The most common cause of dementia, defined by an insidious decline in cognitive function from a previous higher level. Diagnostic criteria state that two or more cognitive domains are affected, including memory impairment and at least one of language, visuospatial function, executive function, and praxis. Pathologically, Alzheimer disease (AD) is diagnosed by semiquantitative analysis of senile plaques, composed of extracellular Aβ-amyloid peptide deposits, and neurofibrillary tangles, composed of intraneuronal tau deposits. Tau accumulation in AD is probably a consequence of Aβ-amyloidogenic neuronal damage rather than a primary event. Progression of tau cortical involvement from entorhinal cortex to hippocampus to isocortex closely reflects the severity of cognitive dysfunction and allows for a reliable way of rating pathological and clinical severity.

The diagnosis of progressive supranuclear palsy (PSP) requires the following: onset of disease over 40 years of age, falls within the first 12 months of disease, and vertical supranuclear palsy. Pathological diagnosis relies on the identification of tau-positive neurofibrillary tangles and neuropil threads at high densities in the pallidum, subthalamic nucleus, substantia nigra, or pons. The pathological signature of PSP is the tufted astrocyte, which is rare in other tauopathies. A proportion of patients are designated as having PSP-parkinsonism and are characterized by an asymmetric onset, tremor, and a moderate initial therapeutic response to levodopa. The factors that lead to tau accumulation and selective vulnerability of basal ganglia structures in PSP are not clear.

Clinically characterized by the onset of behavioral changes and aphasia in the sixth or seventh decade that progress over 10 to 15 years, features of frontal lobe dysfunction include apathy, prominent and distressing social disinhibition, stereotypic behaviors, alterations in food preference, and poor self-care. There are also frontal executive dysfunctions including poor planning, forethought, reasoning, and organization. Progressive nonfluent aphasia characterized by prominent speech production deficits leading to mutism is the most common aphasia seen in this disease. Semantic dementia, defined by loss of language comprehension, and visual agnosia with preserved verbal fluency also occurs. Pathologically, Pick disease is characterized by sharply circumscribed and asymmetrical lobar atrophy of the frontal and temporal lobes with superficial spongiosis. The diagnosis can be made by identification of large numbers of tau-positive spherical cytoplasmic inclusions called Pick bodies throughout the frontal and temporal cortices and in particular the hippocampus.

The clinical presentation of the classical, predominantly movement disorders phenotype is recognizable by the presence of asymmetric bradykinesia and rigidity with myoclonus, dystonia, and cortical sensory loss, which may ultimately lead to the alien limb syndrome. Other clinical presentations are probably more common, characterized by progressive, nonfluent aphasia, frontal lobe behavioral changes, and apraxia with levodopa nonresponsive parkinsonism. Focal cortical atrophy or hypometabolism is often seen on neuroimaging. It is defined pathologically by the presence of achromatic balloon-shaped neurons and prominent diffuse cortical glia tau pathology, including neuropil threads, coiled bodies, and astrocytic plaques.

Clinically manifests as tachycardia, heat intolerance, weight loss, vomiting, diarrhea, and exophthalmic ophthalmoplegia. With profound elevations in T4 levels, thyrotoxic crisis can occur, resulting in fever and cognitive impairment. Crisis may be precipitated by infection or inadequate preparation for thyroid surgery. It is a medical emergency, as it can progress to coma and death if not treated promptly. Treatment involves thiourea agents, sodium iodide, adrenergic blockers, corticosteroids, sedatives, body cooling, and fluid/electrolyte maintenance. Prognosis can be variable; neurologic symptoms following treatment can vary from months to years until return to baseline.

1. I. Steroid-responsive encephalopathy associated with autoimmune thyroiditis may occur; it is due to development of antibodies (antithyroglobulin, antithyroid microsomal and antithyroid peroxidase antibodies).
   
   
   
   1. a. Clinically, it can present with coma, encephalopathy, psychosis, seizures, stupor, and stroke-like symptoms. Often, there are electroencephalography (EEG) abnormalities (generalized slowing or frontal intermittent rhythmic delta activity [FIRDA]) and magnetic resonance imaging [MRI] abnormalities such as subcortical hyperintensities (on fluid-attenuated inversion recovery [FLAIR] images); however, both studies can be normal.
      
   2. b. Symptoms are highly responsive to corticosteroids and with achievement of a euthyroid state.
      
   3. c. Rare cases may require IgIV or plasma exchange.
   
   
2. II. Psychological manifestations
   
   
   
   1. a. Apathetic hyperthyroidism is common in the elderly and may manifest as dementia with apathy and depression.
      
   2. b. Behavioral changes such as irritability and anxiety
   
   
3. III. Peripheral nervous system abnormalities associated with thyroid disease
   
   
   
   1. a. Chronic thyrotoxic myopathy, predominantly associated with proximal muscle weakness
      
      
      
      1. i. Increased prevalence in females compared to males
         
      2. ii. Creatine kinase is usually normal.
         
      3. iii. Electromyography (EMG) reveals short-duration polyphasic motor unit potentials. Muscle power improves as the patient becomes euthyroid.
      
      
   2. b. Acute thyrotoxic myopathy, associated with orofacial involvement (extraocular and bulbar muscles)
      
   3. c. Thyrotoxic periodic paralysis resembles hypokalemic periodic paralysis.
      
   4. d. Myasthenia gravis: Its development is less common in setting of hyperthyroidism. It is rare, with an estimated rate of less than 5%. Hyperthyroidism is more commonly implicated in the course of myasthenia gravis.
      
   5. e. Neuropathy is very uncommon and routine testing is not recommended.
   
   
4. IV. Other central nervous system (CNS) manifestations:
   
   
   
   1. a. Tremor: An accentuation of physiologic tremor, due to increased sensitivity to sympathetic input, is very common in hyperthyroid patients and involves primarily the upper extremities. Treatment consists of correcting the thyroid abnormality; propranolol is also useful.
      
   2. b. Chorea, resulting from hypersensitivity of dopaminergic receptors, responds to neuroleptics.
      
   3. c. Stroke can result from cerebral embolism in thyrotoxic atrial fibrillation. Acute anticoagulation may be appropriate.

Hypothyroidism may present in infancy with mental retardation and growth abnormalities, resulting in Cretinism. Fortunately, this is now rare, because many countries have instituted neonatal screening programs.

1. I. Associated signs of systemic hypothyroidism are variable. Clinical presentation includes muscle aches, fatigue, seizures, cognitive impairment, decreased deep reflexes, constipation, dry skin, and weight gain; psychosis may occur. In the elderly, hypothyroidism may present with cognitive dysfunction, sometimes confused with a primary degenerative dementia. All new-onset dementia patients should be screened for hypothyroidism. Myxedema coma occurs rarely, usually in chronic, severe, undiagnosed disease.
   
   
   
   1. a. Treatment: Emergency management consists of thyroid replacement (PO or IV); corticosteroids; treatment of hypoglycemia, fluid/electrolyte abnormalities, and hypothermia; and ventilator support as needed. Following acute treatment, patients can be managed on levothyroxine with routine monitoring of thyroid functions.
   
   
2. II. Peripheral manifestations occur in a variety of forms.
   
   
   
   1. a. Myopathy: Hypothyroid myopathy consists of weakness (proximal > distal), cramps, pain, and stiffness as common complaints, but objective weakness is less common. Creatine phosphokinase is often elevated. EMG findings are nonspecific. Myoedema, a percussion-induced local mounding of contracted muscle that relaxes slowly, may be elicited, but can also occur in emaciated patients and some normal subjects. The contraction is electrically silent on EMG. Muscle hypertrophy, known as Hoffman syndrome in adults and Kocher-Debré-Semelaigne syndrome in children, is rare. Patients complain of stiffness and painful muscle cramps, and the movements are slow and weak. The muscles are large and firm. Pseudomyotonia, or delayed muscle relaxation after handshake or percussion, may be present and is differentiated from myotonia by its electrical silence on EMG.
      
   2. b. Peripheral neuropathies are mostly entrapment neuropathies (carpal tunnel), resulting from mucoid infiltration of the nerve and the surrounding tissue. Eighty percent of patients complain of distal paresthesia. Polyneuropathies are less frequent.

Acute ischemic stroke treatment has undergone dramatic changes with steadily increasing use of intravenous tissue plasminogen activator (IV tPA) as standard of care since 1996. However, despite its proven efficacy as treatment of acute ischemic stroke in general, pharmacologic thrombolysis does not achieve high reperfusion rates in cases of large proximal vessel occlusions, mainly due to the size and composition of the thrombus. Therefore, the rationale for mechanical removal of flow obstruction has driven the evolution of thrombectomy devices and has ultimately led to a revolution in the treatment of major ischemic stroke with endovascular thrombectomy (EVT).

Multiple randomized trials were unsuccessful at proving superiority of EVT over standard medical therapy until 2015, when five well-designed randomized controlled trials (MR CLEAN, ESCAPE, SWIFT-PRIME, REVASCAT, and EXTEND-IA) finally came out with strong evidence of improved patient outcomes (number needed to treat [NNT] 2.6 to reduce modified Rankin scale by one level and NNT 3.2 to 7.1 to achieve functional independence at 90 days vs. NNT of about 11 for IV tPA within 3 hours of stroke onset, with no difference in hemorrhages and mortality). Despite some differences, these trials had many features in common: newer-generation stent-retriever devices (vs. older coil retriever devices) were used; treatment was initiated within 6 hours of onset for most patients; and patient selection was based on confirmed anterior proximal vessel occlusion and the size of ischemic core.

As a result, the American Heart Association/ American Stroke Association (AHA/ASA) issued the following EVT eligibility guidelines: (1) pre-stroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or middle cerebral artery (MCA) segment 1 (M1); (3) age ≥ 18 years; (4) National Institutes of Health Stroke Scale (NIHSS) score of ≥ 6; (5) Alberta Stroke Program Early CT Score (ASPECTS) of ≥ 6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset. The 6-hour window was further expanded when two trials proved clinical benefit of EVT up to 16 hours (DEFUSE 3) and 24 hours (DAWN) for eligible patients. In both these trials, perfusion imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) was primarily used to assess the core and determine EVT eligibility. Patients having a core-penumbra mismatch or imaging-clinical mismatch would benefit the most with EVT in this extended time window.

EVT with or without IV thrombolysis is now standard of care in eligible acute stroke patients. The currently accepted treatment window for EVT can be up to 24 hours; however, earlier treatment unequivocally leads to better outcomes in most patients. Ischemic core volume and location are very important predictors of outcome, and can be rapidly assessed by using the ASPECT score on CT head (points deducted from 10 for each key area of infarct with score of 6 to 10 indicating a small infarct core) or by CT perfusion imaging, as it can determine the degree of target mismatch (difference between ischemic core and penumbra). Vessel imaging, usually computed tomography angiography (CTA), is essential for confirming a large proximal vessel occlusion. Stent-retriever or direct contact aspiration devices are used for EVT. Reperfusion is considered successful if Thrombolysis in Cerebral Infarction score 2b-3 is achieved (at least 50% of affected arterial territory reperfused). EVT is intended to be performed in a multidisciplinary setting such as a comprehensive stroke center.

While EVT eligibility has now expanded based on the concept of variable physiologic tissue salvageability as opposed to rigid adherence to a given timeframe, multiple clinical, imaging, and procedural challenges remain. There is clinical equipoise on EVT eligibility for strokes with a large ischemic core, distal occlusions, posterior circulation occlusions (BASICS trial ongoing), rapidly improving or mild symptoms, and very old patients. The benefit of IV tPA in addition to EVT, although suggested recently,⁴ is being studied in ongoing MR CLEAN NO IV trial. Use of local anesthesia compared to general anesthesia during EVT is another important area of investigation. Multiple adjuvant therapies like neuroprotectants are being studied as well. Lastly, systemic implementation of rapid EVT to as many eligible patients as possible is an enormously complex task, requiring significant resources and a major shift in the stroke treatment paradigm worldwide.

Tics typically manifest after the age of 3; however, they are most commonly seen between ages 6 to 7 years. Boys are affected three to four times more than girls. Tourette syndrome typically waxes and wanes in severity. Severity may increase with age; however, many patients have a dramatic reduction of tics in their 20s. Comorbidities, such as obsessive-compulsive disorder (OCD occurs in ~ 20% to 40%), attention deficit hyperactivity disorder (ADHD), anxiety, and mood disturbances have a profound impact on both academic and social functions.

Tics are classified as either simple or complex. Examples of simple motor tics include eye blinks or head jerks. These movements are rapid and sudden in nature. On the other hand, complex motor tics include facial gestures, grooming behaviors, jumping, or obscene gestures (copropraxia). Sniffing, snorting, throat clearing, or barking are examples of simple vocal tics. They are often mistaken for other illnesses like laryngitis or asthma. Complex vocal tics include coprolalia (utterance of obscenities), echolalia, and palilalia. In contrast to public perception, coprolalia is quite rare. Tics may be exacerbated by anger or stress. They may diminish during sleep and become attenuated during some absorbing activity. Tics may be voluntarily suppressed for minutes to hours.

Pathogenesis is still unclear. Recent theories have focused on genetics and autoimmune causes, particularly following streptococcal infection. The term PANDAS refers to pediatric autoimmune neuropsychiatric disorder, and this entity is somewhat controversial. Other possible risk factors include maternal caffeine, tobacco, cocaine, and alcohol use, transient perinatal hypoxia, and low Apgar scores. Other causes include side effects of medications or aftereffects of traumatic head injury.

A multidisciplinary therapeutic program must be established, in close collaboration with the parents, child, and school. Treatment should be reserved for those cases in which the child’s self-esteem or social interactions are affected. It is not uncommon for the parents to be more troubled about the tics than the patient. When treatment is initiated, it is often difficult to gauge efficacy because of the natural waxing and waning severity of the disorder. Thus, drastic changes in dose or medications should be avoided, especially during exacerbations, and two medications should not be started together. Clonidine, an α2-adrenergic agonist, has often been used as a first choice to delay use of neuroleptic agents. This medication is also beneficial in treating the associated hyperactivity and warrants first-line consideration based on its efficacy in controlled trials. Dopamine receptor antagonists are the mainstay in treatment. Traditionally, haloperidol and pimozide had been used for treatment, but because of side effects, transition to the “atypical” antipsychotics (fluphenazine, olanzapine, risperidone, quetiapine, and ziprasidone) has been recommended. Risperidone and olanzapine have been found to be efficacious, but their use may be limited in children because of associated weight gain. Botox can be considered if tics are severe. The associated comorbid conditions of ADHD and OCD are often more disabling and should be treated prior to treating tics since these conditions produce stress, which can often make tics worse. Stimulant medications have been accused of exacerbating tics, but this is not supported by randomized trials. These medications should be used in patients who have ADHD. OCD should be treated with selective serotonin reuptake inhibitors, such as clomipramine. Early treatment of tics does not alter the natural history. Nonpharmacologic treatments include behavioral therapy, which help with reinforcement, and techniques to aid in diminishing tics.