Headache With Neurological Deficits and CSF Lymphocytosis

Etiology

The cause of HaNDL syndrome remains poorly understood, but various speculations exist about the etiology. Initially, this condition was thought to be secondary to inflammation or infection due to frequent viral prodrome, monophasic course, and CSF lymphocytosis. However, large-scale viral serological examinations did not reveal a particular association with any infectious agent except isolated reports of echovirus 30, human herpesvirus 6 and 7, and borrelia infection. Based on sophisticated imaging studies (eg, single-photon emission computed tomography, head computed tomography perfusion imaging, magnetic resonance imaging perfusion techniques, transcranial Doppler), pathogenesis similar to migraine is suggested with decreased hypoperfusion linked with cortical spreading depression.

After the findings are similar to migraine pathophysiology, symptomatic explanation secondary to aseptic meningitis due to viral or inflammatory etiology has been a research target. For example, investigation pertains to autoimmune cross-reactivity between inflammatory or viral disease-causing autoantibodies against neuronal or vascular structures that induce an aseptic inflammation in leptomeningeal vasculature.[5] In recent years, results from several studies have also found autoantibodies to a type of calcium channel, CACNA1H, in some patients with HaNDL. CACNA1A pathogenic variants were absent in 8 patients with HaNDL. On the other hand, a minority of patients with HaNDL syndrome also had an antibody related to protein kinase with mitogen activity and another protein kinase with deoxyribonucleic acid (DNA)-dependent catalytic subunit.[2][3]

Results from studies have revealed that autoimmune mechanisms have been implicated in the etiology of HaNDL through protein microarray screening. Findings include the identification of antibodies to 3 DNA repair proteins (mitogen-activated protein kinase-4, DNA-dependent protein kinase catalytic subunit, DNA excision repair protein ERCC6). DNA repair protein antibodies can signify DNA damage and inflammatory causes of HaNDL.[6]

Epidemiology

Headache with neurological deficits and CSF lymphocytosis syndrome is more common in men between 15 and 40 years (68%) compared to women. However, the literature does not consistently report this, and in pediatric cases (which may constitute 15% of the total cases), a significant female predominance may be apparent. Only 26% of the patients have a positive history of migraines, and the typical presentation is moderate to severe intensity headache with a range of 1 to 12 episodes accompanied by neurological deficits.[2] Recurrence of the episodes usually occurs within a brief period of 3 months.[7] All patients typically have a similar course of this illness with a reoccurrence of migraine-like headaches accompanied by variable neurologic deficit and CSF pleocytosis.[8]

HaNDL syndrome is a self-limiting benign condition, and as its name suggests, causes episodes of transient neurological deficits including motor, sensory, aphasia, and, less frequently, visual lasting several hours, accompanied or followed by moderate-to-severe headache and lymphocytosis of the cerebrospinal fluid. The incidence is low in adulthood and highly uncommon in the pediatric age. Recurrence of episodes usually occurs in the first 3 months; however, it has an excellent prognosis.

Cases reported on younger patients include the following symptoms:

• Recurrent episodes of headache for 6 months, with each episode lasting for a week, and in the current episode, the patient is symptomatic for 3 days. These symptoms are associated with paresthesias and CSF lymphocytosis with normal protein and sugar and a family history of migraines. Magnetic resonance imaging (MRI) of the brain with contrast with MR angiography and venography are normal. Work-up for relevant causes of infection and vasculitis are negative. Symptoms resolved on oral antimigraine prophylaxis, and the patients were in remission for the last 8 months.[9]
• Intense frontal headache that suddenly begins on the tenth day of infection, along with clinical signs and symptoms of dysarthria and right hemiparesis with subsequent aphasia and generalized hypotonia.[10]
• Altered consciousness, which is infrequent in adults. Younger individuals also have increased intracranial pressure and papilledema and experience migraine. This feature, together with the benign course of the disease, could favor the probable migrainous pathophysiology of HaNDL syndrome, although this is still questionable.[11]

Pathophysiology

Migrainous pathophysiology, such as vasomotor changes in the middle cerebral artery, may play a role in HaNDL syndrome, causing asymmetrical pulsations in the blood flow, evident on transcranial Doppler ultrasound during and after an episode. Results from several studies demonstrate a reduction in cerebral blood flow to the brain at the contralateral side of neurological deficits.

Previous studies mentioned the association between vasomotor changes and HaNDL pathophysiology as follows:

• Global hemispheric hypoperfusion pattern supporting secondary oligemia induced by a hemispheric wave of cortical spreading depression (CSD). This study speculated that this could be due to the direct spread of CSD-induced vasomotor changes across the anomalous vasculature.[12] 
• Co-incidence of HaNDL symptoms raised the possibility of vasomotor changes in blood vessels, cortical spreading depression, and glutamate excitotoxicity that can lead to intra-myelinic edema in a patient with a 2-week history of intermittent headache, acute right-sided hemisensory deficit where both CSF lymphocytosis and MRI lesion in the splenium of the corpus callosum resolved on follow up 4 weeks later.[13] 

On the other hand, few authors suggest antibodies formed after viral or autoimmune diseases may have led to aseptic inflammation affecting leptomeningeal vessels, causing CSF pleocytosis and neurologic deficits. For example, recent study results have also shown high titers of antibodies against CACNA1H protein, subunits of T-type calcium channels in 2 out of 4 patients with HaNDL, partially supporting the view of autoimmunity contributing to its pathogenesis.[2][3][14]

Further, results from another recent study concluded viral etiology is evident in some patients, and a viral etiology may have a role in HaNDL. Regardless of etiology, the authors suggested the pathogenic mechanism may rely on the viral or other agent triggering cerebral vasoconstriction, explaining both focal symptoms and headache. Likewise, therapeutic options include calcium channel blockers.[15]

Additional cases of viral etiology are documented, particularly on Rotavirus meningitis, in a previously healthy patient who presented with transient aphasia accompanied by fever and headaches at the end of a 1-week history of gastroenteritis. CSF analysis revealed lymphocytic meningitis, and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (PCR) was positive in CSF, and stool examination showed Rotavirus meningitis. MRI revealed no signs of encephalitis. Aphasia resolved in less than 12 hours with no relapse of neurological symptoms despite aciclovir discontinuation. This case suggested that the postviral headache and neurological deficits with HaNDL syndrome may be associated with previously undetected direct viral infection of the central nervous system.[16] There was also a case report on a patient with a clinical history and cerebrospinal fluid findings similar to HaNDL syndrome wherein PCR revealed Borrelia lusitaniae in the cerebrospinal fluid.[17]

History and Physical

Migrainous pathophysiology, such as vasomotor changes in the middle cerebral artery, may play a role in HaNDL syndrome, causing asymmetrical pulsations in the blood flow, evident on transcranial Doppler ultrasound during and after an episode. Some studies demonstrate a reduction in cerebral blood flow to the brain at the contralateral side of neurological deficits.

Previous studies mentioned the association between vasomotor changes and HaNDL pathophysiology as follows:

• Global hemispheric hypoperfusion pattern supporting secondary oligemia induced by a hemispheric wave of cortical spreading depression (CSD). This study speculated that this could be due to the direct spread of CSD-induced vasomotor changes across the anomalous vasculature.[12] 
• Co-incidence of HaNDL symptoms raised the possibility of vasomotor changes in blood vessels, cortical spreading depression, and glutamate excitotoxicity that can lead to intra-myelinic edema in a patient with a 2-week history of intermittent headache, acute right-sided hemisensory deficit where both CSF lymphocytosis and MRI lesion in the splenium of the corpus callosum resolved on follow up 4 weeks later.[13] 

On the other hand, few authors suggest antibodies formed after viral or autoimmune diseases may have led to aseptic inflammation affecting leptomeningeal vessels, causing CSF pleocytosis and neurologic deficits. For example, a recent study has also shown high titers of antibodies against CACNA1H protein, subunits of T-type calcium channels in 2 out of 4 patients with HaNDL, supporting the view of autoimmunity partially contributing to its pathogenesis.[3][2][14]

A recent study concluded that viral etiology is evident in some patients, and a viral etiology may have a role in HaNDL. Regardless of etiology, the authors suggested that the pathogenic mechanism may rely on the viral or other agent triggering cerebral vasoconstriction, which can explain both focal symptoms and headache. Likewise, therapeutic options include calcium channel blockers. [15]

Additional cases of viral etiology are documented, particularly on Rotavirus meningitis, in a previously healthy patient who presented with transient aphasia accompanied by fever and headaches at the end of a one-week history of gastroenteritis. CSF analysis revealed lymphocytic meningitis and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (RT-PCR) was positive in CSF, and stool examination showed Rotavirus meningitis. Magnetic resonance imaging (MRI) revealed no signs of encephalitis. Aphasia resolved in less than 12 hours with no relapse of neurological symptoms despite aciclovir discontinuation. This case suggested that the postviral headache and neurological deficits with HaNDL syndrome may be associated with previously undetected direct viral infection of the central nervous system.[16] There was also a case report on a patient with a clinical history and cerebrospinal fluid findings similar to HaNDL syndrome wherein polymerase chain reaction revealed Borrelia lusitaniae in the cerebrospinal fluid.[17]

Migrainous pathophysiology, such as vasomotor changes in the middle cerebral artery, may play a role in HaNDL syndrome, causing asymmetrical pulsations in the blood flow, evident on transcranial Doppler ultrasound during and after an episode. Some studies demonstrate a reduction in cerebral blood flow to the brain at the contralateral side of neurological deficits.

Previous studies mentioned the association between vasomotor changes and HaNDL pathophysiology as follows:

• Global hemispheric hypoperfusion pattern supporting secondary oligemia induced by a hemispheric wave of cortical spreading depression (CSD). This study speculated that this could be due to the direct spread of CSD-induced vasomotor changes across the anomalous vasculature.[12] 
• Co-incidence of HaNDL symptoms raised the possibility of vasomotor changes in blood vessels, cortical spreading depression, and glutamate excitotoxicity that can lead to intra-myelinic edema in a patient with a 2-week history of intermittent headache, acute right-sided hemisensory deficit where both CSF lymphocytosis and MRI lesion in the splenium of the corpus callosum resolved on follow up 4 weeks later.[13] 

On the other hand, few authors suggest antibodies formed after viral or autoimmune diseases may have led to aseptic inflammation affecting leptomeningeal vessels, causing CSF pleocytosis and neurologic deficits. For example, a recent study has also shown high titers of antibodies against CACNA1H protein, subunits of T-type calcium channels in 2 out of 4 patients with HaNDL, supporting the view of autoimmunity partially contributing to its pathogenesis.[3][2][14]

A recent study concluded that viral etiology is evident in some patients, and a viral etiology may have a role in HaNDL. Regardless of etiology, the authors suggested that the pathogenic mechanism may rely on the viral or other agent triggering cerebral vasoconstriction, which can explain both focal symptoms and headache. Likewise, therapeutic options include calcium channel blockers. [15]

Additional cases of viral etiology are documented, particularly on Rotavirus meningitis, in a previously healthy patient who presented with transient aphasia accompanied by fever and headaches at the end of a one-week history of gastroenteritis. CSF analysis revealed lymphocytic meningitis and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (RT-PCR) was positive in CSF, and stool examination showed Rotavirus meningitis. Magnetic resonance imaging (MRI) revealed no signs of encephalitis. Aphasia resolved in less than 12 hours with no relapse of neurological symptoms despite aciclovir discontinuation. This case suggested that the postviral headache and neurological deficits with HaNDL syndrome may be associated with previously undetected direct viral infection of the central nervous system.[16] There was also a case report on a patient with a clinical history and cerebrospinal fluid findings similar to HaNDL syndrome wherein polymerase chain reaction revealed Borrelia lusitaniae in the cerebrospinal fluid.[17]

Evaluation

The following diagnostic criteria evaluate HaNDL:

• Severe to moderate intensity migraine-like headache lasting for a few hours
• Increased lymphocytes (>15 white cells/mL) in CSF with negative etiologic studies (eg, opening pressure can increase to 400 and 440 mm H₂O;[18] CSF abnormalities may persist longer than the clinical symptoms)
• Temporary neurological deficits and acute headache episodes or developing these symptoms just after headache
• Reappearance of headaches and neurological deficits within 3 months [2]

Cranial imaging studies are negative in HaNDL, except for some abnormalities in perfusion-weighted examinations and diffusion restriction of the corpus callosum splenium region. Results from another study showed a case of the characteristic features of HaNDL and an MRI lesion in the splenium of the corpus callosum. CSF neurofilament light chain (NFL) levels were assessed and revealed significantly lower NFL levels than patients with multiple sclerosis. Results suggested that increased CSF levels of NFL and neuroaxonal loss are not characteristic features of HaNDL. Neurological disorders mimicking HaNDL often present with increased levels of NFL, and thus, CSF measurement of NFL might be useful in the differential diagnosis of HaNDL.[19] 

On the other hand, a similar case revealed a substantial increase of neurofilament light in CSF, which normalized after several months. This suggested nerve damage among patients diagnosed with HaNDL due to a relatively typical course with repeated migraine-like headaches accompanied by various transient neurologic deficits and a mean CSF lymphocytic pleocytosis of 178 cells/mm³.[8]

Single-photon emission, computerized tomography test shows decreased temporal blood flow [20] to the cerebral cortex during an episode with neurologic symptoms. Electroencephalogram reveals diffuse slow wave activity,[21] focal, intermittent theta, or delta waveform.[2][14]. 

Other cases reported are as follows:

• A slow, frontal intermittent rhythmic delta activity and symmetric triphasic frontal waves with a dilation lag was shown by a case.[22]
• Moderate, slow rhythm in the cerebral hemisphere, with temporoparietal predominance and without epileptiform activity has been seen.[23]
• The cerebral hemisphere's slow activity and MR susceptibility weighted sequences showed decreased venous signal in the symptomatic hemisphere, unlike other transient disorders such as migraine aura, where an opposite pattern with the prominence of the venous structures in the symptomatic hemisphere is reflected; this sign could reveal decline in metabolic demands or low oxygen employment by damaged tissue. [24]
• A previous study evaluated a patient with HaNDL and confusional symptoms using transcranial Doppler (TCD) ultrasound, and data from patients with focal involvement revealed changes consistent with vasomotor alterations. Furthermore, the patient displayed pleocytosis, diffused slow activity on electroencephalogram, increased blood flow velocity in both middle cerebral arteries on TCD, and single-photon emission computed tomography findings suggest diffuse involvement, particularly in the left hemisphere. Therefore, TCD may be a useful tool for early diagnosis HaNDL.[14]

Treatment / Management

Treating HaNDL syndrome mainly depends on the severity of the disease. The syndrome is a self-limiting condition and has a good recovery rate without treatment. However, due to the high likelihood of disease recurrence, education and reassurance are crucial in the management process. Symptomatically managing headaches is necessary during an acute attack. During the first 2 presentations, patients usually undergo extensive investigations such as neuroimaging and spinal tap, but after a secure diagnosis of HaNDL, less extensive repeat testing is needed.

Antiepileptic and migraine prevention can help prevent acute attacks because of their close association with migraine-like headaches. However, the response of these drugs is difficult to compare to the natural process of the disease itself due to the self-limiting property.[2] Urgent re-evaluation for elevated intracranial pressure is recommended for recurring headaches or developing visual symptoms after recovery from HaNDL. Short- to medium-term management with CSF drainage and acetazolamide is needed to prevent visual loss.[25] 

A case was presented on a HaNDL patient with a history of severe headaches, motor aphasia, and agraphia, with complete recovery between episodes with a normal neurological examination. A lumbar puncture showed lymphocytic pleocytosis. Cerebrospinal fluid analysis ruled out viral, bacterial, mycobacterial, fungal, treponemal, and N-methyl-D-aspartate receptor antibodies. Brain magnetic resonance imaging and electroencephalogram were normal as well. A focal frontotemporal area of hypoperfusion was detected in brain single-photon emission tomography. The patient was treated with ibuprofen (400 mg, 3 times per day) with excellent response and remained asymptomatic and free of any relapse for 6 months.[26] 

Previous study results reported patients with HaNDL and recurrent transient headaches, involuntary movements (left upper extremity chorea), and paralysis. Lumbar punctures showed intracranial hypertension and cerebrospinal fluid pleocytosis. Symptoms and intracranial hypertension were relieved after administering steroids. In conclusion, this treatment indicates the possible treatment strategy for HaNDL and supports the infectious or postinfectious autoimmune etiology hypothesis.[27](B3)

Differential Diagnosis

Headaches with neurological deficits and CSF lymphocytosis usually present as headache episodes with neurological symptoms and considerable cerebrospinal fluid lymphocytosis but no signs of central nervous system infection. At the same time, MRIs of the brain are normal. Although the etiology is still uncertain, viral infection is one of the factors for consideration. The prognosis is excellent, and symptoms typically resolve within 1 to 3 weeks. Due to similarities of symptoms with other neurological disorders,[28] it is essential to rule out more serious diseases, including:

• Migraine with aura and HaNDL syndrome have similar neurovascular changes pathophysiologically, but they are different in terms of the aura symptoms and CSF pleocytosis.[29][30]
• Familial or sporadic forms of hemiplegic migraine do not have CSF lymphocytosis.
• Acute stroke presents with neurologic deficits such as aphasia, hemiparesis or hemiparesthesia, and headaches that are sustained. Positive findings in the brain MRI lack CSF pleocytosis.[30] A case was reported on a patient treated with intravenous alteplase on suspicion of acute ischaemic stroke but was eventually diagnosed with HaNDL.[31] Another case report mentioned that neuroimaging, including computed tomography perfusion (CTP), can help differentiate HaNDL syndrome from a stroke. Hypoperfusion is apparent in the CTP studies in HaNDL syndrome, extending beyond any cerebral arterial supply. The CTP findings suggested a stroke mimic, and no improvement occurred with thrombolysis. No MRI abnormalities were seen in diffusion, and electroencephalograms (EEGs) showed non-epileptiform changes. Lumbar punctures demonstrated a lymphocytic pleocytosis.[32] 
• Meningoencephalitis, meningitis, and encephalitis are infectious causes of headaches, which present with high fever, neck rigidity, and skin rashes. CSF study may reveal the etiology. Particularly relevant Mollaret meningitis (also known as recurrent benign lymphocytic meningitis), aseptic meningitis secondary to virus or pharmacological agents such as non-steroidal anti-inflammatory drugs 
• Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis presents as a severe multistage neuropsychiatric syndrome. A case report on a patient with anti-NMDA receptor encephalitis with clinical symptoms appeared similar to HaNDL, with recurrent episodes of hemianopia, aphasia, right hemiparesis, throbbing headaches, confusion, and agitation. CSF analysis showed lymphocytic pleocytosis and revealed NMDA receptor immunoglobulin G antibodies in the patient's CSF.[33]
• Viral encephalitis and recurrent cerebral ischemic events are based on CSF characteristics and similar symptoms of migraine headache, hemibody paresthesias, hemibody weakness, and encephalopathy.[34]
• Epilepsy, in patients with a seizure in the postictal state, may present with neurologic deficits. CSF pleocytosis is unusual. EEG may reveal epileptiform discharges.
• CNS vasculitis, granulomatous, and neoplastic arachnoiditis are easily differentiated on brain imaging.
• Neurobrucellosis includes a history of close contact with animals, causing headaches with fever, malaise, and myalgias rather than neurologic deficits.
• Neurosyphilis is consistent with a history of multiple sexual partners or sexually transmitted infections.
• Neuroborreliosis has a history of travel to Lyme endemic areas and bulls-eye skin rash.
• Reversible posterior leukoencephalopathy syndrome is differentiated from HANDL by seizures and altered mental status. These patients have characteristic brain imaging abnormalities.[2]

Prognosis

Headache with neurological deficits and CSF lymphocytosis has a good prognosis; it is generally a self-limiting condition and does not require treatment. However, corticosteroids, calcium channel blockers, and acetazolamide were previously used in treatment.[3]

Complications

In the long term, HaNDLE syndrome can be associated with agitation and psychosis, which may require hospitalization. This syndrome may also lead to cortical blindness, papilledema, and sixth cranial nerve palsy in rare cases.[2]