Epidemiological studies demonstrate elevated rates of migraine in children and adults with autism compared to those without autism.1, 2 Here, we consider the potential clinical interactions of migraine and autism, challenges of migraine diagnosis and management in autism, and therapeutic options that may be ideal for those with comorbid migraine and autism. Autism is a heterogenous neurodevelopmental condition that is marked by (1) challenges in social communication and (2) repetitive or restricted behaviors often with altered sensory responses (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision). Examples of impaired social communication include difficulty interpreting nonverbal cues such as eye-contact or facial expressions. Repetitive or restricted behaviors may include stereotypies (e.g., hand-flapping, spinning), fixation on certain objects or interests (e.g., trains, maps, numbers), or extreme difficulty accepting change. Rates of autism diagnosis have increased over time with an estimated prevalence of one in 44 children in the United States. There is a well-established male predominance of three to one.2, 3 Several genes are associated with autism, yet overall data support a polygenic condition with genetic, environmental, and social risk factors modulating autism development and expression.3 Although most frequently diagnosed in childhood, autism persists into adulthood and is associated with poor quality of life and increased morbidity.2, 4 Migraine and autism share several overlapping features. First, abnormal sensory processing is common to both autism and migraine.5, 6 In autism, altered sensory sensitivity and sensory behaviors (over-responsivity, under-responsivity, and sensory seeking) are part of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision diagnostic criteria, although not required for diagnosis. Studies using a variety of modalities reveal individuals with autism experience hypo- and/or hyper-reactivity to different stimuli as well as altered pain perception.6 Similarly, migraine represents a brain disorder of abnormal sensory processing with, for example, increased sensitivity to light, sound, and smell occurring both during and between migraine attacks.5 In those with autism, the presence of migraine is associated with increased odds of sensory hypersensitivity (tactile, visual, olfactory, and auditory stimuli) compared to those without migraine, suggesting comorbid migraine may augment sensory sensitivity in those with autism.1 Interestingly, rates of central sensitization syndromes, including migraine, fibromyalgia, and irritable bowel syndrome, are higher in those with autism,4 indicating some propensity for central sensitization in autism. An imbalance between neural excitation and inhibition is hypothesized to drive the neurodevelopment of autism. Increased rates of central sensitization syndromes may represent a downstream consequence of this excitation/inhibition imbalance. It remains unclear whether central sensitization or sensory sensitivities drive migraine susceptibility in those with autism. Autism and migraine also share several comorbidities—anxiety, depression, sleep disturbances, and gastrointestinal upset.2, 4, 7 Notably, the presence of these comorbidities drives severity and poor outcomes in migraine and autism, respectively.3, 4, 7 Finally, migraine and autism also share overlapping neurodevelopmental conditions, including epilepsy and attention-deficit/hyperactivity disorder. Many unanswered questions remain regarding migraine in autism. What factors (genetic, clinical, sociodemographic) underlie the significant association between migraine and autism? Does the presence of migraine exacerbate behavioral problems, sleep disruption, and/or gastrointestinal symptoms in autism? Conversely, does the presence of sensory features in autism impact migraine severity or chronicity? Given altered sensory processing and perception, what is the “migraine experience in autism”? Individuals with autism experience barriers to accessing health care and are more likely to report their health care needs (both mental health and physical conditions) as untreated compared to those without autism.8 Thus, the risk of inadequate migraine care (i.e., failure to achieve consultation, diagnosis, and treatment) may be elevated in those with autism. Moreover, considering altered sensory perception and communication impairments, migraine symptoms may be expressed or described differently in those with autism. Worsening behaviors (agitation, aggression) may function as an output for worsening migraine as is the case with other painful conditions in autism, particularly when individuals are nonverbal.6 Finally, migraine-associated symptoms such as nausea or light/sound sensitivity may be masked by other ongoing conditions such as recurrent gastrointestinal upset or baseline sensitivity to sound. Given these diagnostic challenges and the increased rates of headache and migraine in autism, it is prudent to maintain a high clinical suspicion for migraine in those with autism. As a general principle of migraine management, co-occurring conditions should be considered when selecting therapeutic approaches. This remains true in autism, in which comorbidities are frequent.2, 4 Common comorbidities include neurodevelopmental (attention-deficit/hyperactivity disorder, epilepsy, tics), neuropsychiatric (anxiety, behavioral dysregulation), sleep (insomnia), gastrointestinal (chronic constipation, gastroesophageal reflux disorder), and rheumatological (Ehlers-Danlos, fibromyalgia) conditions.2-4 Selecting therapies that offer dual or multiple benefits and/or limit exacerbation of existing co-occurring conditions should be a key goal. Therapies that improve social impairments, repetitive/restrictive behaviors, or sensory sensitivities in those with autism are lacking. The use of behavioral interventions such as applied behavioral analysis are a mainstay in managing maladaptive behaviors and emotional dysregulation.3 Currently, risperidone and aripiprazole are the only two Federal Drug Administration-approved therapies used to treat “irritability” in those with autism. Yet, treating providers employ a range of off- and on-label therapies to manage mood/behavioral dysregulation and associated co-occurring conditions. A guideline for pharmacologic management of co-occurring illnesses in autism was recently proposed.9 Several common migraine preventives are endorsed in this guideline, including amitriptyline and melatonin for sleep disturbances and duloxetine and venlafaxine for anxiety and depression.9 Moreover, tricyclic anti-depressants and valproate are frequently used to treat emotional regulation and repetitive behaviors. Although the specific epilepsy phenotype/syndrome must be considered in close collaboration with treating specialists, valproate or topiramate may be an ideal migraine preventive for select individuals with autism and comorbid epilepsy. Notably, memantine, which is efficacious in migraine, may also represent a therapeutic with dual benefit. A recent randomized, placebo-controlled, double-blind study in children with autism (age 8–17 years, N = 42 for intention-to-treat analysis, N = 16 memantine, and N = 19 placebo) demonstrated memantine significantly reduced social impairments.10 Although these are useful considerations, there are no data to guide migraine management specifically in those with autism and thus, pharmacologic selection should follow standard practice of care, including the use of CGRP-targeting therapies. Finally, sensitivity to medication side effects may be high in those with autism and delays in identifying medication side effects may occur given challenges in communication.8 Thus, starting with low doses and performing gradual up-titration with frequent monitoring are recommended.9 Moreover, phobias or sensory sensitivities may limit the method of drug delivery. Thus, the use of alternate formulations (e.g., compounded liquids or disintegrating tablets) should also be considered when starting medications.9 Although sensory sensitivity may limit use, devices such as the remote electrical neuromodulator, single pulse transcranial magnetic stimulator, or noninvasive vagal nerve stimulator may offer a useful strategy for migraine management that avoids needles/autoinjectors and tablets. Overall, migraine occurs more frequently in those with autism compared to those without autism. Although sparse, current data suggest a clinically meaningful interaction between migraine and autism exists. Initiation of migraine treatment should consider common comorbidities, the presence of sensory sensitivities that may impact the method of drug delivery, and the need for initiating low doses with frequent monitoring for side effects. Future studies with large cohorts are needed to clarify migraine phenotype, burden, and barriers to accessing migraine care in those with autism. Sinifunanya E. Nwaobi: Conceptualization; investigation; writing – original draft; writing – review and editing. The author thanks Dr. Lauren Waldron for her review of language. Sinifunanya Nwaobi received a competitive research award from Amgen and Pfizer.
Sinifunanya E. Nwaobi (Thu,) studied this question.