Neurologic Disorders

Insomnia and Neurologic Disorders: Exploring the Bidirectional Relationship

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A-rear-view-of-a- woman-sitting-alone -on-a-bed-in-room- and-looking-through-the -window-at-night.

Disordered sleep is known to increase the risk for neurologic disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). Similarly, patients with neurologic disorders commonly report sleep disorders, including excessive daytime sleepiness and insomnia, suggesting a bidirectional relationship between sleep and brain health.1

Although researchers have identified a strong association between sleep disorders, specifically insomnia, and neurologic disorders, little is known about their underlying causes, etiology, pathophysiology, and effective treatments.2

Diagnostic Criteria for Insomnia

Recent changes in classification criteria have resulted in the recognition of insomnia as a disorder,3 which is differentiated as transient (persistent symptoms for at least 4 weeks) or chronic (disease duration of at least 3 months). The Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Sleep Disorders (ICSD) have been used to define insomnia in clinical practice; however, patients with insomnia may not meet all the criteria.4 Overall, insomnia has been described by the cardinal symptom of the inability to initiate and maintain sleep or having “poor” sleep, but the presentation of this disorder is much more complex.4

Nonorganic insomnia, which lacks an underlying medical cause, affects 6% of the population in countries including the United States and the United Kingdom. Among individuals with progression to chronic insomnia, 70% still fulfill the diagnostic criteria at 1 year.3,4

Prevalence of Insomnia in Neurologic Disorders

Compared with the general population, patients with neurologic disorders have a higher prevalence of insomnia.5 Based on multinational meta-analyses and reviews, the prevalence of insomnia in neurologic disorders can only be estimated (Table), as the exact prevalence is unknown.2,5 The worldwide prevalence of insomnia symptoms is 30% to 35%.3

More than 50% of secondary insomnias have been indicated to co-occur with psychiatric illnesses, including addiction, alcohol dependence, anxiety, and depression, followed by diseases of the central and peripheral nervous system, restless leg syndrome (RLS), and sleep-related breathing disorders, including obstructive sleep apnea (OSA).4

Research has revealed sex differences in patients with insomnia, with women having a significantly higher prevalence than men do. The increased prevalence of chronic insomnia among women has been attributed to biological factors, including hormonal changes and comorbid medical conditions, and psychosocial factors, including stress and anxiety with regard to burden of family responsibilities.6 Notably, the increased prevalence of sleep disorders in women with neurologic disorders has been underappreciated and -treated because of overlapping symptoms.7

In older adults, insomnia is typically comorbid to other neurologic and psychiatric illnesses and sleep disorders, including OSA and RLS.Approximately 50% of these patients report sleeping difficulties.8

Table: Estimated prevalence of insomnia in neurologic disorders

Neurodegenerative disorders (including PD, AD, and dementia)11%-74.2%
MigraineApproximately 70%
Epilepsy28.9%-74.4%
Multiple sclerosis (MS)40%-50%
Traumatic brain injuryApproximately 30%
After stroke26.9%-50%

Screening and Clinical Evaluation of Insomnia

Due to the wide range of sleep-related disorders, health care professionals across various specialties, including psychiatry, pulmonology, neurology, and otorhinolaryngology, may do insomnia screenings for patients with neurologic disorders.4

The presence of insomnia in neurologic disorders is known to cause a worsening of symptoms and quality of life, heightened depression symptoms, and increased mortality rates.5 Therefore, it is recommended that neurologic evaluations address insomnia while taking patient history, as insomnia may be a distinct entity or the cause of an underlying problem.4

Given the higher prevalence of sleep disorders in neurologic disorders, the importance of understanding assessment tools, both subjective and objective, has been emphasized. Nurse practitioners and treating clinicians have been advised to determine the method of assessment for sleep disorders on a case-by-case basis.8 In a 2019 update on the assessment and management of insomnia, the researchers discussed choosing the appropriate assessment tool for insomnia, such as the use of a sleep diary, actigraphy, personal monitoring devices, polysomnography, and questionnaires.9

Treatment and Management of Insomnia in Neurologic Disorders

Researchers have recommended that insomnia in patients with neurologic disease be treated according to the updated clinical practice guidelines.10,11 General practitioners, specialists, and certified sleep specialists may collaborate in the treatment of patients with insomnia with neurologic disorders, based on the complexity of the cause.4

Based on guideline recommendations, cognitive behavioral therapy for insomnia (CBT-I) is the initial treatment for chronic insomnia disorder because of its significantly favorable benefit:risk ratio.10

The US Food and Drug Administration (FDA) has approved drugs, including benzodiazepines, nonbenzodiazepine hypnotics, suvorexant, and ramelteon, for insomnia treatment.11 Off-label treatments, such as for major depressive disorder, have also been used to treat insomnia; some of them include trazodone, amitriptyline, mirtazapine, and doxepin. In addition, research has shown that melatonin may be beneficial for patients with comorbid insomnia and neurocognitive disorders. Another second-line treatment option is morning bright light therapy.3

However, for the treatment of secondary insomnia in patients with neurologic disorders, pharmacologic interventions may be more targeted to the symptoms and underlying cause.4 Treating physicians have been recommended to continue to counsel patients with neurologic disorders on sleep hygiene.3

Overall, combined therapy of psychologic and pharmacologic treatments may be more beneficial than any single treatment for insomnia.

Vitamin D Deficiency Linked to Neurologic Disorders

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Although decades of research suggest a link between vitamin D deficiency and neurologic disorders including multiple sclerosis (MS), Alzheimer dementia (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS), the role of vitamin D supplementation in the prevention and management of these conditions is unclear.

A brief overview of potential mechanisms underlying the link between vitamin D levels and neurologic disorders is shown in Figure 1.1 Each of these disorders has a unique connection with vitamin D receptors as well as reactions or processes that are enhanced or mitigated by serum vitamin D levels.1

Figure 1. Neurologic disorders and related mechanisms regarding vitamin D homeostasis.
Source: Di Somma et al.1

Vitamin D Deficiency

Vitamin D was discovered to be a steroid-like hormone in 1968 and later was isolated as the active hormonal form of vitamin D3, chemically known as 1,25(OH)2D3.1,2 Vitamin D receptors are found on virtually every tissue in the human body including the brain and entire nervous system.2

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Laboratory evaluation of serum vitamin D level assesses for 25-hydroxy vitamin D [25(OH)D], which is measured in ng/mL and is the sum of both D2 (ergocalciferol) and D3 (cholecalciferol) reflecting the total blood content of vitamin D.3

Several medical societies have issued recommended minimum serum concentrations of 25(OH)D including the National Academy of Medicine (formerly the Institute of Medicine), Endocrine Society, International Osteoporosis Foundation, and American Geriatric Society.1 The National Academy of Medicine not only set a recommended range of 20 to 50 ng/mL but also a maximum of 50 ng/mL, based on an increase in fractures as well as increases in pancreatic and prostate cancers at higher doses.4 A vitamin D level of 30 ng/mL is the average that most societies recommend.1 However, guidance on vitamin D supplementation in patients with neurologic conditions is lacking.

Vitamin D deficiency is more prevalent among people living in areas above the 40th parallel North and below the 40th parallel South or in areas of reduced sunlight, with higher levels of melanin, and who are 65 years and older.3 Sunlight provides approximately 80% to 90% of recommended vitamin D dose per day, far surpassing the amount derived from a well-balanced diet.3

Multiple Sclerosis

Multiple sclerosis is a disease of the central nervous system that encompasses demyelination, neurodegeneration, and chronic inflammation.5 Environmental risk factors have been elucidated in connection with MS, including infections (eg, Epstein-Barr virus), smoking, inflammation, locality (with regards to latitude), climate, and vitamin D deficiency.1,3 Latitude, in particular, is highly correlated with the geographic distribution of MS, with increased frequency in areas above the 40th parallel North and below the 40th Parallel South.1,3 These areas also have higher rates of vitamin D deficiency, which further supports the correlation between MS and hypovitaminosis D.1,3

Vitamin D supplementation may not only prevent the development of MS but also appears to help treat this disease by decreasing the relapse rate.3,5 Several studies have shown possible benefits of supplementation in MS, with dosing varying from 10,000 to 40,000 IU/day, but other trials have not shown favorable outcomes.5 Use of super-high dosing (eg, 50,000 to 2.604,000 IU/day) that result in vitamin D levels of 150 ng/mL and greater can lead to vitamin D toxicity with side effects that mimic MS relapse/progression, including muscle weakness and neuropsychiatric disturbances/psychosis.5 In some cases, irreversible kidney damage, cardiac dysrhythmia secondary to hypercalcemia have been reported.5

Alzheimer Dementia

Alzheimer dementia presents as a progressive cognitive decline with behavioral changes and neurodegeneration secondary to the formation of neurofibrillary tangles and senile plaques.1,6 Landel et al6 noted that studies on vitamin D and AD date back to 1992 with reporting of “…decreased vitamin D receptor (VDR) mRNA levels in the hippocampus of AD patients.” Landel et al performed an extensive review of 38 human and animal studies regarding vitamin D and cognitive outcomes and concluded that vitamin D “may be important in aging and age-related cognitive decline” and “…may be associated with increased risk of developing AD and dementia, without being a causative agent.”6

In the large cross-sectional Rotterdam study, magnetic resonance imaging (MRI) in 2716 participants free of dementia showed that those with vitamin D deficiency had smaller hippocampus volume, brain volume, gray matter, and white matter compared with participants with normal vitamin D levels.7 Findings from a large-scale observational study involving prospective data from the UK Biobank on more than 294,500 people (primarily women older than 60 years) suggest that participants with low vitamin D levels had a 54% greater chance of developing dementia than those with normal levels.8

In a 6-month pilot study involving 43 people newly diagnosed with Alzheimer disease, use of vitamin D supplementation in combination with memantine was superior at halting cognitive decline compared with use of either intervention alone.9 Findings from other studies suggest that vitamin D helps to clear amyloid-b plaques in vitro.10,11 A randomized, placebo-controlled trial involving 210 patients with Alzheimer disease showed that 12 months of supplementation with vitamin D 800 IU per day was significantly associated with improvements in amyloid-β-related biomarkers (P <.001) and information, arithmetic, digit span, vocabulary, block design, and picture arrange scores (P <.05).12 A significant increase in full-scale IQ score was also found (P <.001).12

Researchers have also investigated the potential effects of vitamin D on orientation, memory, cognitive decline, and executive functions (measured by Mini-Mental Status Examination [MMSE]) in older adults without Alzheimer disease.13,14 In a longitudinal study of 1058 older adults who underwent serum vitamin D tests between 1997 and 1999 and follow-up cognitive testing 3 times over the next 12 years, vitamin D deficiency was associated with poorer performance on the MMSE.

Parkinson Disease

Parkinson disease is another progressive neurodegenerative disease and involves dopaminergic neuronal loss.1 Motor symptoms include bradykinesia, rigidity, tremor, gait disorders, and postural instability.15 Although human studies examining the relationship between vitamin D and PD have shown inconsistent and often conflicting findings, one of the most consistent findings is an inverse relationship between vitamin D levels and severity of motor symptoms.15 Other consistent findings are that serum levels of vitamin D are significantly lower in patients with overt PD than in patients without PD, and that serum vitamin D levels progressively decrease with increasing severity of PD.16,17 However, it is unclear whether these associations are linked to reduced mobility and decreased sun exposure as Parkinson disease progresses.15

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a fatal disease of neurodegeneration, with a prognosis of a 3- to 5-year life expectancy after diagnosis.18 The disease is characterized by a progressive loss of motor neurons and is linked to glutamate neurotransmitter abnormalities.18 Although several proteins linking vitamin D to ALS pathology have been identified in genetic studies, evidence supporting a causative role is weak.18,19

In a systematic review and meta-analysis of 24 studies, Lanznaster et al found that ALS patients had slightly lower levels of vitamin D than healthy patients in the control group but could not find evidence supporting the role of vitamin D on ALS diagnosis, prognosis, or treatment.”18 Key limitations of studies on this topic are a lack of consideration of confounding factors.18

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Discussion

Establishing a clinical correlation between vitamin D deficiency and neurologic disorders is difficult given the lack of longitudinal randomized controlled trials. It is unclear whether low vitamin D levels found in patients with these disorders are causative or are the result of confounding factors linked to underlying disease processes and associated disability.20 However, current evidence supports a link between MS and areas with higher rates of vitamin D deficiency, and the use of vitamin D supplementation to help slow cognitive decline in AD and reduce PD symptom severity.1,3

Researchers point to the need for rigorous clinical studies on vitamin D supplementation targeting disease-relevant endpoints. For disorders that do show improvement with vitamin D supplementation, alleviating symptoms or reducing the severity or disease expression can provide improvement in patient comfort and outcomes. Thus, treating vitamin D deficiency in patients with neurocognitive disorders to an endpoint of 50 ng/mL may be considered.

FDA Again Warns on Balloon Angioplasty for Neurologic Disorders

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Says transvascular autonomic modulation is off-label and dangerous

Every year at this time, MedPage Today‘s writers select a few of the most important stories published earlier in the year and examine what happened afterward. 

Balloon angioplasty of the jugular vein — dubbed transvascular autonomic modulation — in an attempt to treat neurological disorders is not only experimental but carries serious risks, the FDA warned.

In 2012 the agency cautioned multiple sclerosis patients that a similar procedure to treat so-called chronic cerebrospinal venous insufficiency (CCSVI) carries serious risks, is not approved, and has no clear evidence of benefit. The vascular hypothesis for MS first proposed by Paolo Zamboni, MD, of the University of Ferrara in Italy has been largely debunked by a series of negative studies.

However, that hasn’t stopped some proponents. The agency said the new warning was prompted by at least one physician broadening the list of neurological disorders he claimed to treat with transvascular autonomic modulation.

Michael Arata, MD, of Synergy Health Concepts in Newport Beach, Calif., has continued to conduct unauthorized clinical research using these devices despite a 2012 warning letter, the FDA noted.

The agency took the first step to block him from receiving investigational products in September 2016 for conducting a transvascular autonomic modulation research study without the review and approval of the FDA.

The FDA noted that balloon angioplasty devices are approved only for use in arteries, with no clear proof for safety and effectiveness in the venous system. Rather, there has been clear evidence of risk.

“After the safety communication issued in May 2012, the FDA received at least one medical device report of a balloon rupturing during placement in a patient’s jugular vein. Physicians ultimately determined the balloon had migrated to the patient’s lung, requiring surgery to remove the ruptured balloon,” the FDA noted in the new safety notice.

“Other serious complications reported to the FDA or in medical journals include: at least one death, blood clots in a vein in the brain (which may lead to a stroke), cranial nerve damage, and abdominal bleeding.

Zika Virus as a Cause of Neurologic Disorders

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Zika virus infections have been known in Africa and Asia since the 1940s, but the virus’s geographic range has expanded dramatically since 2007. Between January 1, 2007, and March 1, 2016, local transmission was reported in an additional 52 countries and territories, mainly in the Americas and the western Pacific, but also in Africa and southeast Asia. Zika virus infections acquired by travelers visiting those countries have been discovered at sites worldwide. Aedes aegypti mosquitoes are the principal vectors, though other mosquito species may contribute to transmission. The virus was found to be neurotropic in animals in experiments conducted in the 1950s, and recent experiments have shown how it can cause neural-cell death. A rise in the incidence of Guillain–Barré syndrome, an immune-mediated flaccid paralysis often triggered by infection, was first reported in 2013 during a Zika outbreak in French Polynesia. An increase in the incidence of microcephaly, a clinical sign that can be caused by underdevelopment of the fetal brain, was first reported in northeastern Brazil in 2015, after Zika virus transmission had been confirmed there. These reports of excess cases of Guillain–Barré syndrome and microcephaly led the World Health Organization (WHO) to declare a Public Health Emergency of International Concern on February 1, 2016, and to recommend accelerated research into possible causal links between Zika virus and neurologic disorders.1

As researchers investigate whether and by what mechanisms Zika virus infections could affect the nervous system, there is a key question for public health: How can currently available evidence about causality guide the choice and implementation of interventions? For this purpose, the WHO is developing a framework for the systematic appraisal of evidence about these causal relationships. How does the available evidence inform current WHO recommendations, and what are the priorities for research going forward?

Besides advancing scientific understanding, the main practical purpose of investigating causality is to evaluate, as accurately as possible, what reduction in the incidence of illness (here, especially neurologic disorders) can be expected from reducing human exposure to the putative cause (Zika virus infection). The conceptual framework is based on factors first proposed by Bradford Hill and commonly used to assess causality: temporality (cause precedes effect), biologic plausibility of causal mechanisms, consistency (same association found in different studies and populations), strength of association (as measured by risk ratio, rate ratio, or odds ratio in cohort or case–control studies), exclusion of alternative explanations, dose–response relationship, cessation (removing the supposed cause reverses the effect), and analogy to cause-and-effect relationships in other diseases.2 Temporality is the single necessary condition; none of the factors on its own is sufficient.

Causal relationships cannot be proven with absolute certainty in epidemiologic studies, but these factors help analysts judge the existence and strength of possible causal links. Their assessment should be complemented by controlled experiments, the most robust approach to drawing inferences about cause and effect.

A systematic strategy for identifying relevant evidence will enable a transparent and replicable approach that can be updated to capture new information. Study methods can be assessed for risks of selection and measurement bias, confounding, and the effect of chance. To illustrate the approach, we conducted a search of PubMed and selected journal and public health websites for information posted through March 4, 2016.

The table Studies of Guillain–Barré Syndrome or Microcephaly in Association with Zika Virus Infection, According to Study Design and Date of Publication. and the Supplementary Appendix (available with the full text of this article at NEJM.org) provide a preliminary summary of population- and individual-level studies on possible associations between Zika virus infection and Guillain–Barré syndrome or microcephaly.

We found three published reports on Guillain–Barré syndrome studied at the population level. During the 2013–2014 outbreak in French Polynesia, the rise and fall of Zika virus infections was followed by a similar rise and fall in the incidence of Guillain–Barré syndrome, with a delay of about 3 weeks.3In the Americas, Guillain–Barré syndrome in the presence of Zika virus has now been reported to the WHO from Brazil, Colombia, El Salvador, Martinique, Panama, Puerto Rico, Suriname, and Venezuela, but we found no reports from these countries linking the syndrome with trends in Zika virus infections.

One study of microcephaly showed a higher-than-expected incidence in the state of Paraíba, Brazil, during the period when Zika transmission began, but data on the timing of Zika infections were not available (see table). In the state of Bahia, Brazil, an outbreak of cases of acute rash, suspected to be Zika virus disease, was followed by an increase in cases of microcephaly. Additional surveillance data describing the temporal relationship between Zika infections and neurologic disorders are likely to be published soon. Some recent epidemiologic observations invite further investigation: microcephaly has been reported in association with Zika infection in Brazil, but not yet in neighboring countries, perhaps because it is still too soon after the introduction of the virus. An outbreak of Zika virus infection in Cape Verde during 2015–2016 involving thousands of cases and possibly caused by an African strain of the virus has not been linked to any neurologic disorders.4

At the level of individual patients, we found 3 studies on Guillain–Barré syndrome and 14 on microcephaly. The only published case–control study showed, among other results, that 41 of 42 patients with Guillain–Barré syndrome diagnosed during the 2013–2014 outbreak in French Polynesia (98%) were carrying Zika virus antibodies, as compared with 35 of 98 hospitalized controls (odds ratio, 59.7; 95% confidence interval, 10.4 to ∞).3 Serologic tests excluded some other infectious triggers for Guillain–Barré syndrome, and there was no association between the syndrome and exposure to dengue, which has the same mosquito vector and was circulating at the same time as the Zika virus outbreak.

One prospective study has compared ultrasound findings in pregnant women with confirmed Zika virus disease and in women with rash apparently from other causes (see table). Ultrasound findings were abnormal, including indications of microcephaly, in 12 of 42 women with Zika virus disease and were normal in all 16 women with no Zika virus disease. Eleven other reports, published between November 2015 and February 2016, involved a total of 93 neonates or fetuses with microcephaly, all in, or linked to, Brazil. In 9 of the 93 cases, Zika infection was detected in fetal or neonatal brain tissue or in amniotic fluid. In 4 cases, Zika virus was found in the brain but not in other organs on postmortem examination. In most case reports or case series, other infections and toxic exposures known to cause microcephaly were not completely excluded. One additional report compiled after the Zika virus outbreak in French Polynesia identified 17 cases of fetal or neonatal brain malformations, which included a number of cases of microcephaly.

The prevailing uncertainty about Zika virus infection and its consequences is now driving a vigorous program of research. One case–control study of Guillain–Barré syndrome and one cohort study of pregnant women described above provide evidence for a causal link. However, most of the data summarized here derive from studies whose designs are typically classified as weak, and the data are not entirely consistent. The available data are mainly observations regarding temporal associations between infection and disease from routine population surveillance and clinical and pathological studies of single cases or groups of cases. Such data are essential for the discovery of new phenomena and as a source of testable hypotheses about cause and effect,5 but a more comprehensive approach to causality is needed. The WHO framework will set out research questions to address the various dimensions of causality as they apply to Zika virus and neurologic disorders and will ensure a systematic review of the literature to synthesize the evidence. Further case–control and cohort studies are already under way to fill critical knowledge gaps.

Even with limited evidence linking Zika virus to neurologic disorders, the severe potential risks demand decisive, immediate action to protect public health. The WHO recommends applying key interventions such as intensive mosquito control; personal protection against mosquito bites; provision of appropriate clinical care for all patients with Guillain–Barré syndrome and for women before, during, and after pregnancy; and prevention of Zika virus transmission through sexual contact or blood transfusion.4 Most of these are not new interventions, but they do need strengthening. Populations must be informed of the potential current and future risks of neurologic disorders, wherever the virus is being or could be locally transmitted and in other regions inhabited by the mosquito vectors. As the putative link between Zika virus and neurologic disorders is reinforced, refined, or even refuted, public health measures will be adjusted accordingly.