Pseudomigraine with transient neurological deficits and cerebrospinal fluid lymphocytosis or HaNDL syndrome: A case report with confusion and positive IgM antibodies to CMV in serum

Dear Editor,

Pseudomigraine with transient neurological deficits and cerebrospinal fluid (CSF) lymphocytosis (pseudomigraine with pleocytosis (PMP) or headache associated with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL) syndrome) is a relatively rare syndrome that was first described in 1980, and is now classified as “Headache attributed to non-vascular intracranial disorders” according to the International Classification of Headache Disorders (Group 7/7.3.5, ICHD second version (II)–third edition beta (3 beta) 2013).

Its clinical presentation is variable, with confusion being one of the least frequent symptoms.

We describe a patient with confusion that fulfils the diagnostic criteria of this syndrome, while his immunological findings show evidence of recent cytomegalovirus (CMV) infection.

Specifically, an immunocompetent 28-year-old Caucasian male presented at the emergency room because of a bilateral, constrictive headache with nausea, vomiting, aggressiveness and acute confusional state. The whole episode lasted five to six hours and was followed by complete recovery. It was the third one during the previous 10 days, the first two episodes sharing similar characteristics. All the episodes were preceded by numbness of the left hand. Specifically, the numbness concerned the entire left hand, starting a few minutes before the presentation of the above mentioned symptoms and lasting up to six hours until the resolution of the whole episode. Between these episodes the patient was totally asymptomatic and presented no fever. His personal and family medical history was free.

The neurological examination was normal as was brain imaging with computed tomography (CT) and magnetic resonance imaging (MRI). The patient underwent a lumbar puncture where the opening pressure was 20 cm H₂O, and CSF analysis revealed a lymphocytic pleocytosis (316 cells/mm³, 95% lymphocytes), an increase in protein (174 mg/dl) and normal CSF glucose. The electroencephalogram (EEG) showed diffuse slow θ and δ waves.

We proceeded with extensive laboratory testing of serum and CSF in research of infection by herpes simplex virus (HSV)1 and 2, Varicella zoster virus (VZV), Epstein-Barr virus (EBV), CMV, echovirus, Coxsackie virus, Borrelia, Brucella and Treponema pallidum and came across evidence of recent CMV infection without central nervous system (CNS) involvement (positive immunoglobulin (Ig)M and IgG antibodies to CMV only in serum).

One and a half months after the first episode, he was admitted for the second time for follow-up. This time the CSF analysis revealed 48 cells/mm³ (95% lymphocytes), a slighter increase in protein (100 mg/dl) and normal CSF glucose. CSF polymerase chain reaction (PCR) for HSV-6 and CMV was negative. The EEG was significantly improved with normal α rhythm and only a few slow waves.

Finally, four months after the initiation of his symptoms, our patient underwent a third lumbar puncture, which came out normal, but for a slight increase in CSF protein (5 cells/mm³, CSF protein: 53 mg/dl, CSF glucose: normal). We would like to emphasize the fact that throughout this four-month period the patient remained free of symptoms and at no time did he receive any treatment.

The etiology of the syndrome remains unclear. The most popular hypothesis is that a viral infection activates the immune system thereby producing antibodies that induce an aseptic inflammation of the leptomeningeal vasculature, accounting for the clinical picture (1,2) More specifically, an association with Epstein-Barr infection has been reported (1), as has a link with recent human herpes virus-6 infection (2).

A recent description of antibodies to a subunit of the T-type voltage-gated calcium channel CACNA1H in the sera of two patients with this disorder supports this view.

Furthermore, a report of an intermittent cerebellar syndrome with headache and mild pleocytosis of the CSF after varicella infection should be mentioned (3) in this case there were elevated levels of IgM and IgG antibodies to VZV in the serum. Nevertheless, there was no virus detection in the CSF.

Given that most patients who experience aseptic or septic inflammation of the leptomeningeal vasculature do not experience symptoms of HaNDL syndrome, this could raise the hypothesis of a possible predisposition or idiosyncratic susceptibility of certain people to the above mentioned immunological reactions. Nevertheless, there has not yet been established a specific genetic predisposition (4).

HaNDL syndrome is a rare entity. Confusion is not a common presentation, but it should always be kept in mind. Although its etiology remains unclear, our case supports its possible association with recent CMV infection.

Patient consent

Written informed consent was obtained from the patient for publication of this letter and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.