Central Nervous System in Myotonic Dystrophy

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Symptoms

Cognitive Impairment: Mental retardation is expected in individuals with clinically evident myotonic dystrophy at birth, but in less severe forms of the disease cognitive and behavioral abnormalities can variably involve IQ, executive function, visual-spatial construction, arithmetic ability, attention and personality. Mental retardation is a static abnormality associated with brain maldevelopment, but whether DM can also cause a progressive, degenerative or even dementing disorder remains controversial. In addition to the primary alteration in brain function caused directly by the myotonic dystrophy mutation, hormonal or other systemic abnormalities in myotonic dystrophy might cause or exacerbate intellectual dysfunction by secondarily affecting the central nervous system (CNS).

Excessive Daytime Sleepiness: Excessive daytime sleepiness (hypersomnia) is common in myotonic dystrophy and can develop at any age. As opposed to generalized fatigue, which is also common in myotonic dystrophy, hypersomnia causes patients to sleep frequently, and often unpredictably, throughout the day despite having normal or greater than normal duration of sleep at night. Hypersomnia in myotonic dystrophy can result from several distinct mechanisms:

  • behavioral abnormalities with an erratic sleep schedule and poor sleep hygiene
  • ventilatory muscle weakness with sleep-related hypoventilation and non-restorative sleep
  • airway obstruction due to pharyngeal weakness and obstructive sleep apnea
  • CNS causes of central alveolar hypoventilation
  • CNS causes of central hypersomnia due to disordered arousal

Behavioral, Emotional and Socialization Difficulties: Behavioral phenotypes such as avoidant personality are more common in patients with low cognitive ability and advanced physical handicap, but have also been described in DM1 and DM2 patients with normal IQ. Behavior, emotional state and socialization are also impacted in severely affected individuals by their physical disabilities, including craniofacial abnormalities, dysarthria and abnormal facial appearance. Substance abuse is frequently encountered in a subset of myotonic dystrophy subjects, but requires additional investigation to determine its cause. Frequency and severity of depression in myotonic dystrophy is often difficult to assess due to the concurrence of apparently unrelated apathetic or avoidant personality, sleep and eating dysfunction, and inexpressive facies due to facial muscle involvement.

Peripheral Neuropathy: Minimal abnormalities in peripheral nerve function have been confirmed by nerve conduction studies, but significant peripheral nerve abnormalities, previously suggested by muscle biopsy features, have not been confirmed. Symptoms attributable to peripheral nerve involvement are uncommon and rarely clinically significant.

Form
Symptoms

Congenital DM1

Childhood/Adolescence:

  • Intellectual impairment due to potentially severe mental retardation. Speech abnormalities, dysmorphic facies and lack of facial expression can make mild or normal cognitive impairment appear more marked.

  • Developmental delays and learning disabilities related to the cognitive impairment and exacerbated by craniofacial abnormalities (dysarthria, lack of facial expression), and distal weakness (lack of dexterity, generalized fatigue).

  • Apparent apathy and inertia can be exacerbated by multiple causes, including cognitive impairment, avoidant personality, daytime hypersomnia, neuromuscular fatigue, and inexpressive facies due to facial muscle weakness

  • Psychiatric disorders (including attention deficit, socialization difficulties, anxiety, substance abuse and depression)

  • Visual-spatial and constructional difficulties due to cognitive deficits are exacerbated by the motor impairment

Adulthood:

  • In addition to static cognitive deficits, executive function abnormalities, daytime sleepiness and psychiatric disorders frequently become more evident with age

Childhood Onset DM1

Childhood/Adolescence:

  • Variable cognitive impairment – DM patients who come to medical attention during childhood but after the neonatal period, may nonetheless have clinically cryptic congenital defects including mental retardation, which is mild compared to those with overt congenital disabilities. Dysarthria, dysmorphic facies and lack of facial expression can result in subjects with mild cognitive impairment appearing more markedly affected than is accurate; these mistaken impressions can occur both during casual interactions and on formal neuropsychological testing unless the evaluator appropriately corrects for the patient’s physical disabilities.

  • Apparent apathy and inertia can result from and be exacerbated by multiple causes, including cognitive impairment, avoidant personality, daytime hypersomnia, neuromuscular fatigue, and inexpressive facies due to muscle weakness

  • Developmental delay and learning disabilities

  • Psychiatric disorders (including attention deficit, socialization difficulties, anxiety, substance abuse and depression)

  • Visual-spatial and constructional difficulties due to cognitive deficits are exacerbated by motor impairment

Adulthood:

  • In addition to any static cognitive deficits, increasing age is associated with more evident executive function abnormalities, daytime sleepiness and psychiatric disorders

 Adult Onset DM1

  • Mental retardation or static cognitive impairment is NOT expected in patients without clinical features of myotonic dystrophy until adulthood (as opposed to those with early onset symptoms who are not correctly diagnosed until adulthood).

  • Progressive cognitive loss can occur in true adult onset DM1, typically in association with multisystemic deterioration, though the relationship of this apparent dementing process with executive function loss and psychiatric disorders that both increase with age requires further investigation

  • Psychiatric disorders (including attention deficit, avoidant personality, socialization difficulties, anxiety, and depression) increase with age, and are exacerbated by hypersomnia and multisystemic disease

  • Excessive daytime sleepiness can be the primary and presenting symptom in some individuals with adult onset disease

  • Visual-spatial constructional difficulties may be present in true adult onset DM1 but have not yet been thoroughly investigated.

  • Executive function deteriorates with age in adult onset DM1 subjects, leading to greater difficulty in organizing and responsibly performing routine lifetime activities (paying bills, keeping appointments, arranging schedules, etc.)

 DM2

  • Overall less is known about CNS effects of DM2, and additional research in needed

  • As in truly adult-onset DM1 patients, mental retardation or static cognitive impairment is NOT expected in DM2

  • As in truly adult-onset DM1 patients, progressive cognitive loss can occur in DM2, typically in association with multisystemic deterioration, executive function loss and psychiatric disorders

  • Psychiatric disorders (including attention deficit, avoidant personality, and depression) become more common with age, and are exacerbated by hypersomnia and multisystemic disease

  • Executive function deteriorates with age in adult onset DM1 subjects, leading to greater difficulty in organizing and responsibly performing routine lifetime activities (paying bills, keeping appointments, arranging schedules, etc.)

 Diagnosis

Evaluation of excessive daytime sleepiness (EDS): Recognition of excessive daytime sleepiness and determination of the underlying cause is important because it results in significant morbidity and mortality due to accidents while driving, at work or at home. In situations requiring quantification, the degree of excessive sleepiness can be formally evaluated by sleepiness scales (a subset of the Stanford Sleepiness Scale has been validated in DM1), but to identify hypersomnia simply and reliably in clinic patients the following questions should be routinely addressed:

  • When do you go to sleep each night and how many hours do you sleep?
  • Do you take one or more naps during the day?
  • Do you at times experience a sudden need to sleep during the day?
  • Do you often fall asleep while watching TV or at the movies or a show?
  • Do you have difficulty being inactive for prolonged periods?
  • Are you generally in great shape and alert during the day?

Sleep disorder screening measures are available to primary care physicians to help them determine whether intervention or referral to a sleep laboratory is indicated:

  • Sleep diaries can help patients and physicians objectify a sense of sleepiness
  • Actigraphy can provide a quantitative measure of sleep habits, recording movements and documenting hours of inactivity and sleep over periods of days.
  • Nocturnal oxymetry performed at home can measure nocturnal hypoventilation, thus helping to determine if ventilatory failure, sleep apnea or central hypoventilation are responsible for impaired sleep and excessive daytime sleepiness

Evaluation methods available at comprehensive sleep centers

  • Polysomnagram – This test monitors electroencephalographic activity to determine sleep stage and duration, and compare it to ventilatory effort and oxygenation, helping define causes of hypoxia during sleep. Due to the multiple potential causes of daytime sleepiness in myotonic dystrophy, qualified comprehensive sleep laboratory evaluation is required to determine presence of any parasomnias, sleep apnea, central or neuromuscular hypoventilation or central hypersomnia., each of which has specific significance and treatment. Unfortunately, many sleep laboratories focus only on sleep apnea, being unaware of the complexities of sleep disturbance in myotonic dystrophy; standard treatment of sleep apnea in non-myotonic dystrophy patients (CPAP) is often contra-indicated in DM patients, so knowledge of the multiple causes of sleep disturbance in myotonic dystrophy is essential.

  • Multiple Sleep Latency Test [MSLT] measures the time it takes to repeatedly fall asleep, and, to assure comparable sleep history, is best performed after a standard night’s sleep monitored with polysomnography. MSLT is often essential for the diagnosis of central hypersomnia in myotonic dystrophy.

Structural assessment: Magnetic resonance imaging (MRI) can identify the high-T2 signal abnormalities that are common in DM1 and DM2 cerebral white matter. The pathophysiological significance of these abnormalities is controversial, so at present the primary importance is to recognize that they are common in myotonic dystrophy so that other abnormalities are not inappropriately diagnosed. Congenital and childhood forms of DM1 are associated with generalized atrophy on MRI studies, and initial studies have shown cerebral volume loss in adults with DM1 and DM2 compared to age-matched controls. In patients with DM1 and DM2 positron emission tomography (PET) studies can identify reduced frontal and temporal lobe blood flow, though the causal relationship of this finding to cognitive or executive dysfunction is yet to be determined.

Neuropsychological assessment: Neuropsychological evaluation may be performed to assess cognitive strengths and weaknesses. In particular, testing in DM1 children should be considered routinely when early signs of congnitive or developmental issues are present. Any evaluation should accommodate the physical impairments that may be present (e.g. hearing loss or speech deficits)and differentiate between physical and mental issues that may be perceived as cognitive dysfunction. Such tests include:

Cognitive skills tests that measure

  • Age appropriate IQ (e.g WPPSI and WISC);
  • Executive function and higher cognition skills
  • Visual-spatial ordering skills
  • Visual Perception/Construction/Memory skills
  • Attention skills
  • Verbal abstract reasoning skills
  • Temporal-sequential ordering skills

 Tests for other neuropsychological function that evaluate

  • attention-deficit/hyperactivity disorder (ADHD)
  • energy levels
  • social skills and general behavior
  • emotional facility (i.e. evaluation of anxiety, withdrawal, depression, conduct disorders).

Treatment

Excessive Daytime Sleepiness (EDS): Wakefulness promoting agents for narcolepsy, such as modafinil, are sometimes prescribed off-label for Attention-Deficit Hyperactivity Disorder (ADHD) and excessive daytime sleepiness. These agents have shown modest benefit as assessed by the Epworth sleepiness scale.

Cognitive Dysfunction: Identification of cognitive dysfunction is crucial to providing appropriate individualized interventions and behavioral therapy. Early intervention for cognitive weaknesses, academic achievement problems, and behavior, attention, or social issues can have significant impact on a child’s success in later life. The knowledge of specific deficits may also inform staff as to how medical problems may affect schoolwork, and therefore aid in behavior management.

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