syndrome of transient headache

Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

Authors Christine L Lay, MD, FRCPC Christina Sun-Edelstein, MD

Section Editor Jerry W Swanson, MD

Deputy Editor John F Dashe, MD, PhD

Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL)

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2014. | This topic last updated: Feb 19, 2014.

INTRODUCTION AND DEFINITION — The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited, benign entity that was first clearly characterized in 1981 [1], when it was called a migrainous syndrome with cerebrospinal fluid (CSF) pleocytosis. It was given its current name in 1995 [2], and has also been referred to as pseudomigraine with temporary neurologic symptoms and lymphocytic pleocytosis (PMP syndrome) [3]. As the name implies, HaNDL is characterized by one or more episodes of severe headache, transient neurologic deficits, and lymphocytic pleocytosis in the CSF.

ETIOLOGY — The precise etiology of HaNDL is not yet fully understood. Though some initially speculated that the syndrome represented a severe migraine [4,5], others favored an inflammatory or infectious origin, given the CSF lymphocytosis, frequent viral prodrome, and monophasic course [1,2]. However, despite extensive viral serological evaluation, there are few reports confirming a viral association. In one early case, echovirus 30 was isolated using cell tissue cultures from a patient with an illness resembling HaNDL [6]. In another case of HaNDL, serologic evidence of human herpesvirus 6 infection was detected by an elevated titer of IgM at presentation that gradually decreased to normal range by four weeks after admission [7].

Findings on single-photon emission computed tomography (SPECT), perfusion imaging with CT and MRI, transcranial Doppler, and electrophysiology studies of patients with HaNDL are suggestive of a migrainous pathophysiology:

Despite the findings suggestive of a migrainous pathophysiology, HaNDL is still thought to have a viral or inflammatory etiology. Most likely, a viral infection results in production of antibodies against neuronal or vascular antigens, inducing an aseptic leptomeningeal vasculitis and subsequently headache and neurologic deficits via a spreading depression-like mechanism [8,14,18]. (See

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SPECT studies have demonstrated focal or widespread areas of decreased blood flow on the side of origin of the neurologic deficits [8-11], suggestive of the spreading depression-like mechanism similar to that proposed for migraine.

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Head CT perfusion scan showed decreased and delayed perfusion involving an entire hemisphere in a patient with HaNDL [12], while MRI perfusion-weighted imaging showed focal parieto-occipital hypoperfusion involving another patient with HaNDL [13]. In both cases, areas of reduced perfusion correlated with the neurologic deficits.

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Transcranial Doppler in two patients showed asymmetrical fluctuations in middle cerebral arterial blood flow velocity and pulsatility, indicative of intracranial vasomotor changes [14], resembling those seen in patients with migraine [15,16].

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Abnormalities on single-fiber electromyography and visual evoked potentials in a 16-year-old girl with HaNDL were similar to those found in patients suffering from migraine with aura [17].

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"Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Cortical spreading depression'.)

Although the symptoms of HaNDL may resemble those of familial hemiplegic migraine (see "Hemiplegic migraine", section on 'Familial hemiplegic migraine'), a heteroduplex analysis and DNA sequencing of the CACNA1A gene associated with familial hemiplegic migraine type 1 failed to identify any CACNA1A mutations in eight patients with HaNDL, and therefore did not support a role of the CACNA1A gene in HaNDL [19]. However, one study found antibodies directed against the CACNA1H subunit of the T-type voltage gated calcium channel in 2 of 4 patients with HaNDL compared with none of 30 healthy controls and none of 80 controls with other neurologic conditions [20], lending some support to an inflammatory or autoimmune etiology.

EPIDEMIOLOGY — HaNDL is a rare condition that is most often seen during the third and fourth decades of life, though cases ranging from age 7 to 52 years have been reported [2,8,21]. Only a minority of patients had a prior history of migraine or family history of migraine [1,2,8]. A preceding viral illness that may include cough, rhinitis, diarrhea, or generalized fatigue has been reported in 25 to 40 percent of cases [2,8]. No consistent gender predominance has been found for HaNDL; in the two largest reports, men accounted for 44 and 68 percent of cases [2,8].

CLINICAL FEATURES AND DIAGNOSIS — HaNDL is characterized by transient episodes of severe headache and neurologic deficits associated with a lymphocytic pleocytosis in the CSF. The most frequent neurologic symptoms associated with HaNDL are hemiparesis, hemisensory disturbances, and aphasia. Visual signs and symptoms are less common, but may include decreased vision, homonymous hemianopsia, and photopsias [2,8]. Papilledema and sixth nerve palsy have also been described [3]. Although HaNDL is usually accompanied by focal deficits, occasional patients have had episodes with more diffuse manifestations such as an acute confusional state [5,22-24].

Some patients with HaNDL have an elevated CSF opening pressure as described below. (See 'Lumbar puncture' below.)

Neurologic symptoms generally last 15 to 120 minutes [1], though a range of five minutes to three days has been reported [8]. Although HaNDL is considered a monophasic disorder, most patients (approximately 75 percent) have repeated attacks of transient headache and neurologic deficits that occur for weeks or even months following the initial attack [2]. The neurologic deficits often vary from one episode to the next, involving different brain regions. In the two largest reports, the mean duration of the illness was 14 and 21 days [2,8].

The headache of HaNDL is moderate to severe, and is usually throbbing in quality. It may be unilateral or bilateral, and can last from one hour to one week, but typically lasts for hours. Often it is associated with nausea and vomiting, and not infrequently with photophobia. Fever was noted in 22 to 33 percent of cases [1,2,8]. Usually, the headache follows the onset of neurologic symptoms by 15 to 60 minutes, but on occasion the headache occurs first [1,2].

Diagnostic criteria — In the International Classification of Headache Disorders, 3d edition (ICHD-3), HaNDL is classified as a "Headache attributed to noninfectious inflammatory disease" [25]. The diagnostic criteria are:

A) Episodes of migraine-like headache fulfilling criteria B and C●

B) Both of the following:●

Accompanied or shortly preceded by the onset of at least one of the following transient neurologic deficits lasting >4 hours:

•

Hemiparesthesia-

Dysphasia-

Hemiparesis-



Differential diagnosis — HaNDL is a diagnosis of exclusion. Given the onset of severe headache and neurologic symptoms, especially in patients lacking a prior history of headache, an extensive work-up is usually prompted at presentation in order to exclude serious conditions such as stroke, other structural brain lesions, meningitis, and seizures. In particular, it is important to rule out treatable entities including Lyme borreliosis, neurosyphilis, human immunodeficiency virus meningitis, encephalitis, and vasculitis of the central nervous system. Thus, a complete evaluation should be obtained when HaNDL is suspected, including brain MRI, electroencephalogram, and angiography.

HaNDL can be distinguished from Mollaret meningitis (also known as recurrent benign lymphocytic meningitis) by the presence of neurologic deficits, the absence of meningismus, and the lack of Mollaret cells in the CSF. (See "Aseptic meningitis in adults", section on 'Recurrent (Mollaret's) meningitis'.)

HaNDL can be differentiated from familial or sporadic forms of hemiplegic migraine by the presence of CSF lymphocytic pleocytosis. (See "Hemiplegic migraine".)

Lumbar puncture — One of the defining features of HaNDL is a cerebrospinal fluid (CSF) lymphocytic pleocytosis [2,8]. In addition, the CSF opening pressure is often elevated and increased protein is common. In the largest series of 50 patients, the mean CSF nucleated cell count was 199 cells/mm (range 10-760 cells/mm ) with a lymphocytic predominance in all patients of >65 percent of

the total cell count, and a lymphocytic predominance in most patients of >90 percent in most patients [8]. The CSF protein was elevated in 48 patients (96 percent), with a mean protein of 94 mg/dL (range 20-250 mg/dL). In 18 cases where it was measured, the CSF opening pressure was elevated in 10 (56 percent) and ranged between 180 and 370 mmH O. The CSF glucose was normal in all 50

patients.

Although data are limited, it appears that the CSF abnormalities associated with HaNDL resolve slowly over several months. In a series of eight patients with HaNDL who had serial lumbar punctures during and after clinically symptomatic periods, the CSF findings of elevated white blood cell count and lymphocytosis gradually improved but persisted long after the resolution of clinical symptoms [26]. At an average follow-up of 99 days (range 56-196), all patients still had CSF lymphocytic pleocytosis, with CSF cell counts in the range of 25 to 67 cells/mm .

Bacterial, viral, and fungal studies from CSF and blood are negative in HaNDL [8].

There are few data regarding CSF IgG levels or oligoclonal bands. In the largest series of 50 patients, IgG was measured in 20, and was increased in 4 patients (20 percent) [8]. Oligoclonal bands were not found in 18 patients who were tested for them, including those with elevated CSF IgG levels.

Neuroimaging — Though normal neuroimaging is a criterion for this syndrome, nonspecific abnormalities are occasionally seen on routine head CT or conventional MRI, such as small areas of high signal unrelated to the clinical symptoms [2,5,8]. Brain MRI with gadolinium at admission in one patient with HaNDL revealed diffuse leptomeningeal enhancement that resolved on repeat imaging four weeks later [7]; another patient had mild leptomeningeal enhancement on MRI attributed to prior lumbar punctures [27]. In other case reports, CT or MRI perfusion techniques have demonstrated

Associated with cerebrospinal fluid (CSF) lymphocytic pleocytosis (>15 white cells/ml), with negative etiologic studies

•

C) Evidence of causation demonstrated by either or both of the following:●

Headache and transient neurologic deficits have developed or significantly worsened in temporal relation to the CSF lymphocytic pleocytosis, or led to its discovery

•

Headache and transient neurologic deficits have significantly improved in parallel with improvement in the CSF lymphocytic pleocytosis

•

D) Not better accounted for by another ICHD-3 diagnosis●

3 3

2

3



global hemispheric or focal regions of hypoperfusion that correlated with neurologic deficits in acutely symptomatic patients with HaNDL [12,13]. In at least one case, diffusion-weighted brain MRI was normal during an acute episode of HaNDL [13].

Initial neurovascular imaging for cases of suspected HaNDL should be obtained using MRA or CTA. In the majority of HaNDL cases, conventional cranial angiography is normal [2,8]. In one study of HaNDL with 12 patients who underwent angiography, the findings were normal in 11 patients [8]. The one abnormal angiogram showed irregularities suggestive of inflammation in the walls of small cranial arteries in the clinically symptomatic area. In several instances, attacks of HaNDL have been precipitated by angiography [1,2].

Given these data, conventional catheter angiography should be considered only in cases where CTA or MRA are normal and there is high suspicion for an alternative diagnosis to HaNDL. Conventional angiography remains the gold standard for diagnosing central nervous system vasculitis, an important differential diagnosis to consider when evaluating patients with headache and focal neurologic symptoms.

Electroencephalography — Electroencephalogram (EEG) done during the symptomatic period in HaNDL is usually abnormal. Unilateral excessive slowing corresponding to the clinical symptoms is often seen, with bilateral slowing occurring less frequently [1,2,8]. In the largest series with EEG obtained for 42 patients, clear EEG abnormalities were present in 30 (71 percent) [8]. The EEG changes disappear after the symptomatic period. Epileptiform abnormalities have not been reported.

MANAGEMENT — Given the self-limited nature of the HaNDL syndrome and the favorable outcome noted in reported patients, therapeutic interventions other than symptomatic treatment of the headache are largely unnecessary. However, education and reassurance about this disorder are important because of the likelihood of further alarming attacks involving transient headache and neurologic deficits that can occur for weeks or even months following the initial attack. These recurrences will almost require emergent evaluation. For patients with a secure diagnosis of HaNDL who present with a characteristic attack within three months of the initial attack, it may be reasonable to limit investigations to a head scan with CT or MRI for each attack and a lumbar puncture for the second attack, though not for subsequent attacks. In the authors’ clinical experience, these investigations are usually required to reassure the treating physician that the presentation is indeed HaNDL and not a coincident secondary etiology such as infarction or central nervous system infection. However, more extensive repeat testing will likely be needed when the diagnosis of HaNDL is not well-established.

SUMMARY AND RECOMMENDATIONS

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited condition. As the name implies, HaNDL is characterized by one or more episodes of severe headache, transient neurologic deficits, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). (See 'Introduction and definition' above.)

●

The precise etiology of HaNDL remains elusive. Despite the findings suggestive of a migrainous pathophysiology, HaNDL is still thought to have a viral or inflammatory etiology. (See 'Etiology' above.)

●

The most frequent neurologic symptoms associated with HaNDL are hemiparesis, hemisensory disturbances, and aphasia. The headache of HaNDL is moderate to severe, and usually throbbing in quality. Many patients have repeated episodes over the duration of the illness, which typically lasts for two to three weeks after onset, but may continue for up to three months. (See 'Clinical features and diagnosis' above and 'Diagnostic criteria' above.)

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Though HaNDL is a self-limited syndrome, a thorough evaluation should be performed to rule out more sinister etiologies. (See 'Differential diagnosis' above.)

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REFERENCES

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13.

One of the defining features of HaNDL is a CSF lymphocytic pleocytosis. In addition, the CSF opening pressure is often elevated and increased CSF protein is common. (See 'Lumbar puncture' above.)

●

Though normal neuroimaging is a criterion for HaNDL, nonspecific abnormalities are occasionally seen on routine head CT or conventional MRI. In the majority of cases, conventional cranial angiography is normal. (See 'Neuroimaging' above.)

●

Electroencephalography done during the symptomatic period in HaNDL is usually abnormal; unilateral slowing corresponding to the clinical symptoms is often seen. (See 'Electroencephalography' above.)

●

Once the diagnosis of HaNDL is established, treatment of the syndrome consists essentially of symptomatic headache management. For patients with a secure diagnosis of HaNDL who present with a characteristic attack within three months of the initial attack, it may be reasonable to limit investigations to a head scan with CT or MRI for each attack and a lumbar puncture for the second attack, though not for subsequent attacks. However, more extensive repeat testing will likely be needed when the diagnosis of HaNDL is not well-established. (See 'Management' above.)

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Disclosures: Christine L Lay, MD, FRCPC Speaker’s Bureau: Allergan [Migraine (Onobotulinum toxin]); Teva [Migraine (frovatriptan)]; Tribute [Migraine (Diclofenac K)]. Christina Sun-Edelstein, MD Speaker's Bureau: Pfizer (Migraine Management in Rural General Practice). Jerry W Swanson, MD Nothing to disclose. John F Dashe, MD, PhD Employee of UpToDate, Inc. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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27.

Topic 14114 Version 7.0

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