Abstract
Introduction
The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) may mimic stroke when patients present with acute/subacute focal neurological deficits. It would be helpful to identify investigations that assist the neurologist in differentiating between HaNDL and stroke.
Case reports
We describe three cases that proved to be HaNDL, but were initially considered to be strokes. Hypoperfusion was noted in the CT perfusion (CTP) studies in all three cases, which extended beyond any single cerebral arterial supply. The CTP findings suggested a stroke mimic, and there was no improvement on thrombolysis. MRI failed to show any abnormalities in diffusion and EEGs showed non-epileptiform changes. Lumbar punctures demonstrated a lymphocytic pleocytosis.
Conclusion
The diagnosis of HaNDL is based on clinical and CSF criteria, but neuroimaging, including CT perfusion, can be helpful in differentiating the clinical syndrome from stroke.
Introduction
The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare disease with a benign and self-limiting course (1). It may present with sudden onset neurological deficits, raising the suspicion of stroke (2,3). Therefore, its final diagnosis should be made by exclusion, and its differentiation from cerebrovascular disease and from stroke mimics is especially important to avoid unnecessary thrombolysis.
We report three cases admitted to our emergency department with acute onset of neurological deficits initially thought to be stroke. Investigations revealed changes typical of HaNDL.
We describe the investigative findings that differentiated the clinical presentations from stroke. These included non-contrast CT, CT angiography and CT perfusion studies as well as an electroencephalogram (EEG) and magnetic resonance imaging (MRI).
Case 1
Clinical, neuroimaging and EEG findings in the three patients.
CT: computed tomography; F: female; M: male; MRI: magnetic resonance imaging; EEG: electroencephalogram; TIRDA: temporal intermittent rhythmic delta activity; CBV: cerebral blood volume; TTP: time to peak.
Electroencephalographic findings in patient 1: Left temporal intermittent rhythmic delta activity (TIRDA). Average reference montage. High-pass filter 0.5 Hz; low-pass filter 70 Hz; notch-filtered; speed 200 Hz.
Case 2
A 35-year-old woman was referred to our emergency department with the sudden onset of severe right temporal headache, photophobia and speech disturbance. She had been on oral anticoagulation (acenocumarol) in the management of a uterine arteriovenous malformation detected following a spontaneous abortion. She had no other relevant medical history and specifically no history of headache. One of her companions revealed that she had firstly described right hand hypoesthesia that progressed over at least 10 minutes to cover the whole right arm and face. A further retrospective history was obtained from the patient that explained that the sensory symptoms developed over 30 minutes before the onset of the dysphasia. Routine blood tests including INR and electrocardiogram were normal, and a left hemispheric hypoperfusion pattern (decreased cerebral blood volume and delayed time to peak) that included cortical MCA and PCA territories was detected on perfusion CT with no vascular occlusion on CT angiogram. Given the acute onset of the symptoms, a vascular etiology was suspected and thrombolytic treatment was prescribed. The patient did not show any clinical improvement. On reassessment a few hours later, it was noted that motor aphasia persisted as did the right hypoesthesia, and there was a right homonymous hemianopia. Her symptoms waned slowly, but she retained a mild dysphasia that resolved over the ensuing 24 hours. No abnormalities were noted in the non-contrast CT scan obtained 24 hours after clinical onset. Cranial MRI showed a left parietotemporal hyperperfusion (increased cerebral blood flow and volume) and EEG revealed left hemispheric slowing with an intermittent and irregular theta/delta activity. The CSF opening pressure was 22 cm H20 and a lymphocytic pleocytosis was detected (212 cells/mm3 with 99% lymphocytes); glucose and protein levels were normal and microbiological tests ruled out infectious disease. Seventy two hours after admission a Transcranial Doppler (TCD) revealed an asymmetry between both middle cerebral arteries (MCA) with increased velocity on the left. The patient showed clinical recovery and resolution within 48 hours of admission. There was no recurrence of neurological complaints over a two-year follow up (Table 1).
Case 3
A 19-year-old man presented to the emergency department with a thunderclap headache. He had been previously well, but had experienced migraine with typical visual aura since his adolescence. The rapid development of the presenting attack was unlike his migraines, although he did experience associated nausea, vomiting, as well as photophobia and phonophobia as with his usual migraines. At presentation, the patient was disorientated in time and place and had a variable capacity to sustain attention. He also showed mixed dysphasia (NIHSS score = 6). His migraines had never been associated with motor, sensory or speech impairments. Non-contrast CT and CT angiogram were performed 180 minutes after clinical onset, but demonstrated no abnormalities. Perfusion CT showed a delayed time to peak in the left parieto-occipital region with normal cerebral blood flow and volume. He was initially diagnosed as stroke and treated with rt-PA with no improvement. His confusional state and neurological deficits improved progressively and resolved within 12 hours. EEG and MRI revealed no abnormalities and the patient was discharged asymptomatic. The patient presented again two weeks later in a similar episode involving headache, inattention and aphasia. On examination on arrival, 30 minutes after clinical onset, no language impairment or focal neurological finding were detected. Twenty minutes later he complained of a more severe headache and expressive aphasia was detected on neurological examination. A multiparametric CT showed no abnormalities. The headache resolved within hours of an intravenous dose of dexketoprophen. The cerebrospinal fluid revealed pleocytosis (75 cells/mm3 with 100% lymphocytes) with a protein level of 51.3 mg/dl and normal glucose level. Bacterial and viral cultures were negative. The patient remained asymptomatic over the ensuing 7 months of follow up (Table 1, Figure 2).
CT perfusion findings in patient 3. (a) Cerebral blood volume: normal. (b) Cerebral blood flow: normal. (c) Time to peak: delayed left hemispheric parieto-occipital time to peak.
Discussion
Our three patients fulfilled all the diagnostic criteria for HaNDL syndrome (4). This rare disease can present with sudden onset focal neurological deficits, and our patients were referred to the neurology service as their symptoms mimicked stroke.
The rate of stroke mimics (SM) ranges from 1.3–25% in patients evaluated by stroke clinicians (5). Along with epilepsy, HaNDL syndrome is one of the most frequent diagnoses within SM, and is usually only suspected after a second presentation (5). Other common differential diagnoses include migraine, encephalitis, conversion disorders and posterior reversible encephalopathy syndrome.
Not surprisingly, two of our patients and up to 55% of the patients with HaNDL are treated with rt-PA (2). Patients with SM receiving thrombolysis are unlikely to suffer ill effects of that treatment (5). Where there is doubt, the neurologist should not withhold rt-PA, as its potential benefits in ischaemic stroke would outweigh the risk of complications in SMs.
Clinical presentation with migratory symptoms from one region of the brain to another over time reflecting spreading depression should make the wary physician question the diagnosis of stroke. Other clinical characteristics such as those found in our patients (younger patients, isolated aphasia, no known vascular risk factors, associated headache) (5) should also raise the suspicion of SM. At the time of presentation the clinical details may not be clear, particularly when patients are aphasic at the time. Investigations, particularly CTP, may be of value in this circumstance.
The initial evaluation of our patients involved mutiparametric CT, a routine in our Emergency Department. We have recently reported our CT perfusion findings in stroke mimics of epileptic origin (6). In the present study, CTP demonstrated increased time to peak in a widespread distribution that was beyond the territory of any single major cerebral artery, and deeper structures, such as basal ganglia, were spared suggesting primarily cortical involvement. There was no large vessel occlusion identified. Similar findings have been described in CT studies of other stroke mimics including migraine and HaNDL (7,8). The pathophysiology of HaNDL is unknown, but it appears that cortical irritation from an atypical meningitis (9,10) may trigger a migraine-like cortical spreading depression (1,7).
A reduction in blood flow has been previously shown by SPECT and TCD (11,12). In the largest series of HaNDL reported with CT perfusion data (2), focal and unilateral hypoperfusion has been demonstrated, much as seen in our cases. It is a common observation that the abnormalities extend beyond territories involving a single major cerebral artery, suggesting that the primary process is not vascular insufficiency but perhaps cortical metabolic change modifying blood flow secondarily (13).
Above any other investigation, lumbar puncture should probably be the test of choice in the case of individuals presenting with repeated atypical headaches with manifestations of cortical spreading depression. EEG is also usually performed to exclude an epileptiform origin to the presentation. Despite the scarce publication on possible EEG abnormalities in patients with HaNDL, serial EEG studies have shown that clinical symptoms of HaNDL correlate with non-specific non-epileptiform changes such as asymmetrical generalized slowing, intermittent rhythmic delta activity and triphasic waves (10). MRI might also be useful to assess a possible perfusion/diffusion mismatch (3) and, in addition, FLAIR images are able to show CSF meningeal enhancement in the sulci of the temporal and occipital lobes (14).
We described our clinical and investigative findings in three patients who were initially suspected of having a stroke in whom the diagnosis of HaNDL was established. Of the investigations, the CT perfusion studies proved helpful in differentiating the presentations from stroke. Other diagnostic tests, such as EEG and MRI, are usually performed to exclude other conditions. However, it is firstly the clinical presentation (slow sensory march with migratory symptoms and atypical headache) that can assist the wary neurologist in differentiating this condition from stroke. A low threshold should be established for obtaining a lumbar puncture in atypical headache presentations to rule out chronic meningitis in general and the possibility of HaNDL.
Clinical implications
HaNDL diagnosis is made based on both clinical and CSF criteria. A slow sensory march is a common clinical finding of cortical spreading depression that assists in differentiating the condition from stroke. A hypoperfusion pattern on perfusion CT in a non-vascular territory with no vascular occlusion should raise the suspicion of a stroke mimic. Non-epileptiform changes such as an asymmetrical generalized slowing, intermittent rhythmic delta activity and triphasic waves can be found in HaNDL patients.
Patient perspective
The patients could share their perspective on their cases if necessary.
Informed consent
The patients included have given informed consent.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.