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 condition that was first clearly characterized in 1981 [1], when it was called a migrainous syndrome with cerebrospinal fluid (CSF) pleocytosis and later referred to as pseudomigraine with temporary neurologic symptoms and lymphocytic pleocytosis (PMP syndrome) [2,3]. HaNDL can be a diagnostic challenge because it is an uncommon condition with clinical and diagnostic features that overlap with other neurologic and infectious entities. This topic will review the clinical features, diagnosis, and management of HaNDL syndrome.

PATHOPHYSIOLOGY — The precise etiology of HaNDL syndrome is unknown, but migrainous and postviral mechanisms have been suggested. Some initially speculated that the syndrome represented a severe migraine due to the clinical features and perfusion imaging findings in symptomatic patients [4,5]. However, others favored an inflammatory or infectious origin given the cerebrospinal fluid (CSF) lymphocytosis, frequent viral prodrome, and monophasic course [1,2].

●Cortical spreading depression – Cortical spreading depression, described in the pathogenesis of migraine as a wave of neuronal and glial depolarization that spreads across the cerebral cortex, may be an important mechanism in HaNDL. This phenomenon can lead to transient abnormalities that may be identified on neuroimaging and other diagnostic testing, including some symptomatic patients with HaNDL syndrome. Several imaging modalities have shown reversible regional cortical hypoperfusion suggestive of vasomotor changes induced by cortical spreading depression including single-photon emission computed tomography (SPECT) and perfusion imaging with computed tomography (CT) or magnetic resonance imaging (MRI) [6-12].

In one case report, hemispheric hypoperfusion on CT perfusion imaging performed during the acute attack subsequently fully resolved on a follow-up study performed 36 hours after resolution of neurologic deficits [11]. In another study, transcranial Doppler in two acutely symptomatic patients showed asymmetrical fluctuations in middle cerebral arterial blood flow velocity and pulsatility, indicative of intracranial vasomotor changes [13], resembling those seen in patients with migraine [14,15]. Abnormalities on single-fiber electromyography and visual evoked potentials in a 16-year-old patient with HaNDL were similar to abnormal findings found in patients suffering from migraine with aura [16]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Cortical spreading depression'.)

●Postviral inflammation – The pathogenesis of HaNDL may involve viral and/or inflammatory processes. An initial viral infection can lead to the production of antibodies against neuronal or vascular antigens, inducing an aseptic leptomeningeal vasculitis; this inflammatory response may trigger a subsequent headache with neurologic deficits such as via cortical spreading depression [13,17,18]. One study comparing patients with HaNDL (n = 5) and matched controls (n = 30) found antibodies to deoxyribonucleic acid (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 [19]. Another study reported two patients with HaNDL who had high neurofilament light chain (NFL) levels, indicating acute neuroaxonal injury [20]. Other studies have reported low NFL levels in HaNDL, suggesting heterogeneity in the etiology of the syndrome [21].

However, despite extensive viral serologic evaluation, there are only a few reports suggesting a viral association, including isolated cases linked to echovirus 30 [22], human herpesvirus 6 infection [23], and human herpesvirus 7 infection [24]; other isolated cases have been linked to Borrelia lusitaniae infection and Epstein-Barr virus in the CSF [25,26].

A genetic susceptibility to HaNDL syndrome has been suggested by limited data identifying elevated P/Q-type voltage-gated calcium channel antibodies (CACNA1A) in some patients, findings associated with the pathologic genetic variant seen in those with familial hemiplegic migraine [27]. Another study found antibodies directed against the CACNA1H subunit of the T-type voltage-gated calcium channel in two of four patients with HaNDL compared with 0 of 30 healthy controls and 0 of 80 controls with other neurologic conditions [28]. 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 [29]. (See "Hemiplegic migraine", section on 'Familial hemiplegic migraine'.)

EPIDEMIOLOGY — HaNDL is a rare condition that most often occurs during the third and fourth decades of life, although cases in individuals from age 5 to 52 years old have been reported [2,17,30,31]. Up to 25 percent of published cases involve children [31,32]. No consistent sex predominance has been found for HaNDL; in the two largest reports, 44 and 68 percent of cases occurred in males, respectively [2,17]. However, in a literature review of pediatric cases of HaNDL, there was a female predominance with a female-to-male ratio of 4:1 [31].

Observational data indicate that only a minority of patients with HaNDL have a prior history of migraine or family history of migraine [1,2,17]. A preceding viral illness that may include cough, rhinitis, diarrhea, or generalized fatigue has been reported in 25 to 40 percent of cases [2,17].

CLINICAL FEATURES — HaNDL is characterized by one or more transient episodes of severe headache and neurologic deficits associated with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF). In the acute setting, symptoms of the HaNDL syndrome can mimic other neurologic conditions such as stroke or seizure.

Neurologic symptoms — The most frequent neurologic symptoms associated with HaNDL are focal and include [33]:

●Hemiparesis

●Hemisensory disturbances

●Aphasia

Right-sided clinical deficits, corresponding to left hemisphere involvement, have been reported more frequently than left-sided deficits in both the adult and pediatric literature [6,8,12,17,31].

Visual symptoms are less common but may include decreased vision, homonymous hemianopsia, and photopsias [2,17]. Ophthalmologic signs including papilledema, central retinal venous occlusion, sixth nerve palsy, and optic ataxia have also been described [3,31,34-36].

Nonfocal manifestations such as an acute confusional state (encephalopathy) have been reported in both adults and children [5,37-41].

The neurologic deficits often vary from one episode to the next, involving different brain regions. HaNDL is generally characterized as a benign disorder, but one case report described a catastrophic presentation with elevated intracranial pressure requiring emergency life support [42]. Other cases of symptomatic elevated intracranial pressure have also been reported and may contribute to encephalopathy [43].

Headache character — The headache of HaNDL is moderate to severe and is usually throbbing in quality [32]. Thunderclap onset is rare [44]. It may be unilateral or bilateral.

Headache is often associated with nausea/vomiting and not infrequently with photophobia and/or phonophobia. Meningismus is not present in HaNDL, but transient fever may be noted in up to 33 percent of cases [1,2,17].

Temporal features and course — Neurologic symptoms within an episode typically persist for four or more hours, though a range of five minutes to three days has been reported [1,17]. 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]. Headache typically persists for several hours but may range from one hour to one week [17].

Approximately 75 percent of patients have repeated episodes (1 to 12) of transient headache and neurologic deficits that occur for weeks or up to three months following the initial attack [2,41]. In the two largest reports, the mean duration of the condition was 14 and 21 days [2,17]. HaNDL is generally considered a monophasic condition. Episodes that relapse or recur beyond three months should prompt diagnostic reevaluation. (See 'Differential diagnosis' below.)

DIAGNOSIS AND EVALUATION — HaNDL syndrome should be suspected in patients with one or more episodes of transient neurologic deficits and headache. The diagnosis of HaNDL is made in patients who fulfill diagnostic criteria after excluding alternative etiologies (algorithm 1).

At first presentation, the clinician should evaluate for other common conditions which may also manifest with headache and neurologic deficits that may be associated with significant short-term morbidity and mortality risk such as stroke, other structural brain lesions, meningitis, and seizures (see 'Differential diagnosis' below). Testing typically includes brain and vascular imaging, cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), and laboratory testing (table 1). Additional testing for neuronal antibodies is warranted when suspected HaNDL is associated with an encephalopathy 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 'Managing subsequent episodes' 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

Lumbar puncture — Lumbar puncture for CSF analysis is required for the diagnosis of HaNDL. In addition to routine assessments including opening pressure, cell counts, and chemical composition, CSF molecular testing, Gram stain, and cultures should also be performed to exclude infectious causes of pleocytosis. This typically includes herpes virus, enteroviruses, West Nile virus, Borrelia species, and syphilis. Further CSF testing for infectious causes depends on specific risk of exposure. The evaluation of patients with aseptic meningitis is discussed separately. (See "Aseptic meningitis in adults".)

In addition, cytology to assess for malignant cells should be obtained for patients with clinical history or imaging findings suspicious for leptomeningeal neoplasm. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Cerebrospinal fluid'.)

Antibody testing for autoimmune and paraneoplastic encephalitis should also be obtained for patients who present with encephalopathy. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

CSF findings in patients with HaNDL syndrome include:

●Lymphocytic pleocytosis – A CSF lymphocytic pleocytosis is a defining feature of HaNDL [2,17]. The CSF lymphocyte count is at least 15 cells/mL but is frequently higher in patients with HaNDL. In the largest series of 50 patients with HaNDL, 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 [17].

●Other CSF abnormalities in HaNDL – CSF intracranial pressure is often elevated in patients with HaNDL, and increased protein is also common [31,32,41]. In one series of 50 patients with HaNDL, opening pressure was elevated in 10 of the 18 patients in whom it was measured (56 percent) and ranged between 180 and 370 mmH₂O [17]. Similarly, elevated CSF protein was found in 96 percent of patients, with a mean protein of 94 mg/dL (range 20 to 250 mg/dL). IgG levels were elevated in 20 percent. CSF glucose concentrations are normal in HaNDL.

Although data are limited, it appears that the CSF abnormalities associated with HaNDL may resolve slowly over several months. In a series of eight patients with HaNDL who had serial lumbar punctures during and after symptomatic episodes, initial CSF findings of elevated white blood cell count and lymphocytosis gradually improved on subsequent tests but did not normalize until months after the resolution of clinical symptoms [46]. 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 as well as molecular testing from CSF and blood are negative in HaNDL [17].

Neuroimaging — Brain and vascular imaging is required for all patients with new symptoms suggestive of HaNDL to exclude alternative entities such as stroke or vasculitis. We prefer brain MRI with and without contrast because it is sensitive for acute infarction and inflammatory conditions; head CT with contrast can be performed as a less sensitive alternative test. Options for noninvasive vascular imaging include brain magnetic resonance angiography (MRA) or CT angiography (CTA). Cerebral digital subtraction angiography (DSA) may be warranted for selected patients with normal CTA or MRA when symptoms are atypical or otherwise when suspicion for vasculitis is high.

Magnetic resonance venography (MRV) or CT venography (CTV) may also be warranted for selected patients with suspected cerebral venous thrombosis when MRI is nondiagnostic.

Neuroimaging findings are typically normal in patients with HaNDL, but mild or nonspecific abnormalities may also be seen in a minority [32].

●Brain imaging – Nonspecific abnormalities are occasionally seen on routine head CT or brain MRI, such as small areas of high T2-hyperintense signal in the corpus callosum or elsewhere unrelated to the clinical symptoms [2,5,17,32,47]. Diffusion-weighted imaging (DWI) sequences are typically normal in patients with HaNDL [10]. Brain MRI with gadolinium may reveal leptomeningeal enhancement [23,26,31]. However, this finding may also be attributed to a preceding lumbar puncture [48].

Advanced imaging such as CT or MRI perfusion studies may show global hemispheric or focal regions of hypoperfusion that correlate with neurologic deficits in acutely symptomatic patients. Such imaging abnormalities may extend beyond a vascular territory, suggesting a widespread underlying cortical metabolic process rather than an arterial lesion typical of an ischemic stroke [9-11,49].

●Vascular imaging – Neurovascular imaging is typically normal for cases of HaNDL [2,17]. In one study of HaNDL with 12 patients who underwent DSA, the findings were normal in 11 patients [17]. The one abnormal angiogram showed mild irregularities suggestive of inflammation in the walls of small cranial arteries in the clinically symptomatic area.

In some instances, clinical symptoms of HaNDL episodes have been precipitated by performing a DSA [1,2].

Electroencephalography — EEG is typically performed for symptomatic patients to exclude seizures as a cause of neurologic deficits. 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 [1,2,17,50]. In the largest series with EEG obtained for 42 patients, EEG abnormalities were present in 30 (71 percent) [17]. EEG abnormalities resolve after the symptomatic period.

Laboratory testing — For patients with suspected HaNDL syndrome, we obtain laboratory testing for Lyme disease and syphilis for those either in endemic areas or with associated risk factors. For patients with encephalopathy, additional testing includes thyroid function tests, vitamin B12 level, and antineuronal antibodies associated with the symptom complex (table 2).

Initial routine laboratory testing for symptomatic patients with acute neurologic deficits including those with encephalopathy may also include a complete blood count, electrolytes, creatinine and glucose levels, as well as other studies such as pregnancy test for females of potential childbearing age, blood alcohol level, and toxicology screening. These issues are discussed separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke", section on 'Blood tests' and "Diagnosis of delirium and confusional states", section on 'Laboratory tests'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HaNDL is extensive and includes other conditions that present with similar clinical features, similar cerebrospinal fluid (CSF) findings, or both. Common conditions that may present with headache and neurologic deficits include acute ischemic stroke, subarachnoid hemorrhage, and seizures. Other causes of CSF lymphocytosis include treatable entities such as Lyme borreliosis, neurosyphilis, infectious meningitis, encephalitis, and vasculitis of the central nervous system.

●Cerebrovascular disease

•Acute stroke – Acute stroke syndromes are characterized by onset of focal neurologic deficits, such as aphasia or hemiparesis. Patients with hemorrhagic presentations (eg, subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematoma) and some patients with acute ischemic stroke may also present with headache, similar to HaNDL syndrome. Neuroimaging of the brain is used to identify these ischemic and hemorrhagic conditions.

-(See "Neuroimaging of acute stroke", section on 'Imaging findings of ischemic stroke'.)

-(See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

-(See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)

-(See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".)

•Cerebral venous thrombosis – Cerebral venous occlusion frequently causes headache, and resultant venous congestion may lead to neurologic deficits. Brain imaging may show venous infarction or hemorrhage or indirect evidence of venous occlusion in some cases. However, MR- or CT-venography may be needed to identify or exclude cerebral venous thrombosis in early or less severe presentations. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

●Seizures – New-onset seizures may be challenging to identify when the characteristic convulsion with loss of consciousness is not observed or absent. The presence of rhythmic repetitive movements (stereotypy) may help identify seizures, when observed. Patients with some forms of focal seizures may present with subtle neurologic deficits, and the postictal phase of seizures may produce headache and transient neurologic deficits. However, migrainous features are uncommon in postictal headaches. Electroencephalography (EEG) is used to identify abnormal brainwave activity suggestive of seizures. CSF findings are often normal in most patients with seizures, unless due to an underlying condition such as meningitis. However, elevated protein levels and even modest lymphocytic pleocytosis (eg, up to 40 cells/mm³) in the CSF have been attributed to unprovoked seizures [51]. (See "Evaluation and management of the first seizure in adults".)

●Migraine with aura – Attacks of migraine may mimic HaNDL if aura symptoms include neurologic deficits such as aphasia, hemisensory, or hemiparesis. However, aura symptoms frequently resolve prior to onset of the headache in migraine, and the shorter duration of the aura (<1 hour) may help clinically distinguish migraine from HaNDL. CSF findings are normal in migraine. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

Hemiplegic migraine is a subtype of migraine with aura that features complex aura symptoms including hemiparesis. Migraine with brainstem aura is a migraine subtype that features two or more brainstem aura symptoms such as dysarthria and ataxia. HaNDL can be differentiated from these forms of migraine by the presence of CSF lymphocytic pleocytosis. (See "Hemiplegic migraine" and "Migraine with brainstem aura".)

●Infectious conditions

•Viral meningitis – Viral meningitis is an important diagnostic consideration in the setting of a CSF lymphocytic pleocytosis, but patients with meningitis do not typically have neurologic deficits unless encephalitis is also present. By contrast, patients with HaNDL do not present with meningismus or other signs of meningeal irritation, unlike those with viral meningitis. CSF cultures may also be helpful to identify an infectious cause to the CSF pleocytosis in viral meningitis. (See "Aseptic meningitis in adults", section on 'Viral meningitis'.)

•Recurrent (Mollaret) meningitis – Mollaret meningitis (also known as recurrent benign lymphocytic meningitis) is characterized by recurrent episodes of fever and meningismus, but patients do not have neurologic deficits. Mollaret cells in the CSF may also help to identify this condition. (See "Aseptic meningitis in adults", section on 'Recurrent (Mollaret) meningitis'.)

•Neuroborreliosis – Nervous system involvement with Lyme disease can include meningitis as well as facial palsy, encephalopathy, or other neurologic deficits, mimicking HaNDL syndrome. However, patients with Lyme meningitis may present with meningeal signs. Lyme disease is diagnosed by antibody testing in the blood and/or CSF. (See "Nervous system Lyme disease".)

•Neurosyphilis – Neurologic manifestations of syphilis are protean and can include both headache and neurologic deficits. CSF analysis typically includes a lymphocytic pleocytosis. Diagnosis is confirmed by antibody testing in the blood and/or CSF. (See "Neurosyphilis".)

●Autoimmune or inflammatory conditions

•Cerebral vasculitis – Primary angiitis of the central nervous system may present with headache and neurologic deficits often along with a lymphocytic CSF pleocytosis, but symptom onset is often insidious and progressive, unlike patients with HaNDL. In addition, brain imaging may show multiple infarcts or multifocal T2-weighted hyperintensities. Noninvasive vascular imaging may show evidence of distal vasculopathy, but digital subtraction angiography (DSA) may be needed to confirm this finding or show vasculopathy affecting smaller cerebral vessels. (See "Primary angiitis of the central nervous system in adults".)

•Autoimmune and paraneoplastic encephalitis – Patients with noninfectious encephalitides commonly present with headache and progressive neurologic symptoms, especially an acute encephalopathy, psychiatric symptoms, or memory impairment. 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 [52]. A lymphocytic CSF pleocytosis may also be present. Antibody testing may identify these conditions. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

●Neoplastic meningitis – Headache is the most common symptom of neoplastic leptomeningeal disease, frequently accompanied by cranial neuropathies or limb weakness from spinal radicular nerve involvement. CSF may show a lymphocytic pleocytosis along with an elevated protein concentration, mimicking HaNDL. A history of cancer can raise the suspicion for leptomeningeal disease, and identifying malignant cells by CSF cytology confirms the diagnosis. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

MANAGEMENT — Given the self-limited nature of the HaNDL syndrome and the favorable outcome noted in reported patients, therapeutic interventions may be limited to symptomatic treatment of the headache with or without short-term preventive treatment for patients with recurrent episodes.

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.

Empiric initial treatment during first episode — Patients presenting with initial symptoms of headache with neurologic deficits suggestive of HaNDL may warrant initial antimicrobial treatment for meningitis until cerebrospinal fluid (CSF) culture results exclude an infectious cause to symptoms. (See "Aseptic meningitis in adults", section on 'Antimicrobial therapy'.)

Symptomatic treatment — For patients who desire symptomatic treatment of headache, we suggest using a nonsteroidal anti-inflammatory drug and/or antiemetic, based on efficacy for acute migraine. (See "Acute treatment of migraine in adults", section on 'Simple analgesics' and "Acute treatment of migraine in adults", section on 'Antiemetics'.)

However, we avoid migraine-specific therapies such as triptans, ergots, calcitonin gene-related peptide antagonists, or lasmiditan due to the theoretical risk of ischemic injury from vasoconstriction in patients with neurologic deficits and absence of evidence supporting safety and efficacy in this condition.

Managing subsequent episodes

●Repeat diagnostic testing – For patients with a secure diagnosis of HaNDL who present with a characteristic repeat episode within three months of the initial attack, we attempt to limit diagnostic evaluations to reduce the burden and cost of repeat testing that may be low-yield. Our typical approach for such patients includes:

•Defer repeat electroencephalogram on repeat presentations.

•Repeat lumbar puncture on the second presentation but defer this test on subsequent presentations unless subsequent symptoms are atypical.

•Repeat neuroimaging such as brain MRI with and without contrast on the second (and possibly third) presentation but defer imaging unless recurrent symptoms are new or otherwise consistent with acute stroke.

In the authors' clinical experience, a single repeat lumbar puncture and repeat neuroimaging are usually required to reassure the treating clinician 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.

●Preventive treatment – For patients who present with a second HaNDL episode who desire preventive treatment, we offer pharmacotherapy with agents used for the prevention of episodic migraine. However, the available evidence on preventive therapy for patients with HaNDL is limited to various case reports suggesting some benefit with acetazolamide, propranolol, valproic acid, nimodipine, and phenytoin [3,5,26,40,53]. (See "Preventive treatment of episodic migraine in adults".)

We wean preventive therapy within three months because HaNDL is a monophasic condition that resolves within weeks to months. Patients who relapse require diagnostic reevaluation. (See 'Differential diagnosis' above.)

SUMMARY AND RECOMMENDATIONS

●Definition – The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare, monophasic neurologic condition characterized by one or more episodes of severe headache and transient neurologic deficits that are associated with a lymphocytic pleocytosis in the cerebrospinal fluid (CSF). HaNDL has also been called migrainous syndrome with CSF pleocytosis and pseudomigraine with temporary neurologic symptoms and lymphocytic pleocytosis (PMP syndrome). (See 'Introduction and definition' above.)

●Etiology – Postviral and migrainous mechanisms have been posited, but the precise etiology of HaNDL is uncertain. An occult viral infection may result in the production of antibodies against neuronal or vascular antigens, inducing an aseptic leptomeningeal vasculitis, and subsequently lead to headache and neurologic deficits via a cortical spreading depression, a mechanism described in the pathogenesis of migraine. (See 'Pathophysiology' above.)

●Clinical features – HaNDL symptoms occur as one or more episodes that may recur over a one- to three-month period. Neurologic symptoms typically persist for four or more hours, and subsequent headache typically persists for several hours but may range from one hour to one week. (See 'Clinical features' above.)

•Neurologic deficits – The most frequent neurologic symptoms associated with HaNDL include hemiparesis, hemisensory disturbances, and aphasia. Encephalopathy has also been reported in both adults and children. (See 'Neurologic symptoms' above.)

•Headache – The headache of HaNDL is moderate to severe, throbbing in quality, and often associated with nausea/vomiting and/or photophobia/phonophobia. Meningismus is not present, but transient fever may be noted in up to 33 percent of cases. (See 'Headache character' above.)

●Evaluation – For patients with new onset or first presentation of symptoms suggestive of HaNDL, the initial evaluation includes (algorithm 1 and table 1) (see 'Diagnosis and evaluation' above):

•CSF analysis – In addition to routine CSF assessments including opening pressure, cell counts, and chemical composition, molecular testing and cell culture should be obtained to exclude infectious causes of pleocytosis. Additional testing for other infectious conditions as well as autoimmune and neoplastic causes depends on clinical symptoms. (See 'Lumbar puncture' above.)

A CSF lymphocytic pleocytosis is a defining feature of HaNDL. CSF opening pressure is often elevated, and an increased protein is also common. However, bacterial, viral, and fungal studies, as well as molecular testing from CSF and blood, are negative in HaNDL.

•Neuroimaging – We prefer brain MRI with contrast due to sensitivity for acute ischemia; head CT with contrast can be performed as a less sensitive alternative test. Options for noninvasive vascular imaging include brain magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) or CT angiography (CTA) and CT venography (CTV). Imaging findings are often normal, but leptomeningeal enhancement may be seen in HaNDL. (See 'Neuroimaging' above.)

•Electroencephalogram – Electroencephalography (EEG) may be abnormal in HaNDL, but epileptiform abnormalities have not been reported. (See 'Electroencephalography' above.)

•Laboratory testing – We obtain testing for Lyme disease and syphilis for those either in endemic areas or with associated risk factors. For patients with encephalopathy, additional testing includes thyroid function tests, vitamin B12 level, and antineuronal antibodies associated with the symptom complex (table 2). (See 'Laboratory testing' above.)

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 'Managing subsequent episodes' above.)

●Diagnosis – The diagnosis of HaNDL is made in patients who fulfill diagnostic criteria after excluding alternative causes to presenting symptoms (algorithm 1). (See 'Diagnostic criteria' above.)

●Differential diagnosis – The differential diagnosis of HaNDL is extensive and includes other conditions that present with similar clinical features, similar CSF findings, or both. Common conditions that may present with headache and neurologic deficits include acute ischemic stroke, subarachnoid hemorrhage, and seizures. Other causes of CSF lymphocytosis include treatable entities such as Lyme borreliosis, neurosyphilis, infectious meningitis, encephalitis, and vasculitis of the central nervous system. (See 'Differential diagnosis' above.)

●Management – Given the self-limited nature of the HaNDL syndrome and the favorable outcome noted in reported patients, therapeutic interventions may be limited to symptomatic treatment of the headache and short-term preventive treatment for patients with recurrent episodes. Education and reassurance are important due to the likelihood of further attacks that can occur in the ensuing weeks to months. (See 'Management' above.)

•For patients who desire symptomatic treatment of headache, we suggest using a nonsteroidal anti-inflammatory drug and/or antiemetic, based on efficacy and safety for acute migraine (Grade 2C). However, we avoid migraine-specific therapies such as triptans, ergots, calcitonin gene-related peptide antagonists, or lasmiditan due to the theoretical risk of ischemic injury from vasoconstriction in patients with neurologic deficits and absence of evidence supporting safety and efficacy in this condition. (See 'Symptomatic treatment' above.)

•For patients with a secure diagnosis of HaNDL who both present with a characteristic repeat episode within three months of the initial attack and desire treatment, we offer pharmacotherapy with agents used for the prevention of episodic migraine. (See 'Managing subsequent episodes' above.)