HaNDL (Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis) syndrome is a self-limited syndrome characterized by transient headache and neurological deficits accompanied by cerebrospinal fluid (CSF) lymphocytosis. It is classified under secondary headache code 7.3.5 in the International Classification of Headache Disorders, 3rd edition (ICHD-3).
First reported in 1981, it was named “HaNDL” by Berg and Williams in 1995. It is a rare disease that predominantly affects young adults. A review of 44 pediatric cases found that 59.1% were girls 2).
The clinical course is characteristic. One to twelve episodes last for several hours and recur over a period of one to three months 7). Thereafter, it usually resolves spontaneously without permanent deficits.
QOnce HaNDL syndrome resolves, does it recur?
A
Episodes recur 1 to 12 times over 1 to 3 months, but after that period, it usually resolves spontaneously, and long-term recurrence has not been reported 7). However, during the acute phase with repeated symptoms, thorough examination and follow-up are necessary.
Symptoms of HaNDL appear recurrently as a combination of headache and neurological deficits.
Headache: Migraine-like headache lasting at least 4 hours. Rarely presents as thunderclap headache (headache reaching maximum intensity within 60 seconds of onset)3). Worsening with positional changes suggests increased intracranial pressure.
Unilateral sensory abnormalities: The most frequent neurological deficit in adults. Present in 71.4% of children2).
Language disorder (aphasia): Most common symptom in children (69.0%)2). Some cases present with global aphasia4).
Hemiparesis: Present in 52.4% of children2).
Visual symptoms: Migraine aura-like visual symptoms occur in 18% of adults and up to 50% of children.
The following neurological findings, including ophthalmological findings, are important.
Ophthalmological Findings
Papilledema: Bilateral papilledema due to increased intracranial pressure. Confirmed by ophthalmoscopy. In cases with papilledema, CSF pressure of 61 mmH2O and CSF cell count of 827 cells/mm³ (95% lymphocytes) have been recorded6).
Abducens nerve palsy: Cranial nerve VI palsy associated with increased intracranial pressure. Presents as impaired abduction of the eye.
Optic ataxia: Visually guided movement disorder due to dysfunction of the posterior parietal cortex. Presents as impairment of hand movements guided by vision6).
Neurological Findings
Cerebrospinal fluid findings: lymphocytic pleocytosis (15–760 cells/μL), protein up to 200 mg/dL, elevated opening pressure. Cell count tends to decrease with each episode (274→385→98→37 cells/μL)1).
MRI findings: Usually normal between episodes. Leptomeningeal enhancement may be seen during an episode7).
Electroencephalography (EEG): Normal or focal slowing. No epileptic activity1).
If increased intracranial pressure is present, systematically perform fundoscopy to confirm papilledema, followed by fluorescein angiography, optical coherence tomography (OCT), CT or MRI to rule out space-occupying lesions, MRV to evaluate cerebral venous sinuses, and measurement of cerebrospinal fluid pressure.
QCan HaNDL syndrome affect vision?
A
Papilledema, abducens nerve palsy, and transient visual field defects may occur6). However, the disease is self-limiting, and no permanent optic nerve damage has been reported. Complete recovery from visual ataxia within 21 days has been documented6).
The etiology is not yet established, but infectious and immune-mediated mechanisms are considered likely.
Viral prodrome: 25–50% of cases report viral-like symptoms (fever, upper respiratory symptoms, etc.) 2–3 weeks before onset 7).
Associated pathogens: HHV-7 (DNA positive in CSF) 1), EBV (primary infection) 7), cytomegalovirus, and SARS-CoV-2 5) have been reported as triggers.
Family history of migraine: Some pediatric cases have a family history of migraine2).
In a case of a 14-year-old boy who developed HaNDL one month after COVID-19 (SARS-CoV-2) infection, CSF cell count was 525 cells/μL (99% lymphocytes) and protein was 98.2 mg/dL5). Cytokine storm-induced vasomotor dysfunction has been proposed as a pathophysiological hypothesis.
The diagnosis of HaNDL is based on exclusion using the International Classification of Headache Disorders, 3rd edition criteria5). The main items are shown below.
Multiple episodes of transient neurological deficits accompanied by migraine-like headache lasting 4 hours or more
Neurological deficits: unilateral sensory abnormalities, aphasia, or hemiplegia
MRI: Normal between episodes. Leptomeningeal enhancement may be seen during episodes7). Diffusion restriction on DWI is usually absent (important distinction from stroke).
CT perfusion / SPECT: May show focal hypoperfusion during episodes. Does not conform to vascular territories (oligemic rather than ischemic pattern).
TCD (transcranial Doppler): May show increased mean flow velocity in the middle cerebral artery (MCA) (normal <80 cm/s). In EBV-associated cases, velocities of 86–91 cm/s have been recorded7).
GRE T2/SWI*: Dilation of the drainage vein (index vein) in the symptomatic area may be observed. In cases showing approximately twice the dilation of the contralateral side, resolution was confirmed on MRI after 3 months 4).
QHow is HaNDL syndrome differentiated from stroke?
A
Key differentiating findings include the absence of restricted diffusion on diffusion-weighted MRI and perfusion abnormalities that do not correspond to vascular territories. Confirmation of lymphocytic pleocytosis in the CSF is also essential for diagnosis. The recurrent nature of symptoms and complete recovery after episodes also help differentiate from stroke.
There is no established specific treatment, and symptomatic therapy is the mainstay. In Japan, the following treatments including management of increased intracranial pressure are performed.
Analgesics: Acetaminophen and NSAIDs (nonsteroidal anti-inflammatory drugs) are used3).
Antiemetics: Metoclopramide and others are used3).
Migraine attack treatment: NSAIDs, oral triptans, and subcutaneous/intranasal sumatriptan are options. Lomerizine hydrochloride (Migsis®) may be used as a preventive medication.
Management of Intracranial Hypertension
Acetazolamide (Diamox®): A cerebrospinal fluid production inhibitor. Although not covered by insurance, it is used as a treatment for intracranial hypertension.
CSF drainage (lumbar puncture): In a case presenting with papilledema and optic ataxia at a CSF pressure of 61 mmH2O, complete recovery was achieved within 21 days with a combination of 30 mL drainage and acetazolamide6).
Severe cases: Mannitol administration, optic nerve sheath fenestration (ONSF), or ventriculoperitoneal (VP) shunt may be required.
Steroid pulse therapy: Improvement has been reported in cases treated with methylprednisolone (Solu-Medrol) 1 g intravenously for 3 days1). It is used as a treatment targeting immune-mediated mechanisms.
Valproic acid: 300 mg twice daily has been reported as maintenance therapy after steroid pulse 1). It may suppress cortical spreading depression (CSD) and have antiviral and anti-inflammatory effects.
QIs there a specific drug for HaNDL syndrome?
A
No specific treatment has been established, and symptomatic therapy is the mainstay. Case reports have suggested the efficacy of steroid pulse therapy, valproic acid, and nimodipine, but none have been established as standard treatment 1, 7). In many cases, spontaneous improvement occurs within 1 to 3 months.
TCD (MCA flow velocity increase 86–91 cm/s), similarity to RCVS
A complex mechanism triggered by infection/inflammation is assumed, and the two hypotheses are not mutually exclusive.
Ion gradient changes due to meningeal inflammation promote the release of inflammatory substances, causing transient vasomotor changes and impaired CSF absorption. This is thought to appear on MRI as leptomeningeal enhancement and in CSF as pleocytosis and elevated protein (increased blood-brain barrier permeability) 7).
Regarding optic ataxia, bilateral dysfunction centered on the posterior parietal cortex can produce symptoms similar to Bálint syndrome (optic ataxia, oculomotor apraxia, simultanagnosia).
As novel biomarkers, elevated CSF CXCL13 (B-cell chemoattractant, 23–62 ng/L) suggests B-cell involvement in the pathology, and elevated NfL (neurofilament light chain, 600 ng/L) indicates transient axonal damage 1).
A hypothesis has also been proposed that autoantibodies against voltage-gated calcium channels (VGCC) trigger CSD and vasoconstriction 7).
7. Latest Research and Future Prospects (Investigational Reports)
Fiamingo et al. (2022) reported rapid symptom improvement in a 29-year-old male with HaNDL triggered by primary EBV infection, treated with oral nimodipine (starting at 60 mg, then tapered to 30 mg every 4 hours, then 30 mg every 8 hours, for 6 weeks) 7). The calcium channel blocker may have suppressed the vasoconstriction mechanism.
HHV-7 and Challenges to the International Classification of Headache Disorders, 3rd Edition Diagnostic Criteria
Sundholm et al. (2023) reported a HaNDL case with positive HHV-7 DNA (low viral load) in cerebrospinal fluid, questioning the diagnostic criterion of “negative etiological workup” required by the International Classification of Headache Disorders, 3rd edition 1). Detection of trace amounts of pathogens may exclude the diagnosis, highlighting the importance of comprehensive pathogen detection using next-generation sequencing (NGS) technology.
Elevated cerebrospinal fluid CXCL13 (a marker of B cell involvement in pathology) is a biomarker first reported in HaNDL and is expected to contribute to future elucidation of the disease mechanism 1). Elevated NfL reflects transient axonal injury and may be applied to assess disease activity.
Garcia et al. (2022) reported a case of a 14-year-old boy who developed HaNDL one month after SARS-CoV-2 infection. CSF showed 525 cells/μL and protein 98.2 mg/dL, suggesting that cytokine storm may trigger vasomotor abnormalities 5).
The index vein (dilated drainage vein in the symptomatic area) detected by SWI/GRE T2* imaging is being studied as a marker for differentiating from stroke 4). It is positioned as imaging evidence of the CSD mechanism, and verification of reproducibility across cases is a future challenge.
Sundholm A, Gustafsson R, Karrenbauer V. Syndrome of Transient Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): HHV-7 Finding in Cerebrospinal Fluid Challenges Diagnostic Criteria. Pathogens. 2023;12(3):476.
Abrate G, Rossi R, Grasso G, et al. Transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) syndrome in children: case report and narrative review. Ital J Pediatr. 2025;51:306.
Parasram M, Malhotra A, Yoo AS, Mir SA. HaNDL Syndrome Presenting with Thunderclap Headache. Case Rep Neurol Med. 2021;2021:9925004.
Alungulese AL, Garcia Soldevilla MA, Izquierdo Esteban L, et al. Index Vein in Headache and Neurologic Deficits With CSF Lymphocytosis. Neurology: Clinical Practice. 2021;11(3):e347-e349.
Garcia JCN, Isasi MTA, Parada CM, Lorenzo JV. HaNDL syndrome after COVID-19. Neurol Perspect. 2022;2:253-255.
Rivas Ruvalcaba F, Moreno-Cortez KM, Badial-Ochoa S, Rodriguez-Leyva I. Optic ataxia in a patient with HaNDL syndrome. BMJ Case Rep. 2022;15:e252055.
Fiamingo G, Canavero I, Gastaldi M, et al. HaNDL syndrome: a reversible cerebral vasoconstriction triggered by an infection? A case report and a case-based review. Eur J Med Res. 2022;27:196.
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