Headache With Neurological Deficits and CSF Lymphocytosis
The syndrome of headache with neurological deficits and elevated CSF lymphocytes (HaNDL) is a rare, benign, and self-limiting condition. It is predominant in young adults and characteristically present with migraine-like headaches, transient neurologic deficits such as hemiparesis, hemiparesthesia, and dysphagia, and lymphocytic pleocytosis in the CSF. This syndrome is grossly underrecognized and underreported.
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The cause of HaNDL syndrome remains poorly understood, but there is various speculation about its etiology. Initially, the thinking was that it was secondary to inflammation/infection due to frequent viral prodrome, monophasic course, and the presence of CSF lymphocytosis. However, large scale viral serological examinations did not reveal particular association with any infectious agent except isolated reports of echovirus 30, HHV6 and 7, and borrelia infection. Based on sophisticated imaging studies(single-photon emission computed tomography, Head CT perfusion imaging, MRI perfusion techniques, transcranial Doppler) pathogenesis similar to migraine also has been suggested with decreased hypoperfusion linked with cortical spreading depression.
Despite the findings similar to migraine pathophysiology, symptomatic explanation secondary to aseptic meningitis due to viral/inflammatory etiology has been a target or research. For example, investigation pertains to autoimmune cross-reactivity between any inflammatory or viral disease-causing autoantibodies against neuronal or vascular structures that induce an aseptic inflammation in leptomeningeal vasculature. In recent years, some studies have also shown autoantibodies to a type of calcium channel, CACNA1H in some patients with HaNDL, CACNA1A pathogenic variants were not present in 8 patients with HaNDL. On the other hand, a minority of patients in HaDNL syndrome also had an antibody related to protein kinase with mitogen activity and another protein kinase with DNA dependent catalytic subunit (DPKCU).
HaNDL syndrome is more common in males between ages 15 to 40 years (68%) compared to females. However, the literature does not consistently report this, and in pediatric cases(may constitute 15% of the total cases), there may be a significant female predominance.
Only 26% of the patients have a positive history of migraines, and typical presentation is of moderate to severe intensity headache with a range of 1 to 12 episodes accompanied by neurological deficits. Recurrence of the episodes usually occurs within a brief period of 3 months. 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.
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, which are 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.
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, which are subunits of T-type calcium channel in 2 out of 4 patients with HaNDL supporting the view of autoimmunity partially contributing to its pathogenesis.
History and Physical
The classic presentation of HaNDL syndrome is as follows:
- Headache (unilateral or global), mostly throbbing in nature, and moderate to severe in severity. The duration of the headache is usually one hour to one week but typically lasts for a few hours. Although headache can be the first sign, it usually follows neurologic symptoms by 15 to 60 minutes. Headache can be associated with nausea, vomiting, and photophobia.
- Fever with leukocytosis (rarely).
- Neurological findings are, in descending order of presentation; (i) sensory disorder;(ii) aphasia;(iii) motor disorders. Neurologic symptoms usually last from a few minutes to 2 to 3 days but typically resolves within 2 hours. The sensory symptoms in HaNDL syndrome-presents as numbness usually starting from hand and progress to the arm, face, and tongue with trunk and legs are rarely affected. Patients also rarely experience acute confusion characterized by a change in consciousness and agitation. This syndrome that usually last weeks to months (usually 2 to 3 weeks), separated by asymptomatic periods or just headache during which the neurological exam is normal. The neurologic deficits are often different from one episode to the next due to the involvement of varying cortical regions. The literature more frequently reports left hemispheric involvement with right-sided neurological deficits.
- Visual symptoms.
- Rarely ophthalmologic complications like blindness, photophobia, and double vision.
- Raised intracranial pressure. Although HaNDL is typically considered a benign disorder, there are reports of rare catastrophic presentation requiring ventilatory or life support.
The evaluation of HaNDL is performed by a diagnostic criterion as follows:
- Severe to moderate intensity migraine-like headache lasting for a few hours.
- Increased lymphocytes (>15 white cells/ml))in the CSF with negative etiologic studies. The opening pressure can increase to 400 and 440 mmH2O. CSF abnormalities may persist longer than the clinical symptoms.
- Temporary neurological deficits along with acute headache episodes or development of these symptoms just after a headache
- The reappearance of headache and neurological deficits within three months.
Cranial imaging studies are negative in HaNDL, except for some abnormalities in perfusion-weighted examinations and diffusion restriction of the corpus callosum splenium region.
Treatment / Management
The treatment of HaNDL syndrome mainly depends on the severity of the disease. It is a self-limiting condition and has a good recovery rate without treatment. But due to the high likelihood of recurrence of the disease, education, and reassurance are crucial in the management process. Symptomatic management of headaches is necessary during an acute attack. During the first two presentations, patients usually undergo extensive investigations such as neuroimaging and spinal tap, but after a secure diagnosis of HaNDL, there is less extensive repeat testing.
Antiepileptic and migraine prophylaxis can help prevent acute attacks since its close association with migraine-like headaches. Although the response of these drugs is difficult to compare to the natural process of the disease itself due to its self-limiting property.
Disease presenting similarly to HaNDL syndrome include:
- Migraine with aura: It can be differentiated from HaNDL syndrome because it lacks typical aura symptoms and CSF pleocytosis.
- Familial or sporadic forms of hemiplegic migraine: They don't have CSF lymphocytosis.
- Acute stroke: The symptoms of neurologic deficits in stroke are not transient, positive findings in the brain MRI, and lacks the typical finding of CSF pleocytosis.
- Meningoencephalitis, meningitis, and encephalitis: These are some infectious causes of headache 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 NSAIDs
- Epilepsy: The neurologic symptom in epilepsy usually present after a seizure in the postictal state. CSF pleocytosis is unusual. EEG may reveal epileptiform discharges.
- CNS vasculitis and granulomatous and neoplastic arachnoiditis: can be easily differentiated on brain imaging.
- Neurobrucellosis: History of close contact with animals, causes headache with fever, malaise, myalgias rather than neurologic deficits.
- Neurosyphylisis: A history of multiple sexual partners or STDs.
- Neuroborreliosis: A history of travel to Lyme endemic areas and bulls-eye skin rash.
- Reversible posterior leukoencephalopathy syndrome: differentiated by seizures and altered mental status. These patients have characteristic brain imaging abnormality.
- Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis
HaNDL syndrome 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.
In the long term, HaNDLE syndrome can be associated with agitation and confusional picture like psychosis, which may require hospitalization. This syndrome may also lead to cortical blindness, papilledema, CN VI palsy in rare cases.
Deterrence and Patient Education
Patients with HANDL syndrome should be educated about the nature of the disease and must be well informed about the benign and self-limiting nature of the disease. The rare occurrence of risk and complications of HaNDL syndrome should also be explained to the patient and their family. Apart from its dramatic and sudden onset, the condition is self-limited and rarely causes any life long complications.
Pearls and Other Issues
- HaNDL syndrome is a benign disorder, mostly unrecognized and underreported.
- Although its presentation is acute and severe, the ultimate prognosis is good.
Enhancing Healthcare Team Outcomes
The management of HaNDL syndrome requires an interprofessional team approach. Acute and severe presentation with headache and focal neurologic deficit generally require the patient to go through a series of investigations to reach this diagnosis. Patients usually present in the emergency department because of the abrupt onset of throbbing headache, along with some neurologic deficits where they usually initiate care under emergency room physicians. Later depending on the severity of the presentation, patients may get admitted to an intensive care setting under the supervision of an intensivist.
The intensivists are particularly necessary if the presentation associated with severe complications(an acute confusional state with an inability to protect airways, raised intracranial pressure) for life-saving support. Complications such as psychosis and papilledema may require the involvement of psychiatrists and regular checkups from an ophthalmologist. Continuous nursing care is requisite during an acute episode with neurologic deficits, which may take a few days to resolve. Neurology consultation is necessary due to acute onset headaches and focal neurologic deficits, and expert guidance by a neurologist is always helpful to rule out other differentials.
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