The unusual presentation of the aforementioned dog has striking resemblance to migraine attacks in people. To the authors' knowledge, a condition with similar clinical signs has not been described in veterinary literature, so we summarize the current literature from human and experimental medicine on migraine.
Classification and Clinical Signs of Migraines in People
The International Classification of Headache Disorders (revision 2) defines 4 primary and 10 secondary groups of headache. Primary headaches include migraine, tension-type headache, trigeminal autonomic cephalalgias, and “other primary headache” (a heterogeneous grouping of primary headaches). Migraine is further divided into 6 major subtypes:
- Migraine without aura
- Migraine with aura
- Childhood periodic disorder
- Retinal migraine
- Complications of migraine
- Probable migraine
Migraines are typically recurrent severe headaches associated with autonomic clinical signs. They can be episodic (less than 15 days per month) or chronic (occurring 15 days or more per month). They can manifest with aura (20%) or without. Aura is a transient phenomenon, which appears usually gradually over 5–20 minutes and lasts less than 60 minutes. It is followed by a headache attack and is characterized by visual (most common), sensory, motor, or both effects. When the aura is not followed by a headache attack, it is called an acephalgic migraine. In some people, a premonitory (or prodrome) and headache resolution (or postdrome) phase can proceed and follow, respectively, a migraine attack with more vague clinical signs of hyperactivity, hypoactivity, depression, craving for specific foods, repetitive yawning, and other less specific clinical signs. The actual headache attack can last 4–72 hours, have unilateral location, pulsating quality, moderate or severe intensity, and they can be associated with autonomic signs (nausea), photophobia, or phonophobia. The aforementioned case was experiencing clinical signs that could reflect all 4 phases, although distinguishing a premonitory phase from aura might not be possible in animals.
Diagnosis in People
Diagnosis of migraine can be challenging. The Headache Classification Committee of the International Headache Society has created the following diagnostic criteria to help the clinician to distinguish migraine from other types of headaches:
- At least 5 attacks fulfilling criteria B through D. For migraine with aura, 2 attacks are sufficient for diagnosis
- Headache attacks lasting 4–72 hours
- Headache has at least 2 of the following characteristics:
Moderate or severe pain intensity
Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)
During headache, at least one of the following:
Nausea, vomiting, or both
Photophobia and phonophobia
Not attributed to another disorder
Although these criteria are intended for people and were created after decades of studying and treating humans with this condition, it is interesting to note that if we could apply them to the aforementioned dog, she would fulfill all of them. The dog had experienced numerous attacks (more than 5), the episodes of vocalization could last from 4 hours up to 3 days, the episodes were severe enough to prevent physical activity, as she was refusing to go for walks. She appeared to be photophobic and phonophobic, and had clinical signs suggestive of nausea, occasionally vomiting. Extensive diagnostic investigation could not identify any known cause that could explain her clinical signs.
Diagnostic imaging cannot currently be used for diagnosing migraines. However, functional MRI (fMRI) has shown activation (hyperoxia and blood volume increase) of the red nucleus and substantia nigra during a migraine attack and increased photoreactivity of the occipital cortex during the interictal period in migraineurs. Diffusion-weighted MRI has shown microstructural white matter alterations in migraine patients and Gentile et al have reported MRI findings of cerebral vasogenic edema in a patient in status migrainosus (migraine headache lasting more than 72 hours). Although diagnostic imaging cannot diagnose migraine, it is important to rule out structural brain lesions, and fMRI studies can provide valuable information to improve our understanding of migraine pathophysiology.
Anatomy of Head Pain
The brain parenchyma is insensate. However, the meninges, meningeal blood vessels, cerebral arteries, venous sinuses, cranial nerves, cervical roots, and other head structures (ie, eyes, ears) are innervated and can cause pain. Intracranial structures rostral to the tentorium cerebelli are innervated by the trigeminal nerve, and those caudal by the cervical nerves C2 and C3, facial (CN VII), glossopharyngeal (CN IX), and vagus (X) nerves. The dura mater and meningeal blood vessels have both sensory and autonomic innervations. Unmyelinated afferent C fibers innervating peripheral structures pass through the trigeminal ganglion, enter the pons and synapse on second order neurons at the trigeminal nucleus caudalis (TNC). The TNC extends from the medulla oblongata into the cervical dorsal horns in a functional continuum that includes a cervical extension. Together the neurons from the TNC and its cervical extension form the trigeminal cervical complex (TCC), which is implicated in the largest proportion of primary headaches.[2, 15] Fibers, from the TCC in return, project through the quintothalamic tract and after decussating in the brainstem, form synapses with the thalamus and collaterals to the autonomic nuclei in the brainstem and the hypothalamus. Thalamic neurons project to the somatosensory cortex, but also to areas of the limbic system. In addition, the TNC has polysynaptic connections to the parasympathetic superior salivatory nucleus in the pons. Efferent parasympathetic axons project from this nucleus through the pterygopalatine ganglion and innervate meningeal vessels and contents of the nasal sinuses and eyes. Brain imaging studies suggest that important regulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus ceruleus, and nucleus raphe magnus.
Over the past few decades, migraine pathophysiology has attracted interest and has sparked a debate on whether it is a vascular disorder or a primary neuronal disorder. It is now clearer that the vascular changes are considered secondary to a primary brain excitability and a sensory dysmodulation disorder. There are certain triggers that have been associated with a migraine attack in people. These include bright lights, loud noise, certain odors, certain foods (aged cheeses and other) or delaying a meal, hormonal changes, head trauma, and nitrous oxide (NO).
A phenomenon named cortical spreading depression (CSD), which proceeds the headache attack, seems to play an important role in migraine pathophysiology, and there is strong association between this phenomenon and the visual aura that 20% of patients experience before a migraine attack. It is believed that CSD is taking place in the cerebral cortex, cerebellum, and hippocampus. During this phenomenon, the intracellular calcium concentration rises and calcium waves are generated, throughout glia, changing vascular activity. A wave of depolarization moves across the cerebral cortex and NO, arachidonic acid, protons, and potassium are released extracellularly. As a consequence, trigeminal neurons of the trigeminovascular pathway release calcitonin gene-related peptide (CGRP), substance P, and neurokinin A, which causes meningeal vasodilation (after an initial phase of vasoconstriction) and inflammation (sterile neurogenic inflammation). This inflammation activates the first-order trigeminal neurons (peripheral sensitization), which is thought to carry pain signals centrally. After activation of the TNC, the superior salivatory nucleus can be activated too through its polysynaptic connections and subsequently parasympathetic fibers innervating the dural vessels release acetylcholine, NO, and vasoactive intestinal polypeptide. Clinically, the patient experiences pounding pain at this stage, which can be associated with miosis, ptosis, red eye, lacrimation, nasal congestion, and rhinorrhea. If the attack is not treated at an early stage, then it can progress and second- (trigeminothalamic) and third-order (thalamocortical) neurons can be activated (central sensitization or wind-up phenomenon) and clinically can be manifested as cutaneous allodynia (facial/neck pain that occurs spontaneously or in response to nonpainful stimuli).
Migraine is typically hereditary and is usually polygenic. Studies on twins indicate a 34–54% genetic influence on the development of migraines. Despite this influence, no single genes predisposing to common forms of migraine have been identified yet. The only single gene-related headache disorder is a form of migraine, named familial hemiplegic migraine (FHM). FHM is a rare subtype of migraine with aura with an autosomal dominant inheritance pattern and is characterized by transient hemiparesis or hemiplegia during the aura phase of a migraine attack. The remainder of the clinical signs of this condition is similar to the other forms of migraine.[2, 19] Mutations in 3 different genes (FHM1, FHM2, and FHM3) have been identified in families with FHM and have been associated with brain hyperexcitability and CSD, as a result of increased glutamate action.
Migraine and epilepsy share many clinical features and underlying pathophysiologic mechanisms. The initial event preceding CSD is increased cellular excitability associated with localized epileptiform discharges.[20, 21] Glutamate seems to be a critical mediator of hyperexcitability in both focal seizures and migraine. Also, epidemiological studies demonstrate that epilepsy and migraine are comorbid conditions that might have a shared genetic basis.
Pharmacology and Treatment
In 1938, Graham and Wolff demonstrated that intravenous administration of ergotamine during migraine attack decreases the amplitude of arterial pulsations, which happened to coincide with the reduction in headache pain. This inspired the vascular theory that an initial cerebral vasoconstriction followed by an extracranial vasodilation leads to a migraine attack. This theory was the basis for research for many decades until recently. Over the years, the migraine research focused on the development of other vasoconstrictive drugs such as the triptans (eg, sumatriptan), but at the same time, it became apparent that other drugs without any vasoconstrictive properties, such as ibuprofen and CGRP antagonists, were equally effective.
It is now believed that ergot drugs, as well as triptans, bind to many different sites, which can affect neurotransmitter release. These drugs primarily bind to serotonin receptors 5-hydroxytryptamine 1D and 1B (5-HT1D and 5-HT1B). The 5-HT1D receptors are presynaptic and they can be located on trigeminal neurons and the TNC. Activation of these receptors prevents the release of CGRP from the trigeminal neurons, whereas activation of 5-HT1B receptors of blood vessels causes vasoconstriction. The latter receptors in the TNC also decrease central sensitization.
Serotonin plays an important role in the pathogenesis of migraine. Blood serotonin levels decrease at the beginning of a migraine attack, while its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels rise. Administration of serotonin depleters during a migraine attack causes aggravation of the clinical signs, whereas administration of serotonin on the other hand can abort the attack, but it can cause severe adverse effects, including those resembling carcinoid syndrome (flushing, diarrhea, heart failure, bronchoconstriction). Triptan drugs are basically modified serotonin molecules that cause fewer adverse effects.
Other drugs that are used mainly for chronic migraine can increase the CSD threshold and subsequently the number of CSD events that trigger migraine attacks. Drugs that have this mode of action include topiramate, valproate, amitriptyline, methysergide, and DL-propranolol. These drugs can also be used as prophylactics.
Topiramate has been an effective drug for treatment of chronic migraine[24-26] and for prevention of episodic migraine in people.[27-32] There is also evidence that topiramate inhibits the trigeminovascular pathway in cats. Topiramate has multiple mechanisms of action. It can inhibit voltage-gated sodium channels, high voltage-activated calcium channels, and glutamate-mediated neurotransmission at a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate receptor subtypes. Topiramate can also enhance GABAA-receptor–mediated chloride flux and modulate trigeminovascular signaling. It remains unclear which of these mechanisms of action contributes the most to the treatment and prevention of migraine, but research on pathophysiology and genetics of migraine suggests dysfunction of multiple systems, so topiramate may contribute in multiple ways.
In Search of an Ideal Animal Model
Migraine has a vast welfare and economical impact on people and significant research has been done to investigate the complex pathophysiology and discover effective drug treatments. A great limitation in all this research is the lack of an animal model that can replicate all the features of migraines. Understanding of migraine pathophysiology has improved markedly over time, and can now be divided into many components, and then recreated within animal models.
There are 3 groups of animal models for migraines: vascular, neurovascular, and molecular/genetic animal models.[8, 34]
The vascular models use vasoconstriction or vasodilation of relevant vessels (carotid arterial bed, arteriovenous anastomoses, and other meningeal arteries) to study vascular changes during a migraine attack and the effect of drugs on them. Pig and dog models have been used in the past, by constricting the external carotid artery. The major limitation of these animal models is that it does not reflect the complexity of a migraine and focuses only on the vascular changes, which, as aforementioned, are an epiphenomenon and not the main cause.[8, 36]
The neurovascular models focus on many different aspects of migraine pathophysiology. One of them targets the expression of a specific protein called Fos (from Finkel, osteogenic, sarcoma) within the TNC as a marker of trigeminal nociceptive stimulation. Although Fos protein can be expressed at low levels in many normal cell types, including neurons and glial cells, it is thought that continuous or deregulated expression might result in cellular transformation. Fos protein expression within the TNC is induced by applying mechanical, electrical, or chemical stimuli in tissues innervated by the trigeminal nerves. This has provided us with valuable maps of functional migraine pathways. A major limitation of these Fos gene expression models is that they can only be as good as the stimulus that drives their expression. Four different substance P-neurokinin-1 receptor antagonists failed to improve or prevent migraine attacks, despite them blocking Fos expression in the TCC.[38-40] Other models in this group target the CSD as a model for migraine aura. Finally, intravital microscopy (studying the dural vasculature in vivo through a small cranial window with the help of microscopic video) has also been used with or without laser Doppler flowmetry, which studies meningeal blood flow.[41-43]
The last group of animal models (molecular/genetic models) include mice with the FHM gene (FHM1) mutation that have been developed either naturally or transgenically, and they express a variety of clinical signs, including ataxia and seizures.
In summary, if animals suffer naturally occurring migraines, and experience most, if not all the features of migraine in people, they would be ideal models for study. If dogs do suffer from migraines or other primary headache disorders, they could provide invaluable information about the pathophysiology of this complex condition.
The current review of the literature does not confirm the existence of migraines in dogs. The dog presented here has shown a combination of unusual clinical signs, which could be suggestive of a migraine or another severe headache disorder. Other differentials for this dog include focal seizure disorder refractory to phenobarbitone and pregabalin, or an unusual somatic pain syndrome refractory to opioids and nonsteroidal anti-inflammatory drugs. Electroencephalography was unfortunately not able to be performed on this dog. The dog had apparently normal mentation during the episodes, had no focal or generalized involuntary movements, and failed to respond to trialed antiepileptic drugs (phenobarbitone and pregabalin). Although this does not rule out a seizure disorder, we thought that a migraine-like disorder could possibly be a better explanation of this dog's clinical signs. The apparently marked response to topiramate, which has been used in humans for management of chronic migraine or prevention, may also support our suspicion of a migraine-like disorder. Many drugs have been used for management of acute migraine in people, including triptans, which are thought to be more effective. In our case, we avoided using triptans because of the lack of safety, pharmacokinetics, and efficacy data in dogs.
The diagnostic approach of similar cases should include taking a detailed history (including a diary of events and video footage), and thorough physical, ophthalmic, and neurological examination. Any foci of apparent pain should be investigated. A behavioral disorder should be ruled out by consulting a clinical behaviorist. An extensive extracranial (blood work, abdominal, and thoracic imaging), intracranial (MRI, cerebrospinal fluid analysis) investigation, and electroencephalography, where applicable, should be performed. If there is suspicion of a seizure disorder, an antiepileptic drug trial could be performed, bearing in mind that there are refractory seizure disorders. If the aforementioned investigation is unremarkable and antiepileptic/analgesic medication fails to improve the clinical signs, then a primary headache disorder should be considered. In such cases, the diagnostic criteria for primary headache disorders in people could be used as a guide. Further understanding and characterization of such conditions and clinical treatment trials will be necessary to validate this approach.
The aim of this review was to summarize the current literature and to create awareness that migraine-like disorders may exist in dogs, and that there are medications available that may be used for the management of similarly frustrating presentations. For centuries, migraines were treated with substantial skepticism and superstition, and it is only during the last few decades that it has been recognized as a severe disabling disease. Further case reports, studies, and an “open mind” will be required to determine whether these conditions are likely to occur in our patients. Even today, migraine and other headache disorders can be difficult to diagnose in people, and will likely be more problematic in animals despite a thorough and accurate history taking and extensive physical and diagnostic examinations. A better understanding of these potential conditions may help solve many disorders characterized by perplexing “episodes” and perhaps provide us with an ideal animal model for primary headaches in the future.