Syndrome of transient headache and neurologic deficits with cerebrospi...

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Official reprint from UpToDate

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Syndrome of transient headache and neurologic deficits with cerebrospinal fluid
lymphocytosis (HaNDL)
Authors
Christine L Lay, MD, FRCPC
Christina Sun-Edelstein, MD

Section Editor
Jerry W Swanson, MD

Deputy Editor
John F Dashe, MD, PhD

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:
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.
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.
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].
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].
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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"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

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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
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/mm3 (range 10-760 cells/mm3) 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 mmH2O. 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/mm3.
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

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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.)
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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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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REFERENCES
1. Bartleson JD, Swanson JW, Whisnant JP. A migrainous syndrome with cerebrospinal fluid
pleocytosis. Neurology 1981; 31:1257.
2. Berg MJ, Williams LS. The transient syndrome of headache with neurologic deficits and CSF
lymphocytosis. Neurology 1995; 45:1648.
3. Morrison DG, Phuah HK, Reddy AT, et al. Ophthalmologic involvement in the syndrome of
headache, neurologic deficits, and cerebrospinal fluid lymphocytosis. Ophthalmology 2003;
110:115.
4. Day TJ, Knezevic W. Cerebrospinal-fluid abnormalities associated with migraine. Med J Aust
1984; 141:459.
5. Walter CT, Grogan WA. Migraine with tardy pleocytosis. Neurology 1986; 36:733.
6. Castels-van Daele M, Standaert L, Boel M, et al. Basilar migraine and viral meningitis. Lancet
1981; 1:1366.
7. Emond H, Schnorf H, Poloni C, et al. Syndrome of transient headache and neurological deficits
with CSF lymphocytosis (HaNDL) associated with recent human herpesvirus-6 infection.
Cephalalgia 2009; 29:487.
8. Gmez-Aranda F, Caadillas F, Mart-Mass JF, et al. Pseudomigraine with temporary
neurological symptoms and lymphocytic pleocytosis. A report of 50 cases. Brain 1997; 120 ( Pt
7):1105.
9. Caminero AB, Pareja JA, Arpa J, et al. Migrainous syndrome with CSF pleocytosis. SPECT
findings. Headache 1997; 37:511.
10. Fuentes B, Diez-Tejedor E, Frank A. Syndrome of headache with neurological deficits and CSF
lymphocytosis: a spreading depression mechanism? The role of SPECT. Headache 1998;
38:324.
11. Fuentes B, Diez Tejedor E, Pascual J, et al. Cerebral blood flow changes in pseudomigraine
with pleocytosis analyzed by single photon emission computed tomography. A spreading
depression mechanism? Cephalalgia 1998; 18:570.
12. Pettersen JA, Aviv RI, Black SE, et al. Global hemispheric CT hypoperfusion may differentiate
headache with associated neurological deficits and lymphocytosis from acute stroke. Stroke
2008; 39:492.
13. Yilmaz A, Kaleagasi H, Dogu O, et al. Abnormal MRI in a patient with 'headache with
neurological deficits and CSF lymphocytosis (HaNDL)'. Cephalalgia 2010; 30:615.

http://www.uptodate.com/contents/syndrome-of-transient-headache-and... 25/11/2014

Syndrome of transient headache and neurologic deficits with cerebrospi... Page 6 of 6

14. Kappler J, Mohr S, Steinmetz H. Cerebral vasomotor changes in the transient syndrome of
headache with neurologic deficits and CSF lymphocytosis (HaNDL). Headache 1997; 37:516.
15. Thie A, Fuhlendorf A, Spitzer K, Kunze K. Transcranial Doppler evaluation of common and
classic migraine. Part II. Ultrasonic features during attacks. Headache 1990; 30:209.
16. Totaro R, De Matteis G, Marini C, Prencipe M. Cerebral blood flow in migraine with aura: a
transcranial Doppler sonography study. Headache 1992; 32:446.
17. Fumal A, Vandenheede M, Coppola G, et al. The syndrome of transient headache with
neurological deficits and CSF lymphocytosis (HaNDL): electrophysiological findings suggesting
a migrainous pathophysiology. Cephalalgia 2005; 25:754.
18. Pascual J, Valle N. Pseudomigraine with lymphocytic pleocytosis. Curr Pain Headache Rep
2003; 7:224.
19. Chapman KM, Szczygielski BI, Toth C, et al. Pseudomigraine with lymphocytic pleocytosis: a
calcium channelopathy? Clinical description of 10 cases and genetic analysis of the familial
hemiplegic migraine gene CACNA1A. Headache 2003; 43:892.
20. Krtnc M, Kaya D, Zuliani L, et al. CACNA1H antibodies associated with headache with
neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL). Cephalalgia 2013; 33:123.
21. Filina T, Feja KN, Tolan RW Jr. An adolescent with pseudomigraine, transient headache,
neurological deficits, and lymphocytic pleocytosis (HaNDL Syndrome): case report and review of
the literature. Clin Pediatr (Phila) 2013; 52:496.
22. Parissis D, Ioannidis P, Balamoutsos G, Karacostas D. Confusional state in the syndrome of
HaNDL. Headache 2011; 51:1285.
23. Giorgetti A, Mariani G, Patruno GM, Romorini A. The transient syndrome of headache with
neurological deficits, cerebrospinal fluid pleocytosis and acute confusional state: a case report. J
Headache Pain 2005; 6:476.
24. Mateo I, Pinedo A, Gmez-Beldarrain M, Garca-Monc JC. [Acute confusional state secondary
to transient headache and neurological deficits with cerebrospinal fluid lymphocytosis].
Neurologia 2004; 19:763.
25. Headache Classification Committee of the International Headache Society (IHS). The
International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;
33:629.
26. Toth CC. Persistent cerebrospinal fluid abnormalities in the syndrome of headache, neurological
deficit, and cerebrospinal fluid lymphocytosis despite resolution of clinical symptomatology.
Headache 2002; 42:1038.
27. Gonalves D, Meireles J, Rocha R, et al. Syndrome of transient headache and neurologic
deficits with cerebrospinal fluid lymphocytosis (HaNDL): a pediatric case report. J Child Neurol
2013; 28:1661.
Topic 14114 Version 7.0

Disclosures
Disclosures: Christine L Lay, MD, FRCPC Speakers 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
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