Coma is a state with multiple etiologies, so it not surprising that some factors may confound the reliability of the clinical examination and ancillary tests. Major confounders could include the use or prior use of sedatives or neuromuscular blocking agents, induced hypothermia therapy, presence of organ failure (e.g., acute renal or liver failure), sensory failure (e.g., blindness, deafness), or shock (e.g., cardiogenic shock requiring pressor support). However, studies in comatose patients have not systematically addressed the role of these confounders in neurologic assessment.

The complexity of evaluation and various options of decision making require neurologic professional expertise. More than one scheduled meeting with the family is generally required to facilitate a trusting relationship. The neurologist can explain that the prognosis is largely based on clinical examination with some help from laboratory tests. In a conversation with the family, the neurologist may further articulate that the chance of error is very small. When a poor outcome is anticipated, the need for life support (mechanical ventilation, use of vasopressors or inotropic agents to hemodynamically stabilize the patient) must be discussed. Fully informed and more certain, the family or proxy is allowed to rethink resuscitation orders or even to adjust the level of care to comfort measures only. However, these decisions should be made after best interpretation of advanced directives previously voiced or written by the patient.

For patients who have rapidly progressive dementia and are strongly suspected of having sporadic Creutzfeldt-Jakob Disease (sCJD), and for whom diagnosis remains uncertain (pretest probability ~ 20% to 90%), clinicians should order CSF 14-3-3 assays to reduce the uncertainty of the diagnosis.

While the 14-3-3 assay has a moderately high diagnostic accuracy, it is highly dependent on pretest probability of the disease. History, clinical presentation, and the specialist’s experience or knowledge about the incidence of sCJD in a particular population should drive this probability. Further, periodic sharp wave complexes on EEG (Sn 66%, Sp 74%) and DWI/FLAIR hyperintensities in the cortical regions and basal ganglia on MRI (Sn 92%, Sp 95%) will markedly increase pretest probability. Protein assay technique should also be considered, as Western blot studies are subjective and interpreted qualitatively, and newer use of quantitative ELISA studies depend on the individual lab sensitivity and specificity cutoffs. Therefore, consideration for the rarity of sCJD (incidence 1 per million per year), the practice setting (community hospital versus tertiary referral center), the patient’s clinical presentation, and the results of already obtained ancillary tests will affect the diagnostic accuracy of 14-3-3 protein of diagnosing sCJD.

Dementia, or neurocognitive disorder, is characterized by a decline from a previous level of function in one or more domains of cognitive criteria that is severe enough to interfere with daily function and independence. According to Diagnostic and Statistical Manual (DSM-5), the criteria for dementia now includes:

• • Evidence from history and clinical assessment of significant cognitive impairment in at least one cognitive domain: learning and memory, language, executive function, complex attention, perceptual-motor function, and social cognition
  
• • Deficits representing a decline from a previous level of functioning
  
• • Deficits interfering with independence in everyday activities
  
• • Deficits of insidious onset and progression
  
• • Deficits occurring outside of delirium
  
• • Deficits not explained by another disorder

Initial assessment of suspected dementia focuses on history provided by an informant (e.g., a family member or someone in whom cognitive disorder is not in suspicion). Adequate history of cognitive and behavioral changes includes drug history, mood disorder, malnutrition, and problems with basic and advanced activities of daily living. Identification of the underlying etiologic subtype is discussed in future chapters related to “dementia syndromes.”

Evaluation and diagnosis often require serial examination necessitating follow-up visits and serial assessments of cognitive function. All patients with cognitive complaints should undergo a careful mental status evaluation with cognitive testing that may include:

• • Mini-mental state examination (MMSE): A 30-point test that is corrected for education; an interpretation of 30-25 shows questionable significant impairment, 20-25 shows mild impairment, 10-20 shows clear impairment, and < 10 is untestable.
  
• • Montreal cognitive assessment: A 30-point test that is a more sensitive screening tool than MMSE for the detection of mild cognitive impairment.
  
• • Mini-Cog: A 3-minute instrument that can increase detection of cognitive impairment in older adults that consists of a clock drawing task and an un-cued recall of three unrelated words.
  
• • Neuropsychologic testing: Extensive evaluation of multiple cognitive domains by a trained neuropsychologist for diagnosis and management.

There is no clear data to support or refute ordering “routine” laboratory studies, such as a complete blood count (CBC), complete metabolic panel (CMP), and liver function tests (LFTs). The American Academy of Neurology (AAN) recommends routine screening for B12 deficiency, hypothyroidism, depression, and structural neuroimaging with either a non-contrast head computed tomography (CT) or magnetic resonance imaging (MRI) (serial imaging is generally not informative). The AAN does not recommend genetic or neurosyphilis screening unless there is a high clinical suspicion. Patients with an atypical syndrome (e.g., younger patients (< 60 years) or those with rapidly progressive dementia), may benefit from a more extensive evaluation, such as cerebrospinal fluid (CSF)-14-3-3 protein when Creutzfeldt-Jakob disease is suspected or lumbar puncture if viral encephalitis cannot be excluded.

Having excluded reversible forms of dementia, management is principally focused upon symptom and risk management. The following medications have been shown to temporarily improve dementia symptoms (for more details, see the table below):

• • Cholinesterase inhibitors: These include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) for treatment of mild to moderate dementia (MMSE 10-26). Cost, tolerance, and physician experience for efficacy appear to be similar across the drug choices. Common side effects include nausea, vomiting, diarrhea, confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations.
  
• • Memantine (Namenda): Treatment for moderate to advanced dementia (MMSE < 17). Add memantine (10 mg twice daily) to a cholinesterase inhibitor or use alone in patients who do not tolerate or benefit from a cholinesterase inhibitor. Common side effect is dizziness.
  
• • Vitamin E: Limited mixed evidenced to support use. Some resources recommend 2000 IU daily for mild to moderate AD.
  
• • Selegiline: Limited evidence to support use.

Drugs with unproven benefits include estrogen replacement, anti-inflammatory drugs, Ginkgo biloba, statins, and dietary supplements (e.g., vitamin B, Omega-3 fatty acids). Non-pharmacological therapies include:

• • Cognitive rehabilitation: Maintain memory and higher cognitive function.
  
• • Occupational therapy: Prevents accidents and manages behavior.
  
• • Exercise programs: Improve physical functioning and slow the progression of functional decline.
  
• • Modifying environment: Reduce distractions and improve structure and routine.
  
• • Educational programs and other support systems for caregivers: Delay time to nursing home placement.
  
• • Risk factor control: Identify and treat risk factors for cerebrovascular disease (CVD), coronary artery disease (CAD), and dementia.

Concussion is a constellation of transient neurologic symptoms reflecting a diffuse brain dysfunction (neurotransmitters and electrolytes abnormalities, excitotoxicity, axonal stretching, and decreased cerebral blood flow) resulting from biomechanical forces conveyed to the brain.

Symptoms of concussion tend to be maximal minutes to hours after the impact and then slowly resolve over the subsequent 7 to 10 days with complete resolution in about 85% of cases. They are nonspecific and range from cognitive symptoms (decreased attention, amnesia, slow thinking, disorientation, and loss of consciousness), physical symptoms (headache, nausea, vomiting, photophobia, phonophobia, dizziness, slurred speech, blurred vision, and incoordination), affective symptoms (emotional lability, depression, anxiety, and mania), to sleep disturbances. While age, sex, and level of competition do not increase the risk of concussion, certain sports such as American football, Australian rugby, and soccer in females carry a greater risk of concussion. Headgears may have a protective effect in sports like rugby, unlike mouth guards. In collegiate football, receivers may have a lower risk of concussion. Body mass index greater than 27 kg/m² and training time less than 3 hours weekly are athlete-related factors that increase the risk of concussion.

Several tools have been developed with various sensitivity/specificity and level of training/specialization required to administer them. Among those tools, the Post-Concussion Symptom Scale and Graded Symptom Checklist, which may be administered by trained personnel, psychologists, nurses, or physicians, or be self-reported, appear to overall have the best sensitivity and specificity.

Poor performance on initial screening diagnostic tools is likely to be associated with more severe or prolonged early post-concussive cognitive impairments, although the evidence is modest. In addition, gait stability dual-tasking testing may help identify athletes with early post-concussion impairments. Ongoing clinical symptoms and prior concussion are the strongest predictors of persistent neurocognitive impairment. In addition, a history of concussion is associated with severe early post-concussion impairment. Evidence is less compelling for the role of early post-traumatic headache, fatigue/fogginess, early amnesia, alteration in mental status or disorientation, younger age, level of play, prior history of headache, dizziness, or playing the quarterback position in football. It seems that neurologic catastrophe cannot be predicted accurately based on clinical factors. Recurrent exposure, prior concussion, pre-existing learning disability, and APOE e4 genotype increase the risk of chronic neurobehavioral impairment.

Several lines of interventions have been proposed such as delaying the return to the field, follow up to a neurology clinic, increased water intake, increased daily caloric intake, and physical and cognitive rest. The level of evidence to support these interventions has generally remained low.

There is strong evidence (Class I) you should:

• • Optimize therapy for WWE before conception.
  
• • Complete antiepileptic drug (AED) therapy changes at least 6 months before planned conception, if possible.
  
• • Do not change to an alternate AED during pregnancy for the sole purpose of reducing teratogenic risk.
  
• • Offer patients being treated with carbamazepine, divalproex sodium, or valproic acid:
  
  
  
  • • Prenatal testing with alpha-fetoprotein levels at 14 to 16 weeks’ gestation.
    
  • • Level II (structural) ultrasound at 16 to 20 weeks’ gestation; and
    
  • • If appropriate, amniocentesis for amniotic fluid alpha-fetoprotein and acetylcholinesterase levels.
    
  • • Counsel women that there is no substantial increased risk of cesarean delivery in WWE.
    
  • • Counsel women that there is no significant risk of late pregnancy bleeding for WWE.
    
  • • Educate women that there is no moderately increased risk of premature contractions or labor for WWE taking AEDs.
    
  • • Encourage breastfeeding for WWE; monitor the neonate for sedation or feeding difficulties.

There is evidence (Class III) you should consider:

• • Monitoring non-protein-bound AED levels during pregnancy. For the stable patient, levels should be ascertained before conception, at the beginning of each trimester, and in the last month of pregnancy. Additional levels should be done when clinically indicated.
  
• • Monitor AED levels through the eighth postpartum week. If AED dosage increases have been necessary during pregnancy, subsequent dosages can probably be reduced to pre-pregnancy levels safely; this may be necessary to avoid toxicity.
  
• • Prescribe 10 mg/day of vitamin K in the last month of pregnancy for WWE taking enzyme-inducing AEDs.

There is strong evidence (Class I) you should:

• • Choose the AED most appropriate for seizure type; goal should be monotherapy.
  
• • Counsel patients entering reproductive years about the decreased effectiveness of hormonal contraception with enzyme-inducing AEDs.
  
• • Counsel women who are contemplating pregnancy that seizure freedom for at least 9 months prior to pregnancy is a good predictor for seizure freedom during pregnancy.
  
• • Begin folic acid supplementation with at least 0.4 mg/day; continue through pregnancy.

There is evidence (Class III) you should:

• • Recommend a formulation containing 50 μg of ethinyl estradiol or mestranol if your patient’s preferred method of birth control is hormonal contraception and treatment involves an enzyme-inducing AED. The risk of contraceptive failure in this setting should be discussed with the patient and discussion documented.
  
  
  
  • • Folic acid supplementation
    
  • • Teratogenic potential of AEDs
    
  • • Possible change in seizure frequency during pregnancy
    
  • • Importance of medication compliance and AED level monitoring during pregnancy
    
  • • Inheritance risks for seizures
    
  • • Vitamin K supplementation last month of pregnancy
    
  • • Pros/cons of breastfeeding

Multiple observational studies, meta-analyses, and three prospective trials have been done in an attempt to prove efficacy and superiority of PFO closure over medical management alone in secondary stroke prevention (currently, there is no evidence to support PFO closure for primary stroke prevention for any patient population). However, the challenge has proven difficult, mainly due to the long recruitment times, inherent periprocedural risk of adverse effects, need for prolonged follow-up time, and low incidence of stroke recurrence.

The first prospective, randomized PFO closure trial was an unsuccessful CLOSURE 1 trial, in which an inferior STARFlex device was used (no longer produced due to risk of atrial fibrillation and thrombogenicity). Subsequently, the PC trial (414 patients; mean follow-up 4 years) and the RESPECT trial (980 patients; mean follow-up 2.6 years) compared the Amplatzer PFO Occluder with medical therapy alone. Again, both trials failed to reach statistical significance in recurrence of the primary outcomes between the two arms. However, the RESPECT trial did show a significant difference in the “as treated” analysis because three strokes in the device arm occurred before PFO closure.

Finally, with longer follow-up of 5.9 years, the “intention-to-treat” analysis of the RESPECT trial announced at International Stroke Conference (ISC) 2017 revealed a significant trend favoring PFO closure over medical therapy alone in preventing nonfatal ischemic strokes (hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.305 to 0.999, log-rank P = .046). However, there was a higher risk of deep venous thrombosis/pulmonary embolism (DVT/PE) in the device arm. In 2017, two more trials (Gore REDUCE and CLOSE) proved superiority of PFO closure over medical therapy alone with the only exception being a small increase in mostly transient atrial fibrillation in the closure arms.

Who can benefit from PFO closure? In general, young patients with PFO and ESUS who do not have other major stroke risk factors; in other words, those whose PFO is probably pathogenic. The well-regarded Risk of Paradoxical Embolism (RoPE) study identified patient-level variables associated with PFO status, which were then used to create a simple 11-point RoPE score (0 to 10). A higher score means a higher risk of PFO pathogenicity with a set of well-chosen criteria for selecting such patients based on risk stratification.

The Food and Drug Administration (FDA) approved the Amplatzer PFO Occluder on October 28, 2016 for PFO closure to reduce the risk of recurrent strokes in patients between 18 and 60 years with ESUS due to presumed paradoxical embolism, as determined by a cardiologist and a neurologist. Currently, despite the need for more research, a wise selection of an appropriate stroke population, especially with an ASA and a large right-to-left shunt, should guide clinicians toward better secondary stroke prevention in presumed PFO-related strokes. Lastly, if PFO closure is declined by the patient or is contraindicated, anticoagulation is preferred to antiplatelet therapy in the appropriately chosen population with presumed pathogenic PFO.