Alice in Wonderland Syndrome, Burning Mouth Syndrome, Cold Stimulus Headache, and HaNDL: Narrative Review

Marcelo M. Valença, MD, PhD; Daniella A. de Oliveira, PhD; Hugo André de L. Martins, MD, PhD

Disclosures

Headache. 2015;55(9):1233-1248. 

In This Article

The Syndrome of Transient Headache and Neurologic Deficits With Cerebrospinal Fluid Lymphocytosis (HaNDL)

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL, ICHD-3 Beta 7.3.5)[8] is, in principle, a self-limited headache disorder, with a benign course, characterized as severe/moderate headache attacks, associated with neurological symptoms, usually of a transient nature, and lymphocytic pleocytosis.[9–11] This disorder was previously known as "migrainous syndrome with CSF pleocytosis" or "pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis."

The ICHD-3 Beta[8] diagnostic criteria are as follows:

"Description:

Migraine-like headache episodes (typically 1–12) accompanied by neurological deficits including hemiparaesthesia, hemiparesis, and/or dysphasia, but positive visual symptoms only uncommonly, lasting several hours. There is lymphocytic pleocytosis. The disorder resolves spontaneously within 3 months.

Diagnostic criteria:

  1. Episodes of migraine-like headache fulfilling criteria B and C;

  2. Both of the following: (1) Accompanied or shortly preceded by the onset of at least one of the following transient neurological deficits lasting >4 hours: (a) hemiparaesthesia, (b) dysphasia, (c) hemiparesis; (2) Associated with CSF lymphocytic pleocytosis (>15 white cells/mL), with negative etiological studies.

  3. Evidence of causation demonstrated by either or both of the following:

  4. Headache and transient neurological deficits have developed or significantly worsened in temporal relation to the CSF lymphocytic pleocytosis, or led to its discovery; Headache and transient neurological deficits have significantly improved in parallel with improvement in the CSF lymphocytic pleocytosis.

  5. Not better accounted for by another ICHD-3 diagnosis."

Three decades after the first clear description of this syndrome[12] its etiopathogenesis remains unknown. Initially, transient neurological deficits were interpreted as the result of local cortical hypoperfusion[13–15] due to the Leão spreading depression phenomenon in migraineurs.[16–18] However, most individuals with the syndrome are not migraineurs and there is a prevalence in males;[11] this is at odds with the idea that HaNDL represents a complication of a migraine attack with a prolonged aura. Recent studies using neuroimaging have shown that there is a hypoperfusion in the cerebral regions, corresponding to the patient's neurologic symptoms.[19] In addition, electroencephalography (EEG) changes (72% of the cases)[20] are usually also recorded in the symptomatic cerebral region, pointing to a local brain dysfunction.[13,21]

It seems that there is an infectious or inflammatory trigger in the pathogenesis of this disorder, as the patients frequently report a prodromal viral illness. Some of the subjects with HaNDL reported that the headache was more intense on the contralateral side of the neurological symptoms,[11] which is suggestive of an inflammatory process in the pathophysiology of the disease. This lateralized headache, together with the lyphocytic pleocytosis (>65%)[10,11] and the fluctuating neurological deficits, lead us to believe that there is an inflammatory process either indirectly producing arterial changes or of a truly vascular origin. It is possible that during a viral infection antibodies against neuronal or vascular antigens are produced, thus causing an aseptic leptomeningeal vasculitis, which, by means of a spreading depression-like phenomenon, would trigger neurological symptomatology. In this regard, an ion channel (T-type voltage-gated calcium channel) autoimmunity seems to play a role in the pathophysiology.[22]

Interestingly, angiographic studies performed in a small number of patients with HaNDL were unable to disclose any major vascular abnormality.[11] In fact, in a few subjects the intra-arterial angiography even enhanced or precipitated the neurological deficit.[11,23] Thus, the use of intravenous contrast should be avoided during the acute phase of the disease. The patient should be studied by magnetic resonance imaging (MRI), including perfusion, diffusion, and angio-MRI.[19,21,24–26] In this regard, the differential diagnosis between HaNDL and ischemic stroke is often very difficult.[24,25,27] A slow, rather than sudden, progression of the neurological deficit over several minutes, associated with headache, in a young adult with vomiting and a normal computerized tomography (CT) scan and/or MRI may be an indication that the neurological symptomatology was not caused by a stroke.

Headache is an important component of the HaNDL syndrome, but headache may be absent or mild.[10,11,28] In several cases, the neurological focal deficits occurred prior to the headache episode. There is usually no clear sign of meningeal irritation.[10,11]

Gomez-Aranda et al[11] reported the largest published series of cases with clinical findings from 50 subjects (34 male, 68%; age 14–39 years) with HaNDL, who had a total of 164 episodes [mean 3/patient, range 1–12/patient; 11/50 (22%) with a single episode] of a transient neurological deficit accompanied by headache. The authors' diagnostic criteria[11] permitted the inclusion of patients with at least one episode of transient neurological deficit with headache and when there was spontaneous resolution of the clinical picture in <4 months.

All patients reported moderate to severe headache (quality: predominantly throbbing 81%, oppressive/throbbing 7%; location: bilateral in 59%, hemicranial always contralateral to the focal symptoms in 37%; duration: 19 ± 30 hours, range 1 hour to 1 week). Isolated headache attacks (without transient neurological deficits) were reported by 16 patients (2.5 ± 2.2; 1–8/patient), while in 2 patients the transient neurological deficit occurred without the expected headache.[11] This indicates that the headache-neurological symptoms-pleocytosis triad may not be fully manifested in the course of the disease, particularly during its typical periods of "exacerbation."

Sensory deficit (70%), aphasic disturbances (66%), weakness (42%), visual complaints (18%), dysarthria and epileptic seizure (1 patient each), nausea and vomiting (54%), isolated nausea (6%), photophobia and phonophobia (16%), and fever (22%) were some of the accompanying signs or symptoms. In 40 of the 50 patients (80%), the transient neurological deficit was restricted to one cerebral hemisphere (37 left side) and in 6% the vertebrobasilar territory was involved. The duration of the neurologic deficit was from 5 minutes to 3 days (5 ± 13 hours). In this series, the total duration of the illness was estimated to be from 6 hours to 49 days (14 ± 10 days).[11]

A typical characteristic of the syndrome is asymmetrical involvement of the cerebral hemispheres, although the involvement may be bilateral in the same attack or in different exacerbations of the disease.

HaNDL may be a more frequent disorder than one might expect.[23] Using the current ICHD-3 Beta diagnostic criteria for HaNDL,[8] it is likely that the disease is been underdiagnosed for at least 2 reasons: (I) Permanent or prolonged neurological deficit as a possible vascular complication in patients with HaNDL may exclude the diagnosis because with a permanent deficit the patient does not fulfill the diagnostic criteria; (II) The pathological process may affect a silent cerebral area, such that the absence of neurological focal deficit would again not meet the diagnostic criteria of HaNDL. In this regard, in 80% of the patients reported by Gomez-Aranda[11] the left cerebral hemisphere was the more affected. A significant number of patients with HaNDL are certainly not included, due to the oligosymptomatic nature of the right cerebral hemisphere, with its larger extension of "silent" cortex. In this regard, Liblau et al[29] reported the case of a nonmigrainous 26-year-old man with a 5-week history of migraine-like attacks and CSF lymphocytosis and with no neurological focal deficit.

Goncalves et al[30] recently claimed that the HaNDL syndrome is rare in children, with less than 20 pediatric case reports.

HaNDL is a diagnosis of exclusion.[31,32] Table 1 displays the main differential diagnoses to be ruled out before diagnosing HaNDL.

Some authors assert that HaNDL "is always a self-limited condition …without leaving any neurologic sequelae" and the treatment would, therefore, be simply symptomatic headache management.[9,30] As a result of a misconception of the presumed benignity of this neurological disease, patients with HaNDL who progress with permanent or prolonged neurological complications do not fulfill the current diagnostic criteria for HaNDL. The neurological deficits occurring during a HaNDL crisis are so dramatic (eg, aphasia, hemiplegia, paresthesia, hemianopia, mental confusion, and transient global amnesia)[9,11,35] that they must not be underestimated on the assumption that they will recede within a few hours. Since there is evidence indicating a vascular focal involvement or a local hypoperfusion of brain tissue,[11] we believe that, despite the dearth of clinical support, the empirical use of nimodipine and magnesium might benefit the patient as a neuroprotective strategy, in a way similar to the treatment regimen used in cerebral vasospasm.[36] Thus, nimodipine should be used for at least 3 weeks, bearing in mind the possibility of a recurrent neurological deficit. In addition, a significant part (73%)[20,37] of the patients with HaNDL develop intracranial hypertension, and a few may present decreased vision, papilledema or sixth nerve palsy, as reported in 2 subjects treated with acetazolamide.[20] One of these received systemic corticoid and even so was left with permanent visual sequelae, indicating that HaNDL is not always a benign condition.

Piovesan et al[37] reported the case of a 23-year-old man with 3 severe headache episodes 4 days apart between the crises. The headache was accompanied by transient sensitive-motor deficits in the left limbs and a very high (440 mm H2O) CSF pressure. This suggests that during clinical exacerbation intracranial hypertension may occur, which may explain the severe intensity of the headache and the usual vomiting episodes. In the third exacerbation of the clinical picture, the patient received dexamethasone (12 mg daily for 3 days), with no recurrence in the following 14 months. Although a number of facts suggest inflammation (cold-like symptoms, fever leukocytosis), the evidence is still limited regarding the efficacy of corticoids or immunosuppressive therapy.

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