Syndrome of Headache Accompanied with Transient Neurologic Deficits and Cerebrospinal Fluid Lymphocytosis

Abstract

The syndrome of headache accompanied with transient neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is a rare, benign and self limiting syndrome. In the 2nd Edition of the International Classification of Headache Disorders, HaNDL syndrome was defined in secondary headache group as “Headache attributed to non-vascular intracranial disorder”. The etiology of HaNDL is still unknown. In recent years, some authors have shown that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis. In this paper, the definition of HaNDL syndrome, clinical picture and epidemiology of HaNDL syndrome, etiopathogenesis, differential diagnosis and treatment will be reviewed with the recent literature.

Definition and History

“Headache accompanied with transient neurologic deficits and cerebrospinal fluid lymphocytosis”; (HaNDL) syndrome was named as “pseudomigraine accompanied by lymphocytic pleocytosis “ previously. Bartleson et al. defined HaNDL syndrome in 1981 for the first time reporting 7 patients with migraine-like attacks in association with CSF lymphocytosis (1). In these patients, severe episodic headache was found before sensory, motor, speech and visual disorders. Berg and Williams reported 7 new patients in 1995 and proposed that this syndrome might be related with a unique response developing to a single virus or various viral agents (2).

In 1997, Gomez-Aranda et al. also made a clinical definition by analysing 50 patients who had HaNDL syndrome (3). In the classification published by the International Headache Association in 2004, HaNDL syndrome was defined in the last order among “headaches related with extravascular intracranial diseases” which is one of the subgroups of secondary headaches (group 7, code 7, 8) (4).

In this classification, the diagnostic criteria of HaNDL were defined as follows: A. Presence of moderate or severe headache episodes which last for hours; B. Neuroimaging with lymphocytic predominant CSF pleocytosis (>15 cells/microliter, normal CSF culture and nomal etiological tests; C. Transient neurological findings accompanied by headache attacks or occurence of these findings just after headache and a close temporal relation between onset of headache and development of CSF pleocytosis; D. Recurrence of headache and neurological finding episodes in approzimately 3 months (4).

Clinical Picture and Epidemiology

HaNDL syndrome is observed more frequently in men aged between 15 and 40 years (68%) compared to women (5, 6). A history of migraine is present in approximately 26% of the patients (7). The typical clinical picture includes moderate or severe headache episodes with a number ranging between 1 and 12 accompanied by variable neurological finding episodes (6, 7). Headaches are unilateral or bilateral and predominatly throbbing (6). Rarely, leukocytosis and fever may also accompany the picture (6, 7). The most common transient neurological findings include sensory disorder (78% of the episodes), aphasia (60%) and motor disorders (56%) (6, 7). Migraine-like visual symptoms may rarely be observed (%12) (6, 7). Sensory signs frequently start with numbness in the hand and progresses iwth a numbness pattern increased in the arm, face and tounge in order. The trunk and legs are rarely involved (3). In HaNDL syndrome, acute confusional Picture characterized with episodic change in consciousness and agitation may rarely be observed. 5 patients presenting with acute confusional picture have been reported in the literature so far (8, 9, 10, 11). In 4 of these patients, agitation has been reported to accompany the clinical picture (9, 10, 11). In addition, long-term confusional picture resembling psychosis and requiring long-term hospitalization and agitation may also be observed in association with HaNDL syndrome (9, 11). Blurred vision, photophobia, homonymous hemianopsia, photopsia, cortical blindness, papilledema, increased intracranial pressure, 6th cranial nerve palsy and transient total external ophtalmoplegia may also rarely accompany HaNDL syndrome (12, 13).

In HaNDL syndrome, CSF lymphocytic pleocytosis (10–760/mm3) and increased CSF protein (96% of the cases) are observed. Oligoclonal band is found to be negative (6, 7). The patients do not show clinical symptoms between the episodes and after symptomatic periods. These episodes which generally end in weeks or months are seperated with headache periods or asymptomatic periods during which neurological examinations are normal (3).

Cranial imaging tests are generally normal in HaNDL syndrome (5, 6, 7, 11). Athough cranial diffusion-weighted magnetic resonance (MRI) tests are normal (14, 15, 16, 17), abnormalities have been reported on perfusion-weighted examinations in recent studies (14, 16, 17). In another study including one case, diffusion limitation was shown in the corpus callosum splenium region (18). In addition, rare small areas of high signal were reported on cranial MRI examination in some studies (19, 20). On single photon emission computarized tomography (SPECT) in HaNDL syndrome, findings compatible with transient focal cerebral hypoperfusion have been found in relation with the neurological findings during the acute phase (3, 8, 21). It has been reported that prominent VEP amplitude (22) or reduced VEP amplitude (23) may be found in addition to normal results (7) on VEP (visual evoked potential) examinations. On electroencephalogram (EEG), focal, non-epileptic, intermittent slow waves with a character of teta or delta wave have been defined (10, 17, 23, 24).

Ethiopathogenesis

Although the ethiology of HaNDL which has a good prognosis and which is observed rarely is not clear (25), theories focused on parainfectious and autoimmune pathophysiology are still being debated (24, 26). In some studies, it has been proposed that the underlying cause may be inflammatory diseases of the central nervous system (CNS) (1, 3, 5, 24). It has been suggested that the antibodies produced by the immune system activated by way of viruses or autoimmune diseases may lead to CSF pleocytosis and aseptic inflammation which affects leptomeningeal sturctures resulting in neurological findings (7). Detailed screening tests performed for infectious agents are found to be negative in most patients with HaNDL, whereas cases with serological evidence of human herpes virus-6 infection have been reported (24). A CMVrelated meningoencephalitis picture which showed similar clinical and laboratory properties as HaNDL syndrome and in which virus was isolated in CSF was reported in a previous study (5).

No mutation or polymorphism was detected in gene analysis studies of CACNA1A which is one of the subunits of the voltagegated calcium channel performed in HaNDL syndrome which shows similar clinical properties as familial and sporadic hemiplegic migraine (27). Recurring and self-limiting transient neurological findings observed in HaNDL syndrome and CSF lynphocytosis are among the properties shared by autoimmune encephalitis related with ion channel antibodies (28). In another study published recently, high titers of antibody against CACNA1H protein which is one of the subunits of T-type calcium channel were found in 2 patients with HaNDL syndrome. This supported the view that ion channel autoimmunity may partially contribute to the pathogenesis of the syndrome (29).

Differential Diagnosis

The pictures which can be confused clinically with HaNDL syndrome include mainly migraine with aura or headache accompanied by recurrent aura and familial hemiplegic migraine in which reversible neurological findings and CSF lymphocytosis may be observed (27). HaNDL syndrome may be differentiated from this picture with absence of classical aura findings and familial history of hemiplegic migraine. Other significant pathologies including acute stroke, meningoencephalitis, meningitis, epilepsy, granulomatous and neoplastic arachnoiditis, neurobrucellosis, neurosyphylisis, neuroborreliosis, mycoplasma infection, reversible posterior leukoencephalopathy syndrome, encephalitis, CNS vasculitis and reversivel cerebral vasoconstriction should be differentiated from HaNDL syndrome both by clinical picture and investigations including serum autoantibodies, CSF examination and imaging (EEG, MRI etc.) (4, 7, 30).

Treatment

HaNDL syndrome which occurs as self-limiting episodes usually does not require treatment, since it has a good prognosis. However, systemic or oral corticosteroids (12, 17), beta receptor or calcium channel blockers (7, 17) and acetozolamide which is given for papilledema which is observed rarely (12) are among the treatment agents used in previous studies.

In addition, agents used in migraine prophylaxis including mainly antiepileptics may be used in preventing the attacks, since attacks similar to the clinical picture observed in migraine with aura are present in this syndrome. However, long-term controlled studies related with treatment of this syndrome which is observed rarely are absent in the literature except for individual case presentations.

In a case presentation published in recent years in which a patient with HaNDL syndrome was presented, 1000 mg/day valproic acid was used in treatment and a positive response was obtained (17). However, long-term controlled studies related with treatment of this syndrome which is observed rarely are absent in the literature except for individual case presentations. In addition, it is difficult to conclude if the responses observed depend on the drugs given or the disease’s natural course because of the selflimiting property of this syndrome.

Conclusion

Since HaNDL syndrome is observed rarely, it may be overlooked or may be diagnosed falsely in clinical practice. In a patient who has headache accompanied by recurrent neurological disorder episodes, CSF pleocytosis and normal imaging tests, HaNDL syndrome should be absolutely considered. It is considerably important that this syndrome which has a good prognosis is defined and differentiated from pictures which need treatment in terms of avoiding unnecessary therapies including thrombolysis and longterm antimicrobial treatment.

Abbreviations

CSF

Cerebrospinal fluid

HaNDL

Headache accompanied with transient neurologic deficits and cerebrospinal fluid lymphocytosis

MRI

Magnetic resonance imaging

SPECT

Single photon emission computarized tomography

VEP

Visual evoked potential

EEG

Electroencephalography

CNS

Central nervous system