. The sensitivity and specificity of a
CT scan without contrast for SAH are high,2 approximately
93% for patients seen within the first day of onset of the
headache. This high sensitivity decreases to 50% after day
5 and to zero by day 10. A cerebrospinal fluid (CSF)
examination to search for xanthochromia, the breakdown
product of hemoglobin, is usually indicated to rule out
SAH when the index of suspicion is high and findings on a
CT scan are normal.
Meningitis, regardless of the cause, typically presents
with fever, headache, altered level of consciousness (less
common with aseptic viral meningitis), nuchal rigidity,
nausea, and vomiting. The absence of meningeal irritation
and the lack of persistent fever make this possibility less
likely. Furthermore, meningitis is associated with focal
neurologic findings in only 15% of patients. Therefore,
meningitis is unlikely but is possible.
Migraine with prolonged aura refers to a migraine
symptom complex accompanied by neurologic deficits that
persist for more than 1 hour but fewer than 7 days. Complicated, hemiplegic, ophthalmic, hemisensory, aphasic, basilar, and confusional migraine are all part of the migraine

*Visiting student from Loma Linda University School of Medicine,
Loma Linda, Calif.
†Resident in Neurology, Mayo Graduate School of Medicine, Mayo
Clinic, Rochester, Minn.
‡Adviser to student and resident and Consultant in Neurology, Mayo
Clinic, Rochester, Minn.
See end of article for correct answers to questions.
Individual reprints of this article are not available. Address correspondence to Brian G. Weinshenker, MD, Department of Neurology,
Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: weinb
@mayo.edu).
Mayo Clin Proc. 2001;76:75-78

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© 2001 Mayo Foundation for Medical Education and Research

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with aura category according to the current International
Headache Society classification system; however, some of
these disorders are clinically distinct, and the underlying
genetic basis has been established for others. A neurologic
deficit secondary to migraine is a diagnosis of exclusion.
The following entities should also be ruled out: head
trauma, vascular and nonvascular disorders, substance
withdrawal, noncephalic infection, metabolic disorder, and
disorders of the cranium, neck, eyes, nose, sinuses, teeth,
and mouth.3 Migraine would not explain the patient’s fever,
but the fever did not persist and was absent when he was
evaluated at our emergency department. At this point, migraine with prolonged aura should be kept in the differential diagnosis, although encephalitis seems more likely.
No tonic-clonic seizures were witnessed despite close
observation of the patient. While postictal confusion may
be associated with focal findings that mimic acute encephalopathy or encephalitis, this confusional state usually recedes over several hours. Possibly, this patient had nonconvulsive status epilepticus, but it is atypical for status
epilepticus to be preceded by headache.
On presentation to our emergency department, the patient was given intravenous acyclovir therapy because of
the possibility of herpes encephalitis. Computed tomography, lumbar puncture, and electroencephalography (EEG)
were performed. The CT scan suggested subtle effacement
of the sulci of the left cerebral hemisphere. Analysis of the
CSF revealed the following: opening pressure, 9 cm H2O
(reference ranges shown parenthetically) (8-20 cm H2O);
total nucleated cells, 1/mL (<5/mL); erythrocytes, 1/mL;
protein, 29 mg/dL (14-45 mg/dL); glucose, 76 mg/dL;
negative gram stain; and no xanthochromia. The EEG suggested diffuse left hemisphere dysfunction with delta frequency activity but no epileptiform discharges. The patient
was admitted to the hospital for further evaluation, which
included cranial magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) of the head and cervical vessels, and magnetic resonance venography (MRV).
The MRI scan (Figure 1) showed a diffuse high signal
throughout the left cerebral hemispheric gray matter, best
seen on the fluid attenuated inversion recovery images,
along with widening of the gyri and obliteration of the sulci
secondary to lateralized cerebral edema. Findings on MRA
and MRV were normal.
2. Based on the laboratory and neuroimaging findings,
which one of the following diagnoses is now most
likely in this patient?
a. Cerebral venous thrombosis (CVT)
b. Acute arterial infarct
c. Migraine with prolonged aura
d. Encephalitis
e. Mitochondrial encephalopathy

Mayo Clin Proc, January 2001, Vol 76

Often, a clue to the diagnosis of CVT is a hemorrhagic
infarct that does not pertain to a single arterial territory or an
elevated CSF opening pressure. Thus, CVT is unlikely in our
patient. Moreover, CVT is unlikely with normal findings on
MRV. In a patient with a unilateral headache and focal
neurologic deficit referable to the same hemisphere, a carotid or vertebral dissection leading to arterial infarction
should be considered. A major cerebral arterial infarction
can produce a similar picture on CT, with hemispheric
edema and obliteration of sulci as the earliest findings; however, the MRI appearances in our patient are atypical for an
arterial infarct in light of the wide extent of the cortical
changes without apparent involvement of the subcortical
white matter. The normal findings on MRA of the head and
neck vessels make arterial dissection unlikely. Furthermore,
although unilateral, the MRI changes do not pertain to the
territory of any single major vessel, as would be expected
with an embolic or thrombotic cerebral infarction.
Migraine with prolonged aura is a diagnosis of exclusion. Based on the normal findings on CSF analysis and
the subtle MRI abnormalities, this is the most likely diagnosis. Similar MRI findings have been reported in patients with migraine with aura.
The extensive involvement of the cortical ribbon over the
entire hemisphere is unusual in viral encephalitis. Herpes
simplex encephalitis is associated with focal MRI abnormalities, but these abnormalities are usually in the medial temporal
structures. The normal CSF results argue against encephalitis.
Mitochondrial encephalopathies are inherited disorders associated with mitochondrial dysfunction. Mitochondrial disorders are often associated with myopathy and lactic acidosis.
The imaging changes most commonly seen in the brain in
patients with MELAS (mitochondrial encephalopathy, lactic
acidosis, and stroke-like episodes) syndrome are multifocal
cerebral infarcts, rather than confluent signal changes involving the cortical ribbon of an entire hemisphere.
On further discussion with family members, we discovered that the patient had a history of recurrent events similar
to the current episode. At 1 year of age, he fell from a chair,
sustaining minor head trauma; a protracted course of emesis
required hospitalization for rehydration. At 9 years of age,
the patient was hit in the head by a ball; over the course of
several hours, he developed headache, nausea, vomiting, and
confusion. He was hospitalized for 1 week; during that time,
CSF analysis and head CT showed normal findings, but EEG
demonstrated diffuse left hemispheric delta activity, suggesting diffuse left hemisphere dysfunction. Over the course
of hospitalization, the patient’s symptoms resolved completely. At 10 years of age, the patient fell from a tree,
sustaining minor head trauma; a severe headache, nausea,
vomiting, and confusion developed. An EEG demonstrated
right hemispheric delta frequency activity.

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A detailed family history revealed that the patient’s
mother had migraine headaches. A maternal first cousin also
had recurrent headaches associated with transient aphasia
and motor neurologic deficits requiring hospitalization.
3. With the information obtained thus far, which one of
the following disorders is most likely in this patient?
a. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
b. MELAS
c. Familial hemiplegic migraine (FHM)
d. Antiphospholipid-antibody syndrome (APLAB)
e. Syndrome of headache, neurologic deficit, and CSF
lymphocytosis (HaNDL)
Recurrent migraine is common to CADASIL, MELAS,
FHM, HaNDL, and APLAB. The inherited disorders
CADASIL and MELAS are consistent with a family history
that could be explained by autosomal dominant or mitochondrial inheritance. However, the lack of a progressive neurologic decline in our patient argues against these 2 diseases. In
addition, the relatively subtle abnormalities on MRI are not
consistent with CADASIL or MELAS. In these conditions,
patients ultimately experience dementia. Patients with
CADASIL have substantial white matter abnormality on
MRI, an abnormality not present in our patient. Characterized by recurrent migraine and hemiplegia, FHM is a genetic
disorder, and often there is a strong family history. Results of
laboratory and imaging studies are relatively unremarkable,
although subtle imaging findings, as in our patient, have
been reported. Patients with FHM recover completely from
each episode. In our patient, FHM is the most likely diagnosis. His clinical presentation is typical for FHM, which has
an autosomal dominant inheritance pattern with variable
penetrance. Antiphospholipid-antibody syndrome, like
MELAS and CADASIL, should also be considered in the
differential diagnosis of migraine accompanied by stroke.
Our patient’s radiological findings were unlike those typically seen in patients with APLAB, which usually show
ischemic strokes. HaNDL, a migrainous syndrome with CSF
pleocytosis and focal neurologic deficits, has a benign
course.4 Our patient’s normal CSF results during a clinical
episode make this diagnosis unlikely.
Based on the patient’s family history and findings on
imaging and laboratory studies, FHM was diagnosed.
4. Which one of the following tests would help to confirm
the diagnosis made in this patient?
a. Muscle biopsy
b. Antiphospholipid antibodies
c. Skin biopsy
d. Temporal artery biopsy
e. Genetic mutation testing and linkage studies

Figure 1. Magnetic resonance fluid attenuated inversion recovery
image reveals hyperintensity (arrows) diffusely throughout the
cortical gray matter of the left hemisphere. Effacement of the
cortical sulci in the left hemisphere is due to edema.

A muscle biopsy would help to confirm a mitochondrial
encephalomyopathy such as MELAS, which might present
with recurrent migraine attacks and stroke. Antiphospholipid antibodies, including anticardiolipin antibodies, may be
found in systemic autoimmune disorders such as systemic
lupus erythematosus and can be associated with arterial and
venous strokes. A skin biopsy might be useful in the
diagnosis of CADASIL. A superficial temporal artery
biopsy may help to confirm an inflammatory vasculopathy.
Based on our patient’s symptom complex, the most likely
diagnosis is FHM. Direct mutation analysis or, if unrevealing,
genetic linkage studies are indicated to determine whether the
patient has inherited a causative mutation in either of the
known loci for FHM in chromosome 19p or 1q31.
The patient made steady improvement over the course
of hospitalization. He was discharged and had only a subtle
aphasia. At follow-up 2 weeks later, findings on examination were normal.
5. Which one of the following medications is least appropriate for this patient if he experiences a future attack?
a. Sumatriptan
b. Prochlorperazine
c. Nonsteroidal anti-inflammatory drugs
d. Verapamil
e. Acetazolamide

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Many options exist to treat acute migraine. Among the
most potent and specific agents are dihydroergotamine and
triptan drugs, the prototype of which is sumatriptan. The
use of serotonin agonists and ergot derivatives is contraindicated in the treatment of FHM since transient hemiplegia
and ischemic stroke are possible complications.5,6 Prochlorperazine, a dopamine antagonist with antiemetic
properties, and nonsteroidal anti-inflammatory drugs are
useful for early treatment of migraine. Long-term prophylactic treatment to reduce the frequency of migraine includes the use of calcium channel antagonists such as
verapamil. Some reports have also described patients with
specific CACNA1A gene mutations on chromosome 19
who responded to acetazolamide.7
DISCUSSION
First described by Clark8 in 1910 as recurrent motor paralysis in migraine, FHM was poorly understood until the past
decade. Genetic linkage analyses have clarified the pathogenesis of the disease and suggest that it is a calcium
channelopathy in a high proportion of cases.
Attacks typically begin in childhood and are frequently
precipitated by minor head trauma that leads to alterations
in consciousness, ranging from confusion to coma. Hemiparesis is frequently mild, and confusion or aphasia dominates the clinical picture. Recurrent encephalitis is commonly diagnosed. The focal features are a component of
the aura and last less than 1 hour to days or weeks before
complete resolution. Usually, no sequelae are permanent.
However, 20% to 40% of patients with the 19p calcium
channel mutation have progressive cerebellar atrophy.9
Because of the broad differential diagnosis of acute encephalopathy, FHM can be difficult to diagnose. When confusion punctuated by acute attacks of migraine dominates the
clinical picture, other entities to consider are MELAS,
CADASIL, and APLAB. This case shows how clinical and
radiological assessments, such as MRI with fluid attenuated
inversion recovery sequences, can distinguish among these
entities. Electroencephalography may also be useful in identifying lateralized hemispheric high-voltage, slow-wave activity, but this finding is nonspecific and can be seen in
various focal encephalitides. Several patients with FHM
have been studied with transcranial Doppler ultrasonography or angiography to assess cerebral blood flow both during
and after the headache phase and were found to have unstable cerebrovascular tone with wide rapid fluctuations in
cerebral blood flow. Whereas initial phases of vasodilatation
are likely responsible for the migrainous headache, vasoconstriction that leads to ischemia is responsible for the subsequent neurologic deficits.10,11
Once the diagnosis of FHM is established clinically, the
mutation status of the proband and other family members

Mayo Clin Proc, January 2001, Vol 76

can be assessed directly. Direct mutation testing can be
performed in a limited number of research institutions that
use allele-specific polymerase chain reaction and singlestrand conformational polymorphism analysis to screen for
common missense mutations.12 When no mutations are
found, linkage analysis may help to detect the responsible
locus if sufficient numbers of affected and unaffected persons in the pedigree are identified and agree to participate.
Mutations in chromosomes 1 and 19 have been described
in affected families with 50% of pedigrees linked to a
chromosome 19p13 locus encoding the CACNL1A4 gene, a
neuronal voltage-gated calcium channel α subunit. Several
causative mutations have been identified in different families. Major deletions, missense mutations, and trinucleotide
repeats in this gene cause episodic ataxia type 2, FHM, and
spinocerebellar ataxia type 6, respectively.9 In our patient,
direct mutation testing for 5 specific mutations and singlestrand conformational polymorphism analysis of 2 other
exons failed to reveal a mutation in selected exons of the
CACNL1A4 gene. The number of affected and unaffected
persons available for linkage analysis was insufficient.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

11.
12.

Whitley RJ. Herpes simplex virus. In: Scheld WM, Whitley RJ,
Durack DT, eds. Infections of the Central Nervous System. 2nd ed.
Philadelphia, Pa: Lippincott-Raven Publishers; 1997:73-89.
Sames TA, Storrow AB, Finkelstein JA, Magoon MR. Sensitivity
of new-generation computed tomography in subarachnoid hemorrhage. Acad Emerg Med. 1996;3:16-20.
Olesen J, Lipton RB. Migraine classification and diagnosis: International Headache Society criteria. Neurology. 1994;44(6, suppl
4):S6-S10.
Bartleson JD, Swanson JW, Whisnant JP. A migrainous syndrome
with cerebrospinal fluid pleocytosis. Neurology. 1981;31:12571262.
Luman W, Gray RS. Adverse reactions associated with sumatriptan
[letter]. Lancet. 1993;341:1091-1092.
Rose FC. Adverse reactions and sumatriptan [letter]. Lancet.
1993;341:1663-1664.
Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene
mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology. 1999;53:38-43.
Clark J. On recurrent motor paralysis in migraine. BMJ. 1910;1:
1534-1538.
Gardner K, Hoffman EP. Current status of genetic discoveries in
migraine: familial hemiplegic migraine and beyond. Curr Opin
Neurol. 1998;11:211-216.
Friberg L, Olsen TS, Roland PE, Lassen NA. Focal ischaemia
caused by instability of cerebrovascular tone during attacks of
hemiplegic migraine: a regional cerebral blood flow study. Brain.
1987;110(pt 4):917-934.
Pierelli F, Pauri F, Cupini LM, Fiermonte G, Rizzo PA. Transcranial Doppler sonography in familial hemiplegic migraine. Cephalalgia. 1991;11:29-31.
Ophoff RA, Terwindt GM, Vergouwe MN, Frants RR, Ferrari
MD, Dutch Migraine Genetics Research Group. Wolff Award
1997: involvement of a Ca2+ channel gene in familial hemiplegic
migraine and migraine with and without aura. Headache. 1997;
37:479-485.

Correct answers: 1. a, 2. c, 3. c, 4. e, 5. a

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