Headache and Neurologic Deficits with cerebrospinal fluid Lymphocytosis (HaNDL)
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Disease Entity
Introduction
Headache and Neurologic Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) syndrome is characterized by a combination of cerebrospinal fluid (CSF) lymphocytosis, elevated protein levels, and neurologic deficits. HaNDL syndrome can lead to increased intracranial pressure and may cause visual loss due to papilledema. HaNDL was first described in 1981 by Bartleson et al, but the term was coined in 1995 by Berg and Williams.[1][2]
Pathogenesis
The pathogenesis of HaNDL syndrome has yet to be clearly defined. It has been posited that cortical spreading depression during viral and bacterial illness is a self-propagating neuronal depolarization phenomenon that triggers a multiphasic cerebral blood flow response responsible for migraine aura.[3][4]Changes in neuronal transmembrane ion gradients releases meningeal inflammatory agents leading to transient vasomotor changes.[3][5] Meningeal inflammation can be caused by viral and bacterial infections and can lead to increased CSF protein levels. This increasing CSF results in impaired CSF absorption seen as leptomeningeal enhancement on magnetic resonance (MR) imaging.[5]
In HaNDL syndrome, CSF lymphocytosis can be elevated in the range of 15 – 760 cells/µL (normal values of 1 – 4 x 103 cells/µL in adults) due to viral prodromes. Total protein levels may increase to up to 200 mg/µL (normal values of 15 - 45 mg/dL in adults).[6]
Diagnosis
Systemic Presentation
The most common symptoms of HaNDL syndrome are episodes of migraine-like headaches accompanied by neurologic deficient such as hemiparesthesia, hemiparesis, and/or aphasia lasting for at least 4 hours.[6] The most commonly presenting symptom is sensory impairment in adults and speech impediment in children.[6] Symptoms of increased intracranial pressure (ICP) can include headaches that worsen with positional changes, nausea, and vomiting.
Ophthalmic Presentation
HaNDL syndrome can lead to elevated intracranial pressure and papilledema. As expected with increased ICP, sixth-nerve palsies and optic atrophy with transient visual field loss may also occur in HaNDL syndrome.[7] No known cases of HaNDL have progressed to later-stages of optic atrophy or permanent optic nerve damage.[7] Aura-like migraine visual symptoms are present in 18% of adult cases, and up to 50% of pediatric patients.[6]
Diagnostic Procedures
The standard work up for increased ICP is neuroimaging (e.g., MR imaging with MR venogram)). Lumbar puncture (LP) can confirm increased ICP on opening pressure and abnormal CSF indices. MR imaging and computed tomography (CT) are normal in-between episodes, but during episodes a CT can demonstrate focal hypoperfusion.[5][6]Although episodes of HaNDL syndrome are frequently misdiagnosed as strokes, the perfusion/diffusion mismatch on neuroimaging can distinguish between the two. In HaNDL, the perfusion changes are not adherent to a vascular territory which suggests oligemic instead of ischemic etiology.[5] [8][9]
Differential Diagnosis
- Stroke
- Migraine with aura
- Idiopathic intracranial hypertension
- Meningitis
- Spinal Tumor
- Spinal epidural abscess
- Multiple Myeloma
- Trauma
Management
Treatment
The management for HaNDL syndrome is supportive, including analgesics and antiemetics. Patients with papilledema may require medical (acetazolamide) or surgical therapy (e.g., optic nerve sheath fenestration or CSF diversion procedures).
Prognosis
The prognosis of HaNDL depends on the degree of elevated ICP. In most patients, prognosis is good with an expected return to neurologic baseline within 3 months.[5] Rarely, patients with elevated ICP can experience prolonged visual loss.
Summary
HaNDL syndrome is characterized by elevated CSF lymphocytosis, neurological deficits, and abnormal neuroimaging such as leptomeningeal enhancement and/or hypoperfusion without a diffusion restriction. Etiology can be infectious, during which inflammatory mediators promote a multiphasic cerebral blood response for migraine aura. Care should be taken by ophthalmologists to diagnose and treat the elevated ICP in patients with HaNDL syndrome, and to obtain CSF diagnostic indices since it may mimic migraine or stroke.
References
- ↑ Bartleson JD, Swanson JW and Whisnant JP. A migrainous syndrome with cerebrospinal fluid pleocytosis. Neurology 1981; 31: 1257–1262.
- ↑ Berg MJ and Williams LS. The transient syndrome of headache with neurologic deficits and CSF lymphocytosis. Neurology 1995; 45: 1648–1654.
- ↑ 3.0 3.1 Chen SP, Ayata C. Spreading depression in primary and secondary headache disorders. Curr Pain Headache Rep. 2016;20(7):44.
- ↑ Dreier, J. P., & Reiffurth, C. (2015). The stroke-migraine depolarization continuum. Neuron, 86(4), 902–922.
- ↑ 5.0 5.1 5.2 5.3 5.4 Armstrong-Javors, A., & Krishnamoorthy, K. (2019). HaNDL Syndrome: Case Report and Literature Review. Journal of child neurology, 34(3), 161–167.
- ↑ 6.0 6.1 6.2 6.3 6.4 Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd Edition (beta). Cephalalgia. 2013;33(9):719.
- ↑ 7.0 7.1 Morrison, D. G., Phuah, H. K., Reddy, A. T., Dure, L. S., & Kline, L. B. (2003). Ophthalmologic involvement in the syndrome of headache, neurologic deficits, and cerebrospinal fluid lymphocytosis. Ophthalmology, 110(1), 115–118.
- ↑ Burke MJ, Lamb MJ, Hohol M, Lay C. Unique CT perfusion imaging in a case of HaNDL: new insight into HaNDL pathophysiology and vasomotor principles of cortical spreading depression. Headache. 2017;57(1):129-134.
- ↑ Pettersen JA, Aviv RI, Black SE, Fox AJ, Lim A, Murray BJ. Global hemispheric CT hypoperfusion may differentiate headache with associated neurological deficits and lymphocytosis from acute stroke. Stroke. 2008;39(2):492.
