Recently, the New England Journal of Medicine (NEJM) published a case in which a 67-year-old man often made some strange movements during sleep, including talking, singing, and moving; sometimes it was difficult to fall asleep, sometimes it suddenly fell asleep, and it did not wake up.
How should this patient be diagnosed? Narcolepsy? Heterodolepsy? Sleep breathing disorder or something else?
The answer is unexpected, let's take a look at the diagnosis and treatment process
Sleep 丨 Figureworm creative
Brief history of the present
A 67-year-old male patient presents at the Sleep Clinic for abnormal sleep behavior, daytime sleepiness, sleep apnea, etc.
1
Three and a half years ago
Patients present with progressive gait imbalances with falls, clumsy hand movements, hoarseness, and dysphagia. Over a period of 3 years, the patient underwent several neurological examinations showing generalized muscle bundle tremor, hypermedullar reflex, gait abnormalities, and low vocalizations, but normal arm and leg strength. Serial EMGs show progressive extensive involvement of muscles, chronic neural reenvation changes, including eventual involvement of the myeloidoid muscles (tongue and masseter muscles) of the cranial bulbar muscles.
2
3 years ago
The patient's wife noticed that he had some strange behaviors while sleeping, including shouting, hyperactivity, and falling out of bed more than once.
3
2 years ago
Patients have prolonged episodes of daytime drowsiness, sometimes falling asleep while sitting, unable to wake up, but waking up on their own after a few hours.
4
4 months ago
The patient fell asleep while washing dishes, resulting in a fracture of the C1 spine. After surgical repair, patients treat insomnia with melatonin and trazodone, and the strange motor behavior during sleep is alleviated, but still makes sounds, including singing, talking, and sometimes showing terror and anger, especially in the early morning.
Cervical magnetic resonance imaging (MRI) of the patient 1 year ago showed narrowing of the bilateral C3-C4 foraminal foramen and no narrowing of the spinal canal. 4 months ago, the patient's head MRI showed semi-elliptical subacute infarction of the left posterior vertebral body, chronic infarction of the left frontal mid-vertebral and right cerebellum, and nonspecific moderate to severe whiteness (below).
MRI imaging of the patient's brain. Dispersion-weighted imaging (Figures A, B) and FLAIR imaging (Figure C) show dotted subacute infarction (arrow) of the posterior vertebral body on the left hemival. FLAIR imaging (Figures C and D) shows nonspecific moderate to severe background white matter changes. T2-weighted imaging (Figures E and F) shows chronic infarction (arrow) in the left frontal midgeal gyrus and right cerebellar hemispheres丨NEJM
At that time, it was considered a slow-progressive motor neuron disease, and treatment with riluzole was initiated. Video fluoroscopic swallowing function test shows severe dysphagia with pharyngeal leakage and silent aspiration; a gastrostomy tube is placed and tube feeding begins.
Home sleep apnea tests showed that the patient had sleep-disordered breathing, a hypopnea index of 20 breathing cycles per hour, and hypoxemia. When the patient sleeps in a supine position, oxygen saturation is severely reduced, accompanied by frequent respiratory events. He was diagnosed with obstructive sleep apnea and several unsuccessful attempts to use continuous positive airway pressure (CPAP) therapy, and was later referred to a sleep clinic.
In addition to sleep and motor neurosyntherapy, other symptoms include snoring, difficulty falling asleep, forgetfulness, urgency and frequency of urination, and night sweats.
Past and family history
Patients have a history of previous type 2 diabetes mellitus with good glycemic control and mild length-dependent sensory neuropathy, which is stable; other histories include hyperlipidemia, heterozygous factor V Leiden mutation, depression, orthostatic hypotension, and gastroesophageal reflux.
Medication history includes alprazolam, bupropion, fenofibrate, insulin, melatonin, metformin, riluzole, sertraline, and trazodone; there are no known drug allergies. The patient drank two alcoholic beverages per day, did not smoke, and had no history of drug use.
The cause of death of the mother is unknown, the father died of trauma, one brother suffered from cardiovascular disease and the other brother suffered from schizophrenia.
physical examination
Body temperature 36.6 °C, blood pressure 112/60 mmHg, pulse 83 beats/ min, respiratory rate 18 times / min, indoor air environment oxygen saturation of 96%. Body mass index (BMI) is 24.2 kg/m2. Patients have some alertness and a sense of direction, but their attention is reduced. The pupils respond consistently to light, the extraocular movement is complete, the field of vision is wide, and the facial sensation and muscle strength are normal. Weak pronunciation and ambiguity. The palate is raised symmetrically and the tongue moves normally.
The deep tendon reflexes of the arms are active, and the legs are mildly spasmodic. Normal plantar reaction, mild myoclonic movements of both hands, unstable gait, positive Lomber sign.
Patients are treated with positive airway pressure ventilation. Electromyography signals show elevated rapid eye movement (REM) muscle tone, but no sleep abnormalities. After two weeks of outpatient follow-up, the patient did not respond to sternal friction, and the vital signs and blood glucose were normal. He was transferred to the emergency department and regained normal consciousness without intervention. EEG shows frequent intermittent diffuse polymorphism δ slow waves, bifrontal dominant type, but no epileptiform abnormalities are seen. Positive airway pressure ventilation was continued for several weeks with good efficacy and compliance.
But in the following time, the frequency of the patient's unresponsive seizures increased, each lasting up to 3 hours, and the wife was completely unable to wake him. There was no improvement in taking modafinil. After that, he was admitted to the epilepsy intensive care unit for long-term monitoring and EEG examination. During this period, the patient had two more non-reactive events, during which blood pressure, heart rate, and blood glucose levels were normal.
differential diagnosis
1. Sleep Disorders of Breathing (SDB)
Symptoms of snoring, apnea during sleep, and daytime sleepiness in this patient support the diagnosis of sleep apnea disorders. The first home sleep apnea test diagnosed obstructive sleep apnea.
The standard treatment for sleep-disordered breathing is positive airway pressure ventilation, with continuous positive airway pressure therapy being used most frequently. In addition to apnea or hypopnea, patients with neuromuscular disease may present with clinically significant hypoventilation at night and may receive bi-level positive airway pressure ventilation.
2. Abnormal behavior during sleep
Patients have sleep-related problems, particularly difficulty falling asleep and abnormal behavior during sleep. Difficulty falling asleep can be due to insomnia at the beginning and can be caused by a variety of causes. Abnormal behaviors during sleep include making sounds and hyperactivity, and even falling out of bed. These behaviors suggest dysjamia, a sleep disorder characterized by abnormal behavior during sleep.
(1) Dysomnias
There are two forms of dysomnia: non-rapid eye movement (NREM) dysomnias and REM dysomnias. Patients with NREM dysomnamate are mainly manifested as sleepwalking, night terrors and confusion of awakening, mostly young patients, mainly in the middle of the night, usually do not remember the content of dreams, and are not easily awakened.
Some of the abnormal behaviors of the patients in this case occurred mainly in the second half of the night, characterized by vocal and hyperactivity during sleep, and showing fear and anger in dreams. These behaviors indicate that the patient is acting according to their dreams, which is also a hallmark feature of REM dysjab.
(2) Rapid eye movement sleep behavior disorder (RBD)
RBD differs from sleepwalking and night terrors, being easily awakened, clearly recalling the contents of dreams, and disappearing from vocal and hyperactivity during sleep.
In this case, a sleep test was performed, the sleep breathing disorder was reduced, and the examination also found an increase in muscle activity during REM sleep, which also confirmed the diagnosis of RAPID EYE movement sleep behavior disorder. Patients are treated with melatonin, one of the few drugs used to treat the disease, capable of reducing the number of dreams.
3. Narcolepsy
The patient fell asleep while washing dishes, and there were several unresponsive episodes that failed to wake up, but the patient eventually woke up on their own and returned to normal. During the episode, no signs of involuntary movement, urinary incontinence, or cardiopulmonary distress are mentioned.
Despite CPAP treatment, the patient remained drowsy and was given modafinil. Although drowsiness is the defining phenotype of narcolepsy, there are no other clinical features suggestive of narcolepsy, and such a prolonged unresponsive seizure is not a typical manifestation of narcolepsy.
Due to the frequent episodes of non-reaction, patients are transferred to a neurology department for long-term monitoring. During admission, two unresponsive events occurred, and the corresponding EEG monitoring results were consistent with sleep, mainly NREM sleep stage 2 (N2) and stage 3 (N3), with no signs of epileptic activity.
In summary, the patient's sleep-wake phenotype includes sleep-disordered breathing in response to CPAP treatment, RAPID EYE movement sleep behavior disorder in response to melatonin therapy, and excessive lethargy with unresponsive (sleep) prolonged seizures, which were not weakened after modafinil treatment.
Are there other diagnoses?
As the patient's understanding of the sleep-wake phenotype deepens, doctors try to combine symptoms of poor sleep quality and poor vigilance with other symptoms, especially motor neuron phenotypes (mainly spherical dysplasia and dysphagia), autonomic dysfunction, and decreased balance. Sleep breathing disorders are often associated with motor neuron disease, but RAPID EYE movement sleep behavior disorder and autonomic symptoms are not associated. In addition, given the patient's normal arm and leg strength, his poor balance is unlikely to be associated with motor neuron disease.
1. Neurodegenerative diseases
RAPID EYE movement sleep behavior disorder is associated with neurodegenerative diseases, mainly associated with Parkinson's disease, Lewy body dementia, and multisystem atrophy. The patient's signs and symptoms do not match all three neurodegenerative disorders.
2. Anti-IgLON5 antibody disease
Anti-IgLON5 antibody disease is characterized by sleep disturbances and extensive neurologic symptoms. Patients may present with daytime sleepiness, and other symptoms include dysarthria, dysphagia, gait instability, chorea, eye movement abnormalities, cognitive changes, muscle bundle tremor, and myoclonus.
In addition to sleep-related disorders, other clinical manifestations of anti-IgLON5 antibody disease include abnormal eye movements, progressive supranuclear paralysis-like syndrome, cognitive syndrome, and hyperexcitation with spasm, myoclonus, and bundle tremor.
The clinical presentation of anti-IgLON5 antibody disease is heterogeneous, coupled with slow disease progression and rare cases, often delaying diagnosis. Anti-IgLON5 antibody disease needs to be distinguished from the following disorders: isolated sleep breath disorder, rapid eye movement sleep behavior disorder, motor neuron disease, myasthenia gravis, progressive supranuclear palsy, Huntington's disease, multisystem atrophy, etc.
Current understanding of the treatment of the disease is limited. Most patients receive immunotherapy, including glucocorticoids, immunoglobulins, plasmapheresis, rituximab, cyclophosphamide, azathioprine, and mycophenolates.
To confirm the diagnosis, the patient was tested for IgLON5 autoantibodies. The final diagnosis is a neurological disorder associated with anti-IgLON5 antibody disease.
Treatment and follow-up
Intravenous methylprednisolone is given 1000 mg daily for 5 consecutive days. Due to the COVID-19 outbreak, treatment of patients has been delayed. Intravenous immunoglobulin (2 g/kg per month) is treated for 2 months until two induced infusions of intravenous rituximab (1000 mg, each time at an interval of 2 weeks) can be arranged.
In the first 4 months after initiation of treatment, symptoms of REM sleep behavior disorder and sleep-disordered breathing were relieved. About 1 month before the implementation of the first maintenance dose of rituximab (planned for 6 months after the second induction therapy), the symptoms of rem sleep behavior disorder in patients worsened. The interval between rituximab doses is shortened to 4 months later, symptoms are reduced, and episodes of excessive daytime drowsiness are resolved after the start of rituximab therapy.
For persistent gait instability, physical therapy is carried out; however, patients still have cognitive impairment and speech impairment, and the Montreal cognitive assessment screening score is 22 points (0 to 30 points), and the problem of dysphagia is also more serious, and gastrostomy is still needed.
It was first reported internationally in 2014 and first reported in China in 2016
Anti-IgLON5 antibody-related encephalopathy is a rare autoimmune disease of the central nervous system that has only been reported in recent years. The disease has the characteristics of both autoimmune diseases and degenerative diseases of the nervous system, and the specificity of clinical symptoms is not strong, and it is easy to be confused with diseases such as multisystem atrophy, supranuclear ophthalmoplegia, and familial fatal insomnia.
Anti-IgLON5, also known as anti-IgLON5 antibody-associated tau protein disease, is a rare autoimmune encephalitis with sleep disorders as the prominent clinical manifestation, with anti-neuronal surface antigen antibodies - anti-IgLON5 antibodies. Since it was first reported in 2014, there have been more than 100 confirmed cases in the world, about 10 cases of anti-IgLON5 have been confirmed in China, and the first patient in China was reported by Ren Haitao of Peking Union Medical College Hospital in 2016.
In 2017, the "Expert Consensus on the Diagnosis and Treatment of Autoimmune Encephalitis in China" introduced the clinical characteristics of anti-IgLON5 antibody-related encephalopathy:
It is more common in the elderly population, and the median age of onset is around 60 years;
With sleep disorders and movement disorders as the main manifestations, there are walking instabilities, ataxia, dysarthria, dysphagia, central hypopnea, dance-like movements, oral and facial involuntary movements, etc.;
Neuroimaging and routine cerebrospinal fluid examination have no specific findings;
Simultaneous video polysomnography can be seen in obstructive sleep apnea, stridor, and rembosmot sleep behavior disorder, as well as abnormal movements and sleep structure abnormalities in both non-REM and RAPID EYE movement phases;
Neuropathological examination can reveal neuronal loss with tau protein deposition, with the brainstem covered with significant hypothalamic involvement;
Treatment and prognosis: most do not respond well to immunotherapy, and in a few cases, sudden death can occur.
Author: Tian Xinfang
Source: Health Community - Clinical Frontline
Resources
Aleksandar Videnovic, Suma Babu, Brian Zhao, et al. Case 1-2022: A 67-Year-Old Man with Motor Neuron Disease and Odd Behaviors during Sleep. N Engl J Med. 2022;386:173-180.
Xu Jiuyang, Li Xinyao, Shen Hang, et al. A case of anti-IgLON5 antibody-related encephalopathy[DB/OL]. Chinese Clinical Case Results Database, 2020(2020-06-28).
Neurology Branch of Chinese Medical Association. Expert consensus on the diagnosis and treatment of autoimmune encephalitis in China. Chinese Journal of Neurology. 2017; 50(2):91-98.