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

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 cerebrospinal fluid (CSF) lymphocytosis, frequent viral prodrome, and monophasic course [1,2]. However, despite extensive viral serological evaluation, there are only few reports suggesting a viral association, including isolated cases linked to echovirus 30 [6], human herpesvirus 6 infection [7], and human herpesvirus 7 infection [8]; other isolated cases have been linked to Borrelia lusitaniae infection and Epstein-Barr virus in the CSF [9,10].

Findings on single-photon emission computed tomography (SPECT), perfusion imaging with computed tomography (CT) and magnetic resonance imaging (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 [11-14], suggestive of the spreading depression-like mechanism similar to that proposed for migraine.

●Head CT perfusion imaging and MRI perfusion techniques in several studies have demonstrated global hemispheric or focal regions of hypoperfusion correlating with neurologic deficits [15-19]. In one case report, a follow-up CT perfusion study 36 hours after resolution of the patient's neurological deficits showed full reversal of this hypoperfusion, supporting cortical spreading depression as an important mechanism in the pathophysiology of HaNDL [18].

●Transcranial Doppler in two patients showed asymmetrical fluctuations in middle cerebral arterial blood flow velocity and pulsatility, indicative of intracranial vasomotor changes [20], resembling those seen in patients with migraine [21,22].

●Abnormalities on single-fiber electromyography and visual evoked potentials in a 16-year-old patient with HaNDL were similar to those found in patients suffering from migraine with aura [23]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Cortical spreading depression'.)

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 [11,20,24]. One study comparing patients with HaNDL (n = 5) and matched controls (n = 30) found antibodies to DNA repair proteins in three of the five HaNDL sera but in none of the control sera, suggesting DNA damage and lending further support to an inflammatory etiology [25]. Another study reported two patients with HaNDL who had high neurofilament light chain (NFL) levels, indicating acute neuroaxonal injury [26]. However, low NFL levels have also been reported in HaNDL, suggesting heterogeneity in the etiology of the syndrome [27].

The symptoms of HaNDL may resemble those of familial hemiplegic migraine, and elevated P/Q-type voltage-gated calcium channel antibodies (CACNA1A) have also been reported in HaNDL [28]. Another 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 0 of 30 healthy controls and 0 of 80 controls with other neurologic conditions [29]. However, a heteroduplex analysis and DNA sequencing of the CACNA1A gene associated with familial hemiplegic migraine type 1 failed to identify any CACNA1A pathogenic variants in eight patients with HaNDL [30]. (See "Hemiplegic migraine", section on 'Familial hemiplegic migraine'.)

EPIDEMIOLOGY — HaNDL is a rare condition that is most often seen during the third and fourth decades of life, though cases ranging from age 5 to 52 years have been reported [2,11,31,32]. Up to 25 percent of published cases involve children [32,33].

Only a minority of patients had a prior history of migraine or family history of migraine [1,2,11]. A preceding viral illness that may include cough, rhinitis, diarrhea, or generalized fatigue has been reported in 25 to 40 percent of cases [2,11]. No consistent sex predominance has been found for HaNDL; in the two largest reports, 44 and 68 percent of cases occurred in males [2,11]. However, in a literature review of pediatric cases of HaNDL, there was a female predominance with a female-to-male ratio of 4:1 [32].

CLINICAL FEATURES — HaNDL is characterized by transient episodes of severe headache and neurologic deficits associated with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF).

●Neurologic symptoms – The most frequent neurologic symptoms associated with HaNDL are hemiparesis, hemisensory disturbances, and aphasia [34]. Visual symptoms are less common but may include decreased vision, homonymous hemianopsia, and photopsias [2,11]. Visual signs including papilledema, central retinal venous occlusion, sixth nerve palsy, and optic ataxia have also been described [3,32,35-37]. Right-sided clinical deficits, corresponding to left hemisphere involvement, have been reported more frequently than left-sided deficits in the adult and pediatric literature [11,12,14,19,32].

Although HaNDL is usually accompanied by focal deficits, more diffuse manifestations such as an acute confusional state have been reported in both adults and children [5,38-42].

●Headache character – The headache of HaNDL is moderate to severe and is usually throbbing in quality [33]. Thunderclap onset is rare [43]. 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 [1,2,11]. Usually, the headache follows the onset of neurologic symptoms by 15 to 60 minutes, but on occasion the headache is the first sign of an episode [1,2].

●Symptom duration and recurrence – Neurologic symptoms generally last 15 to 120 minutes [1], though a range of five minutes to three days has been reported [11]. 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 [2,11].

HaNDL is generally characterized as a benign disorder, but one case report described a catastrophic presentation with elevated intracranial pressure requiring emergency life support [17]. Other cases of symptomatic elevated intracranial pressure have also been reported and may contribute to an acute confusional state [44].

DIAGNOSIS AND EVALUATION — HaNDL is a diagnosis of exclusion made in patients who fulfill diagnostic criteria after excluding alternative etiologies. Given the usual 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 to exclude serious conditions such as stroke, other structural brain lesions, meningitis, and seizures.

For patients with new onset or first presentation of symptoms suggestive of HaNDL, a complete evaluation should be obtained, including cerebrospinal fluid (CSF) analysis, neuroimaging, and electroencephalography (EEG). Additional testing for neuronal antibodies is warranted when suspected HaNDL is associated with an acute confusional state or behavioral abnormalities.

A more limited evaluation may be performed for patients with an established diagnosis of HaNDL who present with subsequent characteristic attacks within three months of the initial attack. (See 'Management' below.)

Diagnostic criteria — In the International Classification of Headache Disorders, 3^rd edition (ICHD-3), HaNDL is classified as a "Headache attributed to noninfectious inflammatory disease" [45]. 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

•Associated with 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 — The differential diagnosis of HaNDL includes other conditions that present with headache and neurologic deficits such as ischemic stroke and intracranial hemorrhage. In addition, it is important to rule out other causes of CSF lymphocytosis including treatable entities such as Lyme borreliosis, neurosyphilis, infectious meningitis, encephalitis, and vasculitis of the central nervous system. As an example, in one case report, anti-N-methyl-D-aspartate (NMDA) receptor encephalitis presented with recurrent stereotyped episodes of transient neurologic deficits and severe headache resembling HaNDL [46].

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".)

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

Lumbar puncture — Lumbar puncture is required for the diagnosis of HaNDL. One of the defining features of HaNDL is a CSF lymphocytic pleocytosis [2,11]. In addition, the CSF opening pressure is often elevated and increased protein is common [32,33]. In the largest series of 50 patients, the mean CSF nucleated cell count was 199 cells/mm³ (range 10 to 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 of the total cell count [11]. The CSF protein was elevated in 48 patients (96 percent), with a mean protein of 94 mg/dL (range 20 to 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. In one review of 41 symptomatic patients with HaNDL, two-thirds of patients with acute confusional state had elevated opening pressure [42].

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 [47]. At an average follow-up of 99 days (range 56 to 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 [11].

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) [11]. Oligoclonal bands were not found in 18 patients who were tested for them, including those with elevated CSF immunoglobulin G (IgG) levels.

Neuroimaging — We suggest brain and vascular imaging for all patients with new symptoms suggestive of HaNDL to exclude alternative entities such as stroke or vasculitis.

●Brain imaging – Nonspecific abnormalities are occasionally seen on routine head CT or brain MRI, such as small areas of high signal unrelated to the clinical symptoms [2,5,11,33,48]. Brain MRI with gadolinium may reveal leptomeningeal enhancement [7,32]; in one reported case, mild leptomeningeal enhancement on MRI was attributed to prior lumbar punctures [49]. Diffusion-weighted imaging (DWI) brain MRI sequences are typically normal in patients with HaNDL [16]. However, CT or MRI perfusion techniques have demonstrated global hemispheric or focal regions of hypoperfusion that correlated with neurologic deficits in acutely symptomatic patients. Imaging abnormalities may extend beyond a vascular territory, suggesting an underlying cortical metabolic process rather than vascular insufficiency [15,16,50].

●Vascular imaging – Noninvasive neurovascular imaging for cases of suspected HaNDL should be obtained using magnetic resonance angiography (MRA) or CT angiography (CTA). In the majority of HaNDL cases, conventional digital subtraction angiography (DSA) is normal [2,11]. In one study of HaNDL with 12 patients who underwent DSA, the findings were normal in 11 patients [11]. 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 DSA [1,2].

Cerebral DSA should be considered only in cases where CTA or MRA are normal and there is high suspicion for an alternative diagnosis to HaNDL. DSA 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 — EEG is typically performed for symptomatic patients to exclude seizures as a cause to symptoms. EEG may be abnormal in HaNDL, but epileptiform abnormalities have not been reported. Unilateral excessive slowing corresponding to the clinical symptoms is often seen, with bilateral slowing occurring less frequently [1,2,11,51]. In the largest series with EEG obtained for 42 patients, clear EEG abnormalities were present in 30 (71 percent) [11]. The EEG changes disappear after the symptomatic period.

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 once the diagnosis has been made.

●Initial presentation – It is prudent to rule out other etiologies on first presentation. (See 'Diagnosis and evaluation' above.)

Once the diagnosis of HaNDL has been made, education and reassurance about this disorder are critical components of treatment 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 always require emergent reevaluation to exclude other causes.

●Recurrent attacks – 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

●Etiology and epidemiology – The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is characterized by one or more episodes of severe headache, transient neurologic deficits, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). The precise etiology of HaNDL remains elusive. (See 'Etiology' above.)

Migrainous, viral, or inflammatory etiologies have been suggested. HaNDL is a rare condition that is most often seen during the third and fourth decades of life. (See 'Epidemiology' above.)

●Clinical features – 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. 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' above.)

●Diagnosis and evaluation – Though HaNDL is a self-limited syndrome, a thorough evaluation should be performed to rule out other etiologies such as stroke, other structural brain lesions, meningitis, and seizures. (See 'Diagnosis and evaluation' above.)

•Lumbar puncture is required for the diagnosis of HaNDL. One of the defining features of HaNDL is a CSF lymphocytic pleocytosis. Opening pressure and protein levels in the CSF are frequently elevated but glucose is typically normal and CSF cultures are negative. (See 'Lumbar puncture' above.)

•We suggest brain and vascular imaging for all patients with new symptoms suggestive of HaNDL to exclude alternative entities such as stroke or vasculitis. Nonspecific abnormalities may be seen on routine head computed tomography (CT) or conventional magnetic resonance imaging (MRI). CT or MR perfusion studies may show focal or diffuse hypoperfusion in acutely symptomatic patients. (See 'Neuroimaging' above.)

•Electroencephalography (EEG) is typically performed for symptomatic patients to exclude seizures as a cause to symptoms. EEG done during the symptomatic period in HaNDL is usually abnormal; unilateral slowing corresponding to the clinical symptoms is often seen. (See 'Electroencephalography' above.)

●Management – Once the diagnosis of HaNDL is established, treatment of the syndrome consists of symptomatic headache management. For patients with an established diagnosis of HaNDL who present with a recurrent 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.)