Rare clinical findings in a patient with sporadic hemiplegic migraine: FDG-PET provides diminished brain metabolism at 10-year follow-up

Introduction

Sporadic hemiplegic migraine (SHM) is defined as migraine attacks associated with some degree of motor weakness during the aura phase and where no first-degree relative has identical attacks (1).

SHM has a wide inter- and intraindividual clinical spectrum and, in case of prolonged aura symptoms and disturbed consciousness, can mimic several other acute neurological diseases prompting emergent diagnostic work-up. We report the clinical findings and results of various diagnostic tests in a patient with SHM over a follow-up period of 10 years.

Case report

In 1996, during his wedding night, a 28-year-old man developed left face, arm and leg weakness, nausea and a throbbing headache (predominantly occipital, also bifrontal). Neurological examination on presentation revealed stupor, fever, meningism and left hemiplegia. There were no abnormalities on emergency magnetic resonance imaging (MRI) with gadolinium and magnetic resonance angiography (MRA) of the intracranial cerebral arteries. Lumbar puncture showed mild lymphocytic pleocytosis and slightly elevated protein. Meningoencephalitis was suspected and treatment with cefotaxime and acyclovir was started. On day 2, electroencephalography (EEG) showed diffuse slowing with high-amplitude theta/delta waves slightly pronounced over the right hemisphere. Transcranial Doppler (TCD) sonography showed increased flow velocity in the right middle cerebral artery. [99m Tc] hexamethyl-propyleneamine-oxime-single photon emission computed tomography (HMPAO-SPECT) was consistent with diffuse hyperemia in the right cerebral cortex.

When five days after admission there was complete neurological recovery and normalization of EEG and TCD findings, careful history-taking made clear that the patient suffered from hemiplegic migraine (HM). Subsequent genetic analysis revealed the T666M mutation in the CACNA1A gene of chromosome 19, which is associated with this calcium channelopathy. The parents and four siblings of the patient neither had a history of migraine attacks nor any of the known mutations in the same gene. He was diagnosed to have SHM.

His headaches had begun in his early teens and occurred, on average, every three months. Migraine attacks without aura were rare, approximately four out of five attacks were accompanied by aura symptoms. During most attacks, he developed photophobia and phonophobia and at least three aura symptoms—usually visual disturbances for 15–20 minutes consisting of bright white zigzag lines in the periphery of both visual fields, followed by unilateral sensorimotor symptoms affecting face and arm, or face, arm and leg with sensation of numbness and tingling and varying degrees of weakness particularly of the arm, sometimes accompanied by dysarthria and dysphasia with sometimes pronounced word-finding difficulties. During most attacks, aura symptoms lasted several hours to days. About once a year he had very prolonged aura symptoms, mostly sensory, outlasting the headache by more than a week. The headaches were described as pulsating, throbbing and steady in nature and mostly unilateral with preference for the left side. Headaches would start in the frontoorbital or temple region and spread to the entire hemicranium and neck. Some of these episodes were triggered by physical exertion, exposure to the sun, or mild head trauma. Similar episodes without headache but with reversible neurological deficits and sometimes prolonged disturbance of consciousness over several days had occurred earlier in childhood. At age 2 and at age 18 he was (mis?)diagnosed with meningoencephalitis. Both times he recovered without neurological residuae. At the age of 6 he was diagnosed with epilepsy. Unfortunately, the seizure semiology could not be extracted from old hospital letters. Although epileptic seizures had not been observed since childhood, treatment with carbamazepine (600–1200 mg/d) was continued over 22 years until admission to our hospital in 1996.

Since 1996 the patient has been repeatedly admitted to our hospital because of HM attacks. In 1998 he caused a car accident because hemiparesis, confusion and somnolence had evolved within a very short time. On another occasion he had marked gait ataxia lasting several days without concomitant headache or other neurological symptoms. For several years there has been interictal jerk nystagmus on horizontal gaze, but there are no other clinical or imaging signs of permanent cerebellar disease.

In 2005, at the end of another episode of HM, he for the first time developed an episode of paranoid psychosis. He displayed delusions of persecution believing that the doctors and nurses were enemy agents and hallucinating that there were agents in his room giving him instructions for counterspying. He responded well to calming down by talking and reassuring that he was in a friendly environment wishing him to get better and discharged from hospital as soon as possible. He only once received lorazepam 2.5 mg p.o. for sedation, but otherwise did not need additional medication. The psychiatric symptoms resolved within a week. Complex neuropsychiatric symptoms in patients with HM during or after migraine attacks are rare and have been published elsewhere (2).

In the course of the last 10 years extensive diagnostic testing has been carried out (Table 1). In summary, all perfusion SPECT and TCD studies performed in the first days of HM attacks were consistent with hyperemia of the hemisphere contralateral to the neurological signs. Standard T2- and T1-weighted images were normal at all stages. During attacks with prolonged aura, MRA of the large intracranial arteries was repeatedly unremarkable.

OPEN IN VIEWER

Table 1.

Clinical presentation and follow-up findings in the course of 10 years.

Year	Symptoms	HMPAO-SPECT (day 1–3)	TCD (day 2–4)	EEG day 2–4)	Brain MRI (day 1)	CSF (day 0–1)
1996	Hemiparesis (L), stupor, meningism	Hyperemia of right hemisphere	Velocity in right MCA ↑	Diffuse slowing R > L	Normal	Mild lymphocytic pleocytosis
August 1998	Hemiparesis (L), stupor, meningism	Hyperemia of right hemisphere	Velocity in right MCA ↑	Diffuse slowing R > L	Normal	Mild lymphocytic pleocytosis
September 1998	Hemiparesis (R), aphasia	n.p.	n.p.	n.p.	Normal	n.p.
2001	Hemiparesis (R), aphasia, somnolence, meningism	Hyperemia of left hemisphere	Velocity in left MCA ↑	Diffuse slowing L > R	n.p.	Normal
January 2004	Hemiparesis (R), aphasia, somnolence, meningism	Hyperemia of left hemisphere	Velocity in left MCA ↑	Diffuse slowing L > R	Normal (CCT)	Mild lymphocytic pleocytosis
March 2004	Gait ataxia	n.p.	Normal	n.p.	Normal	n.p.
2005	Hemiparesis (L), somnolence, anxiety, visual hallucinations	n.p.	Velocity in right MCA ↑	Diffuse slowing R > L	n.p.	n.p.

EEG in the first days repeatedly showed marked slowing especially in the hemisphere contralateral to the deficits.

[18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in January 2013 revealed a diffuse reduced glucose metabolism of the supratentorial cortex and a marked asymmetric hypometabolism of the left cerebellum (see Figure 1(a)). Those findings were new in comparison to the FDG-PET preexaminations (see Figure 1(b)). Methodically FDG-PET scans were obtained with a Philips Gemini GXL PET/CT. The patient fasted for a minimum of six hours before injection of FDG to ensure standardized metabolic conditions; 185 MBq of FDG was injected intravenously (i.v.). PET/CT images were acquired 30 minutes post-injection (three-dimensional (3D) acquisition). Technical PET/CT data are described in detail elsewhere (3). OPEN IN VIEWER

Interval therapy with metoprolol (95–190 mg/d, 1996–1998), propranolol (20–40 mg/d, 2001–2002) and verapamil (sporadically) has had no influence on the frequency of migraine attacks and was repeatedly complicated by dose limitations because of fatigue and orthostatic intolerance. He refused other treatments including acetazolamide. Today the patient takes no medication other than aspirin for treatment of attacks.

Discussion

Epilepsy was suspected in childhood and he subsequently was put on carbamazepine (CBZ) for 22 years. Unfortunately we do not know which clinical features had led to the diagnosis of epilepsy. Previous episodes of SHM in childhood may have been misdiagnosed as a feature of epilepsy. However, epileptic seizures (mostly generalized) occur in up to 7% of patients with familial forms of HM (4).

Otherwise, in only 8% of patients with SHM do aura symptoms last more than one day (5). The duration of non-HM aura may be longer than one hour in a significant proportion of migraineurs. It was proposed reinstating the category of prolonged aura for patients with symptoms longer than an hour and less than one week (6). On several occasions our patient had persistence of the neurological deficits for more than one week. Every time stroke could be ruled out with regard to the clinical and radiological findings, as there was always full neurological recovery and brain T2- and T1-weighted MRI were repeatedly normal.

At the end of one HM attack our patient displayed paranoid behavior with anxiety and visual hallucinations when the headache and the neurological deficits had already vanished. Recurrent episodes of acute psychosis have been reported in a family with HM. To the best of our knowledge our patient is the first patient with SHM reported to have had a psychotic episode with visual hallucinations at the end of a migraine attack.

There is limited experience on the management of HM. Therapeutic interventions are mainly based on the management of common types of migraine, both in the acute phase and with prophylactic management. In case of an association with ataxia/cerebellar dysfunction, acetazolamide might be effective. An excellent overview is given by Russell and Ducros (7).

Our patient was found to have a T666M mutation in the CACNA1A gene on chromosome 19p13. This mutation is quite a common finding in FHM (type 1). Otherwise, in a series of 27 patients with SHM only one patient had a T666M mutation (8). Patients with HM and a T666M mutation are thought to carry a higher risk of developing cerebellar symptoms and signs with cerebellar atrophy on MRI. Our patient has had interictal jerk nystagmus on horizontal gaze and recurrent episodes with paroxysmal gait ataxia, but MRI has not shown any cerebellar atrophy yet.

Imaging studies in patients with HM have brought conflicting results concerning the hemodynamic changes during attacks depending on the timing of the examination. Hypoperfusion as well as hyperperfusion have been reported in patients with familial HM (9).

Cerebral glucose metabolism investigated by FDG-PET showed rather normal findings in 2001 and 2006, according to observations of Freilinger et al. (10), whereas the same author also found left-sided cortical hypermetabolism in a different patient report (11). Kassab et al. found differences in resting brain glucose uptake in headache-free migraine patients relative to a control population—but located in white matter (12). Regional supratentorial cortical hypometabolism has also been described in familial HM (13). The finding of progressive cortical metabolic dysfunction over years—as presented by our patient—appears as a new finding. Glucose hypometabolism in regions of the affected hemisphere has been looked at as a possible explanation for a primary neuronal dysfunction as the cause of the prolonged deficits. There is evidence for altered synaptic transmission due to alteration of voltage gated calcium currents, which might result in prolonged blockage of synaptic transmission (14). As maintaining of synapses is a glucose-consuming process at least subtle changes over years might be caused by HM attacks. Even more impressive is the asymmetric cerebellar glucose metabolism in our patient. It has to be kept in mind that cerebellar signs are the most frequent manifestation associated with HM (7). Metabolic imaging by FDG-PET might precede changes being observable later by morphologic imaging such as MRI.

Clinical implications

The correct diagnosis of SHM can be challenging, as SHM has a wide inter- and intraindividual clinical spectrum.