Recurrent insomnia is an uncommon manifestation that is encountered rarely in a sleep clinic. We report a woman with recurrent insomnia due to an autoimmune process that resolved after a course of immunotherapy.
Sabharwal P, Mahmoudi M, Berberi N, Vasquez BA, Friedman D, Kothare SV. A case of recurrent insomnia: extending the spectrum of autoimmune encephalitis. J Clin Sleep Med 2016;12(5):763–765.
Insomnia has been associated with various CNS autoimmune disorders such as in Morvan syndrome, where thalamo-limbic dysregulation is seen in association with voltage-gated potassium channel (VGKC) antibodies, and the anti-NMDA antibody syndrome with insomnia/hypersomnia.1,2 We describe a case of recurrent insomnia in association with elevated anti-glutamic acid decarboxylase (GAD) antibodies and anti-VGKC antibodies. As in the case of relapsing remitting multiple sclerosis, where immune system activation correlates well with periods of “relapses,” we posit an immunological basis for the recurrent insomnia in our case. Complete resolution of symptoms post-immunotherapy also corroborates our hypothesis. Our case highlights recurrent insomnia as a primary manifestation of autoimmune disease and emphasizes timely recognition and treatment with complete symptom remission.
REPORT OF CASE
A 28-year-old woman with spastic diplegia presented with 6 episodes of insomnia in 2 years. Each episode lasted for 5–10 days with complete lack of sleep at onset. Insomnia was accompanied with excessive appetite, fatigue, and visual hallucinations. No seasonal predilection was noted. Interictal sleep history was unremarkable with 7–8 hours of daily reported sleep. She was taking trazodone and melatonin at initial evaluation and had failed trials of zolpidem, alprazolam, and diazepam. She denied any associated snoring, mouth breathing, abnormal arousals, daytime sleepiness, manic episodes, loss of consciousness, abnormal movements, leg twitching, or dry mouth during these episodes.
Birth history was significant for premature spontaneous vaginal delivery, a birth weight of 2.3 kg, low Apgar scores, and hypoxic ischemic encephalopathy. Prenatal and postnatal course were reportedly uneventful. Early developmental milestones were reportedly delayed for gross motor functions. She was a computer science graduate from a community college. Family history was unremarkable for diabetes, neurological, psychiatric, and autoimmune disease. Neurological exam was significant for bilateral lower > upper extremity spasticity with hyperreflexia and a spastic gait necessitating crutches.
Concurrent presentation of visual hallucinations and paranoia prompted further workup; which is summarized in Table 1 and Figure 1. Quetiapine and trazodone achieved partial improvement, but her insomnia recurred after stopping these medications. A 5-day IVIG trial resulted in complete symptom remission and she was able to titrate off all medications. A month after discharge, she developed arthralgias, was diagnosed with rheumatoid arthritis, and started on methotrexate. She has been symptom free for the past 1 year.
Diagnostic workup of insomnia in our patient.
Diagnostic workup of insomnia in our patient.
Subtraction SPECT scan.
All panels reveal statistical difference SPECT scans in coronal, sagittal and axial sections. (A) Reveals a focus of relatively increased perfusion (yellow and orange, T = 14.2, corrected p < 0.0001) in the right frontal lobe and decreased perfusion (blue) in the right mid parietal lobe. (B) Shows a region of hyperperfusion in the right prefrontal and left fusiform gyrus (T = 14.9, corrected p < 0.0001). (B,C) There was a large cluster of hypoperfusion in bilateral precentral cortex, maximal on the left (blue and pink; T = 20.1, corrected p < 0.0001).
We report a case of recurrent insomnia in association with elevated anti-GAD and anti-VGKC antibodies. High anti-GAD titers, principally seen in association with type 1 diabetes mellitus (DM-1), can also have a wide spectrum of neurological presentations.3 While lower titers (< 100 IU/mL) are seen in patients with isolated DM-1, higher titers (> 100 IU/mL) are seen with concurrent poly-endocrine and autoimmune neurologic disease. Our patient, though, had normal HbA1C levels (5.8%). Though our patient was spastic secondary to cerebral palsy, the absence of rigidity and spasms along with a normal EMG argues against an insomnia-predominant stiff-person variant of autoimmune encephalitis in our patient.3 Further, a negative imaging screen for underlying neoplasms argues against an underlying paraneoplastic process in our patient.3 Insomnia in association with anti-VGKC antibodies is also reported in Morvan syndrome, which is characterized by complete loss of sleep and persistent motor/autonomic hyperactivation and remits with IVIG therapy.1 Lastly, an elevated rheumatoid factor titer also alludes to an underlying autoimmune process.4
Studies of sleep wake mechanisms posit insomnia as a state of hyperarousal where increased brain activity during sleep coexists with reduced activity during wakefulness, thus implying that reduced prefrontal cortical activity during wakefulness leads to impaired cognitive function in insomniacs. This is consistent with the SPECT data from our patient (Figure 1), where relative bilateral precentral cortical hypoperfusion was seen during periods of insomnia versus normal sleep.5 Interestingly, depression, often seen with insomnia, is also described as a state of hyperarousal. However, recent functional neuroimaging studies hint toward a distinctive signature in depression (hyperperfusion in limbic and posterior cortices and hypoperfusion in medial frontal and striatal regions) that was not observed in our case. In addition, she had no clinical symptoms suggestive of depression.5
Interactions between the immune system and the sleep wake cycle have been recognized since Von Economo's reports of “encephalitis lethargica.” Analogous to relapsing remitting MS, where “relapses” occur secondary to immune activation, we hypothesize an autoimmune basis for recurrent insomnia in our patient. Further, our patient showed complete resolution of symptoms with IVIG treatment, supporting an autoimmune basis for recurrent insomnia.
In conclusion, we report a case of cyclic insomnia in association with anti-GAD and anti-VGKC antibodies. Though the exact role of anti-GAD and anti-VGKC antibodies is not clear, our case underscores the importance of early clinical recognition, awareness of association with autoimmune disease, appropriate diagnostic testing and the possibility of complete recovery with timely therapy.
This was not an industry supported study. The authors have indicated no financial conflicts of interest.