Abstract
Objective
To describe three new cases of the headache syndrome of long-lasting autonomic symptoms with hemicrania (LASH), and to establish a clinical phenotype utilizing all LASH cases noted in the medical literature.
Methods
A case series of patients was evaluated in an academic headache clinic over a two-year time period. LASH syndrome was defined by episodic headache attacks with associated cranial autonomic symptoms that start before headache onset, last the entire duration of the headache and continue on for a period of time after the headache ceases.
Results
Three patients were noted to have LASH syndrome in a two-year time period (2017–2018). One patient was diagnosed with primary LASH, while two others had probable secondary LASH from a secretory pituitary tumor. The primary LASH patient was female. She had on average one headache per week lasting 1–3 days in duration. She experienced migrainous associated symptoms along with their cranial autonomic symptoms. She also developed a fixed Horner's syndrome along with a typical headache attack, which was present for 6 months at the time of consultation. She had complete headache relief with indomethacin and her miosis and ptosis also resolved with treatment.
Secondary LASH was diagnosed in two patients (one male, one female) both with prolactin secreting pituitary microadenomas. One of the patients had his headaches abolish with dopamine agonist therapy while the other patient did not respond to hormonal modulation but became pain free on indomethacin. Secondary LASH patients had less frequent headache episodes and lacked any migrainous associated features, but exhibited agitation with headache.
Conclusion
LASH syndrome may be rare, but more reported cases are entering the headache literature. The temporal profile of onset and offset of cranial autonomic symptoms is key to making the diagnosis. Primary and secondary LASH may present differently based on gender predominance, the presence of migrainous associated features, and attack frequency. Secondary LASH appears to be indomethacin responsive, suggesting that medication effectiveness should not obviate the need to do testing for secondary etiologies.
Introduction
The headache syndrome of long-lasting autonomic symptoms with hemicrania (LASH) is a rare primary headache disorder that appears to be part of a trigeminal autonomic cephalalgia (TAC) spectrum of headaches that includes cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks. LASH also appears to be an indomethacin-responsive headache disorder. LASH is truly characterized by its cranial autonomic symptoms, which begin prior to headache onset, last the entire duration of a long lasting headache (typically 1–3 days) and then continue on for a period of time after head pain resolves (1). During the headache phase patients can experience migrainous associated symptoms along with the cranial autonomic features. The headache pain phase alone is very reminiscent of what is noted in HC, but unlike HC, patients with LASH are pain free in between headache exacerbations. LASH was initially put forth in the medical literature in 2000 by the author (2). There are only four cases reported thus far (3). Three new cases of LASH will be presented with an expanding clinical phenotype including: LASH with a persistent Horner's syndrome and LASH secondary to a secretory pituitary tumor.
Methods
This was a retrospective case series. All patients were seen at an academic headache clinic. Diagnosis of LASH was made based on the temporal profile of cranial autonomic symptoms along with a side-fixed headache. Having no interictal pain between headache attacks was required to make a diagnosis of LASH, thus excluding HC as a diagnosis. Investigation for secondary causes of headache included MRI of the brain with/without gadolinium, MR angiography head and neck with dissection protocol and serum studies for pituitary hormones including prolactin, IGF-1 and growth hormone. The study was given exempt status by the Mayo Clinic IRB. Case patient 3 gave consent for images to be utilized in the manuscript.
Statistical analysis
This is a descriptive case-series study only, so no statistical analysis was utilized.
Results
Demographics and clinical characteristics of LASH (present case series and previously documented cases).
Presumed secondary LASH was diagnosed in two patients (Cases 2 and 3), both with prolactin secreting pituitary microadenomas, located on the same side as the headache. One of the patients (Case 2, Table 1) had his headaches abolish with dopamine agonist therapy (cabergoline) with concurrent suppression of prolactin levels to normal. After 4 months on treatment, the dose of cabergoline was lowered with a slight rise in prolactin levels and recurrence of his headaches with the same pattern of cranial autonomic symptoms preceding head pain. Reinstituting the higher effective dose abolished his headaches. He has been followed for 6 months. Indomethacin was considered as the first line treatment of his headaches, but endocrinology wanted to utilize cabergoline to alter tumor size and normalize prolactin levels. As his headaches resolved on cabergoline, indomethacin was never tried. Injectable indomethacin could have been considered to prove indomethacin responsiveness prior to cabergoline treatment, but this therapy is not available in the United States. The second case (Case 3, Table 1) was suggestive of pituitary tumor-induced LASH but was not as proof positive as Case 2. Her LASH syndrome developed at the time her prolactinoma was initially diagnosed. Brain imaging, which denoted the pituitary lesion, was completed as the patient had developed new headaches. The prolactinoma was treated successfully with dopamine agonist medication but headaches never dissipated until she tried indomethacin, 13 years after headache onset. At the time of consultation her prolactin levels were normal, with a small side-locked tumor on brain imaging. She has been on indomethacin preventively (sustained preparation 75 mg/day) for 6 months and continues to do well. She has been hesitant to stop the medication. The two secondary LASH patients had less frequent headache episodes than noted in primary LASH. They also lacked any migrainous associated features. Both, however, exhibited agitation during the headache phase. Case patient 3 provided images of her cranial autonomic symptoms both prior to headache onset and images after headache resolution with continuation of the cranial autonomic features (Figures 1 and 2). Her main cranial autonomic feature was periorbital edema. She was evaluated during attacks by ophthalmology and otolaryngology looking for secondary lesions like lacrimal gland dysfunction, but nothing was found.
Patient (Case 3) with LASH syndrome having right-sided only headaches. This image was taken 2 hours prior to a headache episode noting right-sided periorbital edema. No head pain at time of image. The same patient as in Figure 1. This image was taken 2 hours after spontaneous cessation of head pain. Of note is right eye periorbital edema with additional distinct lid edema.
Discussion
There are now four primary LASH cases (the present case series and three previously published cases) that are available to interpret the clinical characteristics of the syndrome (3). (Table 1) All are female, with a mean average age of onset of 33 years (age range 19–46 years). Primary LASH patients have an average mean diagnostic delay prior to diagnosis and effective therapy of about 3 years (range 1–5 years). Primary LASH episodes appear to last 1–3 days and at least two episodes per month are noted to occur in the majority (3/4) of patients. The lowest headache frequency is one per month. With regard to cranial autonomic symptoms, orbital edema, lacrimation, and nasal congestion and/or rhinorrhea occurred in all primary LASH patients. A full or partial Horner's syndrome was noted in three of four patients, with one individual having a persistent Horner's syndrome develop during a typical headache episode. Conjunctival injection occurred in three of four patients, while agitation occurred in only one of four patients. Migrainous associated symptoms were noted in three of four primary LASH cases. The majority (3/4) had no prior headache history before developing LASH.
Secondary LASH, of which there are now three cases reported, can occur in males and females, unlike primary LASH (4). Average age of onset is 40 years (range 29–49). Agitation was a predominant symptom in the two pituitary tumor-based LASH patients. Agitation associated with TACs is probably a hypothalamic or hypothalamic-pituitary axis-driven phenomenon (5,6). Migrainous associated features did not occur in secondary LASH, possibly a distinguishing feature from primary LASH.
There were two unique findings from the present case series. Patients with LASH may develop a persistent Horner's syndrome with trigeminal-autonomic complex activation. Developing a persistent or partial Horner's syndrome with TACs has been reported rarely and only noted with cluster headache and in one patient with SUNCT (7,8). The effect of treating the primary headache disorder on the oculosympathetic symptoms has not been reported. The author has recently documented the first cases of LASH (Case 1 in this case series) and HC with persistent Horner's syndrome of long duration (6 months and 2 years respectively) and resolution of the Horner's syndrome after successfully treating the TAC (9).
The present case series is also the first documentation of LASH secondary to a secretory pituitary tumor. TAC-like headaches have been associated with pituitary tumors, both secretory microadenomas and non-secretory macroadenomas (10). If LASH is part of the TAC spectrum of headaches, one would predict that this headache syndrome could arise with a pituitary neoplasm. Both cases were associated with prolactinomas. These two cases suggest the need to look for underlying pituitary lesions in this patient subgroup, at least with serum pituitary hormone studies. Prolactinoma-based LASH may or may not be responsive to dopamine agonist treatment and normalization of prolactin levels. This has been previously noted with other TAC-based headaches linked to secretory pituitary tumors (10).
In regard to treatment, LASH appears to be another indomethacin-responsive headache disorder. Both short-acting and long-acting indomethacin preparations are effective in prevention and in both primary and secondary cases. Short-acting indomethacin should be dosed using the same protocol as in HC and CPH, thus 25 mg taken 3 × per day (TID) for 3 days days and, if no better, 50 mg TID × 3 days and, if no improvement, 75 mg TID × 3 days. If the sustained release preparation is utilized, then the suggested starting dose is 75 mg per day × 7 days followed by an increase to 2× per day if headaches break through. Based on the LASH cases that are now documented, effective dosing can be as little as one 75 mg sustained release dose per day up to 200 mg per day of short-acting indomethacin. Choosing a short-acting or long-acting formulation of indomethacin can be based on patient preference, as both seem equally effective. A trial of melatonin as an alternative treatment to indomethacin is suggested for those LASH patients who cannot taper off indomethacin without headache recurrence. For this case series, none of the patients have tried melatonin as yet. Cases 1 and 3 did not want to alter their effective treatment, while Case 2 was dopamine agonist responsive LASH. The author will normally treat with indomethacin for 3–6 months before switching to melatonin to assess if the TAC syndrome can be cured by indomethacin rather than just being suppressed. Recent literature suggests that melatonin is only fully effective in about 25% of indomethacin-responsive TAC syndromes (11).
With now multiple cases in the literature, should LASH be considered part of the TAC spectrum of indomethacin-responsive headaches and should it be adopted into the ICHD criteria (12)? There is still a consideration that LASH is actually a variant of hemicrania continua, either without interictal pain and/or with such low-grade daily discomfort that patients disregard or do not recognize the pain and thus feel pain free in between episodes (13). The author has repeatedly questioned LASH patients about interictal pain, even using the statement that a pain level of .0001 is pain, but they continue to deny any interictal discomfort. The temporal profile of the cranial autonomic features starting before head pain is also not typical for HC, although how many HC patients that have been documented in the literature were asked when their cranial autonomic features started and ended? Thus, is there a subtype of HC that has cranial autonomic features starting before pain exacerbation periods, continuing along with pain exacerbation and persisting beyond the pain spike? This could be termed HC with long-lasting autonomic symptoms. The remitting form of HC can also be considered in the differential for LASH. The author still believes LASH is a unique condition that sits within the TAC spectrum of headaches, but an overlap condition with HC still remains a possibility until more cases are published.
Limitations
For any newly-recognized headache disorder with minimal documented cases, it is impossible to state what the true demographics and clinical features are until more cases have been published. Thus, what is presented here are the probable norms for primary and secondary LASH. Complete indomethacin responsiveness will also be questioned until more cases are published. In addition, do we need to consider LASH as an HC subtype with more prolonged cranial autonomic symptoms rather than a stand-alone condition?
Conclusion
LASH syndrome may be rare but more reported cases are entering the medical/headache literature. The temporal profile of onset and offset of cranial autonomic symptoms is key to making the diagnosis. Primary and secondary LASH may present differently based on gender predominance, the presence of migrainous associated features, the presence of agitation, and attack frequency. Secondary LASH appears to be indomethacin responsive, suggesting that medication effectiveness should not obviate the need to do testing for secondary etiologies.
Footnotes
Key findings
Key to diagnosis of LASH syndrome is asking about the temporal profile of onset and offset of cranial autonomic symptoms.
LASH syndrome appears to be rare but additional reported cases have established a clinical phenotype.
Secondary LASH can still be indomethacin responsive.
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.