Key Points for Issue

Neurology of Systemic Disease p. 10.1212/01.CON.0000669264.55769.d3 June 2020, Vol.26, No.3 doi: 10.1212/01.CON.0000669264.55769.d3
KEY POINTS FOR ISSUE
BROWSE ARTICLES

Neurology of Systemic Disease

Article 1: Cardiac and Pulmonary Disorders and the Nervous System

Natalie R. Weathered, MD, MS. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):556–576.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the neurologic complications encountered with cardiac and pulmonary disorders, specifically focusing on endocarditis, cardiac arrest, heart failure, hypercapnia, hypoxia, and cystic fibrosis. As neurologic dysfunction is one of the most frequent complications of these diseases and may even be the presenting symptom, it is important to be familiar with these complications to foster early recognition and intervention.

RECENT FINDINGS

Advances have been made in the identification of which patients can safely undergo valvular surgery for treatment of infective endocarditis in the setting of stroke, which, ideally, will minimize the risk of recurrent stroke in these patients. Additionally, technologic advances are improving our ability to use a multimodal approach for prognostication after cardiac arrest.

SUMMARY

The neurologic complications from the described disorders range from cerebrovascular complications to encephalitis, cognitive impairment, sleep-disordered breathing, headache, and increased intracranial pressure leading to coma or even death. Given the severity of these symptoms, it is paramount that neurologists be closely involved in the care of patients with neurologic complications from cardiac and pulmonary disorders.

KEY POINTS

  • Antiplatelets, anticoagulants, and recombinant tissue plasminogen activator should not be used in the acute phase of an ischemic stroke due to infective endocarditis without strong clinical indication.
  • Infectious intracranial aneurysms tend to be distal, and often multiple aneurysms are present.
  • Most infectious aneurysms remain clinically silent, and if they are small, they may fully resolve with antimicrobial therapy.
  • In the setting of clinically silent infarcts or transient ischemic attack, valvular surgery has been shown to be safe.
  • Current American Heart Association Guidelines recommend targeted temperature management for all patients who are comatose after a cardiac arrest without regard to initial rhythm or whether they were outpatient or inpatient at the time of arrest, with a goal temperature between 32°C (89.6°F) and 36°C (96.8°F) for at least 24 hours.
  • Prognostication in patients who are comatose after cardiac arrest should be done no earlier than postarrest day 3 if the patient was not cooled or 72 hours after reaching normothermia if cooled.
  • It is imperative to ensure that all sedating medications and paralytics have been cleared from the system of patients who are comatose before proceeding with the prognostication examination to minimize confounding effects.
  • A multimodal approach is often ideal for prognostication in patients who are comatose after cardiac arrest, combining the clinical examination with supportive studies.
  • Anticoagulation lowers the risk of ischemic stroke due to low cardiac ejection fraction; however, that effect is counterbalanced by the increased risk of hemorrhage.
  • The use of anticoagulation for the primary prevention of stroke in the setting of heart failure with reduced ejection fraction should be decided on a case-by-case basis, weighing the risk of hemorrhage if anticoagulation is started.
  • The cognitive impairment associated with heart failure ranges from delirium to mild cognitive impairment and dementia.
  • The neurologic sequelae of hypercapnia include inattention, memory deficits, confusion, lethargy, asterixis, tremor, headache, papilledema, and seizures. These symptoms occur as a consequence of cerebral edema and increased intracranial pressure.
  • Most of the neurologic complications of cystic fibrosis are due to deficiencies of the fat-soluble vitamins.
  • Vitamin E deficiency in cystic fibrosis causes cognitive impairment, microcephaly, dysmetria, ataxia, and spinal cord demyelination.
  • Vitamin K deficiency in cystic fibrosis can result in spontaneous intracerebral hemorrhage.

Article 2: Gastrointestinal Disorders and the Nervous System

Halina White, BM BCh, MA, MRCP. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):577–590.

ABSTRACT

PURPOSE OF REVIEW

This article describes the neurologic sequelae of various nutritional micronutrient deficiencies, celiac disease, inflammatory bowel disease, and liver disease. Where relevant, appropriate treatments for these conditions are also discussed. The developing field of the microbiome and nervous system interaction is also outlined.

RECENT FINDINGS

Pathology in the gastrointestinal system can affect the nervous system when it causes micronutrient deficiency, when immune responses created by the gastrointestinal system affect the nervous system, when toxins caused by gastrointestinal organ failure harm the nervous system, and when treatments aimed at a gastrointestinal medical condition cause damage to the nervous system as a side effect.

SUMMARY

This article addresses familiar concepts and new developments in the treatment and understanding of diseases that affect the gut and nervous system simultaneously.

KEY POINTS

  • The neurologic complications of celiac disease include headaches, mood disorders, seizures, white matter lesions, impaired cognition, gluten ataxia (ataxia of arms, legs, and gait; dysarthria; myoclonus), myelopathy, myopathy, peripheral neuropathy (usually sensorimotor axonal), mononeuritis multiplex, and autonomic neuropathy.
  • Peripheral neuropathy is one of the most common neurologic complications of celiac disease.
  • The neurologic complications of inflammatory bowel disease include peripheral neuropathy, cranial neuropathies, myelopathy, myopathy, ischemic stroke, cerebral venous sinus thrombosis, cerebral vasculitis, and posterior reversible encephalopathy syndrome.
  • Crohn disease is sometimes associated with Melkersson-Rosenthal syndrome, a triad of recurrent facial nerve palsy, intermittent orofacial swelling, and fissuring of the tongue (lingua plicata).
  • The neurologic complications of acute liver failure include encephalopathy, cerebral edema, intracranial hypertension, seizures, coma, and herniation.
  • The neurologic complications of cirrhosis include cognitive decline, encephalopathy, parkinsonism, cerebellar dysfunction, basal ganglia dysfunction, hepatic myelopathy, and hepatic neuropathy.
  • The neurologic complications of Wilson disease include dysarthria, dystonia, intentional and postural tremor, parkinsonism, cognitive impairment with a frontal syndrome or subcortical dementia, seizures, hyperreflexia, myoclonus, and autonomic dysfunction.
  • Dysfunction of the microbiome, called dysbiosis, may contribute to the pathogenesis of many diseases, including some that were previously considered to be strictly neurologic, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.
  • Lewy bodies and α-synuclein, the neuropathologic hallmarks of Parkinson disease, appear in the enteric nervous system and parasympathetic nerves leading to the gut in the early stages of Parkinson disease, before they appear in the central nervous system.
  • Periodontal disease and poor dental hygiene are associated with the development of mild cognitive impairment and Alzheimer disease, but no causal relationship between these two conditions has ever been established in humans.

Article 3: Rheumatologic Disorders and the Nervous System

Pantelis P. Pavlakis, MD, PhD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):591–610.

ABSTRACT

PURPOSE

This article describes the neurologic manifestations of systemic autoimmune diseases.

RECENT FINDINGS

Systemic autoimmune diseases can be associated with a wide spectrum of neurologic comorbidities involving the central and peripheral nervous systems. Systemic lupus erythematosus (SLE) can be associated with a number of manifestations predominantly affecting the central nervous system (CNS), whereas peripheral neuropathy is less common. Sjögren syndrome can be associated with peripheral neuropathy in 10% of cases and CNS disease in 2% to 5% of cases. The risk of stroke is increased in SLE, rheumatoid arthritis, temporal arteritis, psoriatic arthritis, and ankylosing spondylitis. Systemic vasculitides present most commonly with mononeuritis multiplex but can also affect the CNS. Cognitive dysfunction is a common symptom among patients with systemic autoimmune diseases, most commonly seen in patients with SLE or Sjögren syndrome.

SUMMARY

Neurologic manifestations of systemic autoimmune disease are important to recognize, as they may often be the presenting manifestation leading to diagnosis of the systemic disease or may be associated with increased morbidity, other complications, or mortality. Timely diagnosis and institution of appropriate treatment, often requiring multidisciplinary care, is essential to minimize morbidity and decrease the risk of permanent neurologic deficits.

KEY POINTS

  • Patients with systemic lupus erythematosus, rheumatoid arthritis, temporal arteritis, psoriatic arthritis, and ankylosing spondylitis have increased risk of stroke.
  • Patients with systemic lupus erythematosus have increased risk of developing posterior reversible encephalopathy syndrome.
  • Neuromyelitis optica spectrum disorders can overlap with systemic lupus erythematosus or Sjögren syndrome.
  • Small fiber neuropathy is the most common peripheral neuropathy in Sjögren syndrome. It may present with length-dependent or non–length-dependent distribution of symptoms and tends to be associated with fewer extraglandular manifestations than large fiber neuropathy.
  • Patients with Sjögren syndrome and small fiber neuropathy are less frequently seropositive for anti-Ro and anti-La antibodies. Therefore, their absence should not preclude the diagnosis of Sjögren syndrome in an otherwise appropriate clinical setting.
  • Sensory ataxic neuropathy (neuronopathy) can be seen in patients with Sjögren syndrome due to lymphocyte infiltration of dorsal root ganglia. The differential diagnosis includes paraneoplastic syndromes (usually in cases of small cell lung carcinoma) human immunodeficiency virus infection, platinum-based chemotherapy, or vitamin B6 toxicity.
  • Neuromyelitis optica spectrum disorders can overlap with systemic lupus erythematosus or Sjögren syndrome.
  • Patients with rheumatoid arthritis have increased risk of cervical spinal stenosis, particularly at the atlantooccipital, atlantoaxial, or subaxial level.
  • Pannus formation is a mechanism by which patients with rheumatoid arthritis can develop cervical spinal stenosis. The imaging modality of choice to detect it is MRI.
  • Mononeuritis multiplex is the most common peripheral neuropathy associated with vasculitis. Over time, confluent neurologic deficits can mimic a distal symmetric polyneuropathy.
  • Combined nerve and muscle biopsy increases the sensitivity for vasculitis diagnosis.
  • In a patient with known or suspected systemic autoimmune disease or constitutional symptoms, coexisting deficits of subacute onset that localize to the central and peripheral nervous systems should raise the suspicion of vasculitis.
  • Peripheral neuropathy is present in more than 50% of patients with polyarteritis nodosa and is often a presenting manifestation.
  • Pituitary involvement can be seen in granulomatosis with polyangiitis.
  • Cerebral venous sinus thrombosis is associated with Behçet disease and is often of insidious onset.
  • Cognitive symptoms are common among patients with systemic autoimmune diseases, ranging from mild subjective cognitive symptoms to more severe cognitive dysfunction.
  • Patients with rapidly progressing cognitive decline should be evaluated for other central nervous system processes, such as vasculitis, infections, aseptic meningitis, autoimmune encephalitis, or prion diseases.
  • Cognitive dysfunction is seen more frequently in systemic lupus erythematosus and Sjögren syndrome, followed by rheumatoid arthritis.
  • Tumor necrosis factor-α inhibitors can cause central demyelination or demyelinating neuropathies.
  • Demyelinating neuropathy associated with tumor necrosis factor-α inhibitors persists after their cessation and requires treatment with IV immunoglobulin.

Article 4: Obstetric and Gynecologic Disorders and the Nervous System

Mary Angela O’Neal, MD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):611–631.

ABSTRACT

PURPOSE OF REVIEW

This article highlights the multiple intersections between obstetric/gynecologic issues and neurologic disorders.

RECENT FINDINGS

Neurologic issues can arise related to contraceptive medications, infertility treatments, pregnancy, and menopause. This article explores these areas in chronologic order, beginning with women’s neurologic conditions that overlap their reproductive years and those that may occur during pregnancy and continuing through menopause. For each disorder, the epidemiology, pathophysiology, complications, and best sex-based treatment are described. Recent findings and treatments are highlighted.

SUMMARY

Obstetric and gynecologic disorders may present with neurologic symptoms, so it is important for neurologists to understand these intersections to deliver the best care for our female patients.

KEY POINTS

  • Migraine is more prevalent in women because of the effects of estrogen on the condition.
  • Migraine without aura is more hormonally driven than migraine with aura.
  • Migraine with aura conveys a small increased risk for stroke, which is further magnified by combined hormonal contraception.
  • The risk of stroke in women who have migraine with aura is significantly increased when combined with other traditional stroke risk factors.
  • Ovarian hyperstimulation syndrome is a rare iatrogenic condition that increases the risk of thrombotic events.
  • Rising levels of human chorionic gonadotropin given for follicular maturation to trigger ovulation or related to pregnancy are pivotal in the development of the increased vascular permeability that is the core feature of ovarian hyperstimulation syndrome.
  • Pregnancy causes major changes in clotting factors, resulting in a hypercoagulable state.
  • The hypercoagulable changes that occur in pregnancy are most prominent in the last trimester and persist up to 12 weeks in the postpartum period.
  • Migraine frequency (especially migraine without aura) generally improves during pregnancy.
  • Women with a history of migraine have almost double the risk of preeclampsia than those without migraine.
  • Preeclampsia/eclampsia is a major risk factor for stroke in pregnancy and remains a stroke risk factor even decades later.
  • Posterior reversible encephalopathy syndrome is the radiographic correlate of preeclampsia/eclampsia.
  • The causes of stroke in pregnancy and the postpartum period are diverse.
  • Pregnant women with an ischemic stroke who meet criteria for either recombinant tissue plasminogen activator or endovascular therapy should be offered these therapies.
  • Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome should be thought of as occurring on a continuum, with similar etiologies and treatment during pregnancy and postpartum.
  • Dissection of the carotid or vertebral arteries in pregnancy is most commonly related to trauma associated with labor.
  • Cerebral venous thrombosis is treated with anticoagulation even in the presence of a venous hemorrhage.
  • Pituitary apoplexy can be a neuroendocrine emergency due to acute adrenal insufficiency.
  • Postpartum neuropathies/plexopathies are usually related to a traumatic or compressive injury during labor and delivery and are seldom related to neuraxial anesthesia.
  • Bell’s palsy is 2 to 4 times more prevalent in pregnancy, usually occurring in the last trimester and the first week postpartum.
  • Migraines may worsen due to the hormonal fluctuations during the menopause transition.
  • Sleep disturbances are common during the menopausal transition.

Article 5: Electrolyte Disorders and the Nervous System

Nuri Jacoby, MD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):632–658.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview of the major electrolyte disorders and discusses in detail the homeostasis, etiologies, neurologic manifestations, and treatment of these disorders.

RECENT FINDINGS

The diagnosis and management of hyponatremia continue to evolve. Diagnostic accuracy is improved by assessing serum and urine osmolality as well as urinary sodium. Avoiding overcorrection of hyponatremia is crucial to avoid osmotic demyelination syndrome, although even careful correction can cause osmotic demyelination syndrome in patients who have other risk factors. The clinical presentation of osmotic demyelination syndrome has expanded, with many patients presenting with extrapontine myelinolysis in addition to central pontine myelinolysis.

SUMMARY

Electrolyte disorders often present with neurologic manifestations. Whereas disorders of some electrolytes, such as sodium, preferentially affect the central nervous system, disorders of others, such as potassium and calcium, have significant neuromuscular manifestations. An understanding of the pathophysiology of these disorders and recognition of these manifestations are crucial for the practicing neurologist as the symptoms are reversible with correct management.

KEY POINTS

  • Water homeostasis is regulated by thirst and antidiuretic hormone, with antidiuretic hormone playing a larger role.
  • The etiologies of hypoosmolar hyponatremia can be separated into three categories based on volume status: hypovolemia, euvolemia, and hypervolemia.
  • The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can be due to neurologic or pulmonary etiologies, drugs, or malignancy.
  • Medications that cause SIADH include selective serotonin reuptake inhibitors; serotonin norepinephrine reuptake inhibitors; tricyclic antidepressants; and antiepileptic drugs such as carbamazepine, oxcarbazepine, and eslicarbazepine acetate.
  • SIADH, which is the most common cause of hyponatremia and occurs in patients who are euvolemic, must be differentiated from cerebral salt wasting, which occurs in the setting of hypovolemia. In SIADH, the treatment is fluid restriction, whereas in cerebral salt wasting, the treatment is fluid resuscitation.
  • Low osmolality due to hyponatremia produces a shift in the osmotic gradient, causing water to flow into the intracellular compartment, with resultant intracellular edema and rupture of cell membranes.
  • Hyponatremia is more likely to cause symptoms if it occurs rapidly (ie, within hours). When levels decrease rapidly to lower than 115 mmol/L to 120 mmol/L, a risk of brain herniation and respiratory arrest exists.
  • For acute hyponatremia or symptomatic hyponatremia regardless of duration, guidelines recommend a bolus of 3% sodium chloride (100 mL over 10 minutes, up to 3 times as needed).
  • For chronic hyponatremia, guidelines recommend increasing plasma sodium concentration by ≤8 mmol/L/d, with consideration of slower correction if a high risk of osmotic demyelination syndrome is present. First-line treatment for chronic nonhypovolemic hyponatremia is to reduce free water intake (<1 L/d).
  • Risk factors for the development of osmotic demyelination syndrome in the setting of correction of hyponatremia are alcohol use disorder, malnutrition, concurrent hypokalemia, and liver transplantation.
  • Patients with central pontine myelinolysis present with a flaccid quadriparesis that later becomes spastic, dysarthria, dysphagia, and, potentially, ocular motor abnormalities.
  • Osmotic demyelination syndrome that occurs outside the pons is called extrapontine myelinolysis, which can occur concurrently with central pontine myelinolysis or alone. Extrapontine myelinolysis often presents with parkinsonism and other movement disorder symptoms.
  • Although seizures can be seen in hypernatremia, they are less common than in hyponatremia.
  • Treatment of hypernatremia is with hypotonic fluids. In acute hypernatremia (<2 days), hypotonic saline can be given to decrease plasma sodium concentration by 2 mmol/L per hour until plasma sodium concentration is 145 mmol/L. In chronic hypernatremia or if timeline is unknown, a slower correction of up to 10 mmol/L per day is recommended.
  • Neurologic symptoms of hypokalemia generally occur at levels lower than 3.0 mmol/L and include generalized proximal greater than distal weakness, leg cramps, paresthesia, irritability, and rhabdomyolysis.
  • The most dangerous manifestations of hyperkalemia are cardiac arrhythmias, which typically develop before neurologic manifestations.
  • The periodic paralyses are rare autosomal disorders due to mutations in skeletal muscle sodium, calcium, and potassium channels. They are characterized by episodes of flaccid muscle paralysis typically associated with hypokalemia or hyperkalemia.
  • Diagnosis of all periodic paralysis disorders can be done through genetic testing, which identifies 60% to 70% of all cases. Electrodiagnostic testing and clinical features can be helpful in cases in which genetic testing is negative.
  • Treatment of the periodic paralyses includes behavioral changes to minimize triggers, potassium treatment (either supplementation or avoidance), and medications.
  • Calcium and phosphorus levels are regulated by parathyroid hormone, calcitonin, and vitamin D metabolites.
  • The neurologic manifestations of hypercalcemia are primarily neuropsychiatric and neuromuscular and include subtle personality changes, difficulty concentrating, confusion, dementia, and proximal muscle weakness.
  • Neurologic symptoms can be seen in hypocalcemia if levels are reduced quickly or are lower than 7.5 mg/dL. Neurologic signs and symptoms include neuromuscular manifestations, including the Trousseau sign and Chvostek sign, seizures, confusion, and psychosis.
  • Treatment of acute symptomatic hypocalcemia is IV calcium, typically calcium gluconate diluted in 5% dextrose infused over 10 minutes.
  • Mildly reduced levels of phosphate are generally asymptomatic, although in severe cases, encephalopathy, hallucinations, coma, and cerebellar and extrapyramidal signs such as ataxia, tremor, and nystagmus can be seen.
  • As hypomagnesemia often causes both hypocalcemia and hypokalemia, it is difficult to determine which neurologic symptoms are due to which electrolyte abnormality.
  • Hypermagnesemia can worsen disorders of the neuromuscular junction such as myasthenia gravis and Lambert-Eaton myasthenic syndrome; thus, magnesium should be used with caution in patients with those disorders.
  • In acid-base disorders, a change in the partial pressure of carbon dioxide (Paco2) causes a compensatory change in the bicarbonate concentration (HCO3), whereas changes in bicarbonate cause a compensatory response in the Paco2.
  • Metabolic disorders (either acidosis or alkalosis) occur when the primary change is in the bicarbonate level, and respiratory disorders (either acidosis or alkalosis) occur when the primary change is in the Paco2 level.
  • In respiratory acidosis, cerebral vasodilation occurs at Paco2 levels higher than 50 mm Hg, which can lead to increased intracranial pressure.
  • Respiratory alkalosis can be due to any etiology that causes hyperventilation and presents with dizziness, paresthesia of the limbs and perioral area, headaches, muscle cramps, blurry vision, and seizures.
  • Metabolic acidosis can be classified as high anion gap and normal anion gap disorders, with the distinction important for determining the underlying etiology.
  • Neurologic symptoms of metabolic acidosis are nonspecific and can include headache, lethargy, stupor, and coma.

Article 6: Blood Cell Disorders and the Nervous System

Alexander E. Merkler, MD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):659–674.

ABSTRACT

PURPOSE OF REVIEW

This article discusses the epidemiology, diagnosis, treatment, and prevention of neurologic complications of common and rare blood cell disorders.

RECENT FINDINGS

A growing number of preventive treatment options are available for stroke in sickle cell disease. Paroxysmal nocturnal hemoglobinuria and immune thrombocytopenia can lead to stroke. Thrombotic thrombocytopenic purpura frequently causes neurologic symptoms and should be considered in the differential diagnosis of a patient with neurologic symptoms, thrombocytopenia, and hemolytic anemia. Polycythemia vera and essential thrombocythemia are rare causes of stroke.

SUMMARY

This article discusses sickle cell disease and the most recent advances in stroke preventive therapy as well as neurologic complications of paroxysmal nocturnal hemoglobinuria, immune thrombocytopenia, thrombotic thrombocytopenic purpura, polycythemia vera, and essential thrombocythemia.

KEY POINTS

  • Sickle cell disease is a multisystem disease that causes myriad acute and chronic medical complications. Stroke affects 1 in 10 children with sickle cell disease and is one of the most devastating consequences because of its propensity to lead to physical and cognitive impairment and a decreased quality of life.
  • Patients with sickle cell disease are at risk for all types of stroke, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.
  • In patients with sickle cell disease, strokes due to moyamoya syndrome are typically found in either the distribution of a large intracranial artery or at the watershed zone between the large arteries.
  • Cerebral infarction occurs in approximately 11% of patients with sickle cell disease by age 20, 15% by age 30, and 24% by age 45.
  • Red blood cell transfusion is the mainstay of primary and secondary stroke prevention in children with sickle cell disease.
  • Guidelines recommend that children 2 to 16 years of age undergo annual TCD to monitor velocities; in patients with mean velocities greater than 200 cm/s, transfusion therapy should be initiated to reduce sickle hemoglobin to less than 30% and hydroxyurea should be considered.
  • Cerebral venous sinus thrombosis or thrombosis of an intracranial vein is the most frequent neurologic complication of paroxysmal nocturnal hemoglobinuria and occurs in 2% to 8% of patients.
  • In patients with a cerebral venous thrombosis of unknown etiology, a diagnosis of paroxysmal nocturnal hemoglobinuria should be considered when patients are young, have evidence of hemolysis, or have any cytopenia.
  • Intracranial hemorrhage is a feared complication of immune thrombocytopenia given its association with severe long-term morbidity and high mortality.
  • Based on a large meta-analysis, the frequency of intracranial hemorrhage is approximately 1% in patients with immune thrombocytopenia.
  • Predictors of bleeding in immune thrombocytopenia include the presence of severe thrombocytopenia, previous bleeding, and advanced age.
  • Patients with immune thrombocytopenia and intracranial hemorrhage should receive immediate therapy with platelet transfusion/continuous infusion and concomitantly be treated with high-dose corticosteroids with consideration of IV immunoglobulin as an adjunctive therapy.
  • Thrombotic thrombocytopenic purpura is due to a severe deficiency in ADAMTS13, which is a metalloproteinase that is responsible for the breakdown of von Willebrand factor.
  • Overall, more than 90% of patients with thrombotic thrombocytopenic purpura have neurologic involvement, including ischemic stroke, hemorrhagic stroke, and posterior reversible encephalopathy syndrome.
  • Diagnosis of thrombotic thrombocytopenic purpura requires demonstration of a severe deficiency in ADAMTS13, defined as activity of less than 10%.
  • Plasma exchange is the first-line therapy for treatment of thrombotic thrombocytopenic purpura.

Article 7: Critical Medical Illness and the Nervous System

Matthew B. Maas, MD, MS, FAAN. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):675–694.

ABSTRACT

PURPOSE OF REVIEW

Nervous system tissues have high metabolic demands and other unique vulnerabilities that place them at high risk of injury in the context of critical medical illness. This article describes the neurologic complications that are commonly encountered in patients who are critically ill from medical diseases and presents strategies for their diagnosis, prevention, and treatment.

RECENT FINDINGS

Chronic neurologic disability is common after critical medical illness and is a major factor in the quality of life for survivors of critical illness. Studies that carefully assessed groups of patients with general critical illness have identified a substantial rate of covert seizures, brain infarcts, muscle wasting, peripheral nerve injuries, and other neurologic sequelae that are strong predictors of poor neurologic outcomes. As the population ages and intensive care survivorship increases, critical illness–related neurologic impairments represent a large and growing proportion of the overall burden of neurologic disease.

SUMMARY

Improving critical illness outcomes requires identifying and managing the underlying cause of comorbid neurologic symptoms.

KEY POINTS

  • Nervous system tissues have high metabolic demands and other unique vulnerabilities that place them at high risk of injury in the context of critical illness. Approximately 20% of circulation and energy consumption occurs in the brain, which accounts for less than 2% of body mass.
  • Patients with chronic neurologic disease have increased susceptibility to neurologic dysfunction from systemic causes.
  • Patients with resolved focal deficits may experience a reemergence of those deficits during critical illness, a phenomenon called recrudescence.
  • Specific chronic neurologic diseases may pose unique complications in the context of new medical complications.
  • Medications, monitoring equipment, invasive devices, and impaired mental status can complicate safe examination of patients. High situational awareness, attention to the effects of medications, and assistance from nursing colleagues will maximize safety.
  • Ischemic and hemorrhagic strokes are the principle causes of acute focal brain injuries during critical illness.
  • Encephalopathy is the clinical syndrome of generalized brain failure. It can be caused by a single etiology or a combination of many factors. Etiology is often hard to distinguish by clinical examination findings alone.
  • Delirium is a syndrome of decreased arousal and attention with incoherent thought and speech that may occur due to any process that provokes encephalopathy. The incidence of delirium during critical illness is associated with hospital complications, increased mortality, and worse long-term cognitive outcomes.
  • Delirium is best prevented and treated by care bundles to address multiple factors that variably contribute to delirium risk in many patients. Care bundles are most effective when implemented uniformly for entire patient care areas.
  • Encephalopathy in the context of sepsis is associated with microvascular brain injuries (infarcts, hemorrhages, and microabscesses). Therefore, recovery of encephalopathy often lags resolution of systemic disease.
  • Neuropharmacology becomes very complicated in patients who are critically ill because of polypharmacy and dynamic changes in liver and kidney function that affect drug metabolism and clearance. The potential for medication toxicity should be considered for every patient who is encephalopathic.
  • Many critical illnesses can cause diffuse microvascular injuries in the brain and peripheral nerves. Unlike large vascular lesions, focal symptoms are relatively uncommon, and, in many cases, damage occurs in lesions below the resolution of standard neuroimaging studies.
  • Withdrawal syndromes caused by alcohol, opiate, or benzodiazepine dependence are relatively common in patients who are critically ill.
  • Critical illness and multiorgan failure alone are sufficient to trigger seizures, although a history of epilepsy or focal brain lesions increase risk. Many seizures in patients who are critically ill are nonconvulsive. EEG monitoring should be considered in patients who are critically ill with unexplained alteration of mental status.
  • Polyneuropathy and myopathy are widespread in patients who are critically ill and frequently go unrecognized. Strict glycemic control, maximizing nutrition, and mobilizing patients as early as possible may reduce the risk of these complications.
  • Post–intensive care syndrome, a constellation of cognitive, psychological, and physical disability seen as sequelae of acute neurologic comorbidities of critical illness, occurs in more than half of critical illness survivors and is a major cause of chronic disability.

Article 8: Sarcoidosis and the Nervous System

Siddharama Pawate, MD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):695–715.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview and update on the neurologic manifestations of sarcoidosis.

RECENT FINDINGS

The 2018 Neurosarcoidosis Consortium diagnostic criteria emphasize that biopsy is key for diagnosis and determines the level of diagnostic certainty. Thus, definite neurosarcoidosis requires nervous system biopsy and probable neurosarcoidosis requires biopsy from extraneural tissue. Without biopsy, possible neurosarcoidosis can be diagnosed if the clinical, imaging, and laboratory picture is compatible and other causes are ruled out. Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious when other treatments are inadequate.

SUMMARY

Sarcoidosis is a multisystem noninfectious granulomatous disorder that is immune mediated, reflecting the response to an as-yet unidentified antigen or antigens. Neurosarcoidosis refers to neurologic involvement due to sarcoidosis that clinically manifests in 5% of cases of sarcoidosis, with asymptomatic involvement in as many as another one in five patients with sarcoidosis. Sarcoid granulomas can occur in any anatomic substrate in the nervous system, causing protean manifestations that have earned neurosarcoidosis the sobriquet the great mimic. Nevertheless, central nervous system sarcoidosis occurs in well-defined presentations that can be classified as cranial neuropathies, meningeal disease, brain parenchymal (including pituitary-hypothalamic) disease, and spinal cord disease. In addition, the peripheral nervous system is affected in the form of peripheral neuropathy and myopathy. Glucocorticoids are the cornerstone of treatment, especially in the acute stage, whereas steroid-sparing agents such as methotrexate, mycophenolate mofetil, and azathioprine are used for prolonged therapy to minimize steroid toxicity. Anti–tumor necrosis factor agents may help in refractory cases.

KEY POINTS

  • Sarcoidosis is a multisystem noninfectious immune-mediated inflammatory granulomatous disease. The histopathologic hallmark of sarcoidosis is the noncaseating granuloma.
  • African Americans in the United States are 10 times more likely to have sarcoidosis than whites, and African American women have the highest incidence.
  • Neurosarcoidosis has acquired the reputation of being a challenging disease to diagnose because of its protean manifestations, earning it the nickname the great mimic. However, it is helpful to recognize that neurosarcoidosis occurs as well-defined neurologic manifestations: cranial neuropathies, meningitis, parenchymal disease, spinal cord disease, peripheral neuropathy, and myopathy.
  • The facial nerve and optic nerve are the most commonly affected cranial nerves in neurosarcoidosis.
  • In the brain parenchyma, hypothalamic-pituitary involvement is common and causes a variety of neuroendocrine manifestations.
  • Seizures and focal neurologic deficits can result from parenchymal neurosarcoidosis. The specific manifestations depend on the size, location, and speed of development of the inflammatory process.
  • Both the leptomeninges and the dura can be affected in neurosarcoidosis. Headache is a common presentation in these cases. Hydrocephalus can develop as a secondary complication of meningitis.
  • A longitudinally extensive transverse myelitis can be seen in neurosarcoidosis and can be difficult to differentiate from neuromyelitis optica spectrum disorders and other causes.
  • The neuropathy of neurosarcoidosis cannot be distinguished from other immune-mediated neuropathies clinically, by nerve conduction studies and EMG, or by response to immunotherapies.
  • Small fiber neuropathy in sarcoidosis is termed a paraneurosarcoidosis, reflecting that it is not due to direct granulomatous invasion of small fibers but a distant effect due to circulating inflammatory mediators.
  • CSF studies are sensitive to demonstrate intrathecal inflammation but lack specificity for neurosarcoidosis. CSF findings in neurosarcoidosis include pleocytosis, increased protein, decreased glucose, elevated IgG index, and the presence of oligoclonal bands.
  • The Neurosarcoidosis Consortium Consensus Group criteria for neurosarcoidosis seek to standardize the definition of neurosarcoidosis encompassing both central nervous system and peripheral nervous system involvement. They affirm the vital role of biopsy in the diagnosis.
  • A biopsy of the nervous system lesion is required for the diagnosis of definite neurosarcoidosis. Extraneural biopsy consistent with sarcoidosis, in conjunction with central nervous system inflammation suggestive of sarcoidosis, allows the diagnosis of probable neurosarcoidosis. In the absence of histopathologic confirmation, possible neurosarcoidosis can be diagnosed in the presence of appropriate clinical, imaging, and laboratory findings.
  • As with CSF, MRI is sensitive to the presence of inflammation but is not specific for neurosarcoidosis.
  • Chest imaging is a vital initial study in the investigation of neurosarcoidosis because 90% of patients with sarcoidosis will have intrathoracic involvement. A chest CT can pick up additional cases missed by chest x-ray.
  • If clinical suspicion is high and chest imaging is negative, positron emission tomography can show extrathoracic systemic sarcoidosis and provide targets for biopsy.
  • Corticosteroids are the first-line agents in therapy of neurosarcoidosis, but their long-term use is fraught with adverse effects. The goal should be to minimize their use to the shortest possible duration.
  • Steroid-sparing agents have been used in patients requiring long-term immunotherapy to minimize steroid adverse effects; they include methotrexate, mycophenolate mofetil, and azathioprine.
  • Infliximab has emerged as a cornerstone in the treatment of refractory or severe cases of neurosarcoidosis.

Article 9: Commonly Used Drugs for Medical Illness and the Nervous System

Mary L. Vo, MD, PharmD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):716–731.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview of the neurologic side effects of commonly prescribed medications, some of which can result in significant impairment if not addressed. This article aims to help clinicians recognize neurologic adverse drug reactions of a range of medication classes.

RECENT FINDINGS

Adverse drug reactions are a source of significant morbidity and rising health care costs. Failure to recognize neurologic adverse drug reactions may prompt unnecessary testing to identify a primary neurologic condition and expose the patient to continued adverse effects of a medication. Familiarity with the side effect profiles of newer medications, timing of side effects, pattern of reaction, medication rechallenge, and concurrent medical issues and awareness of significant medication interactions may aid in the identification of a medication side effect.

SUMMARY

Early recognition of neurologic adverse medication reactions can be challenging but is essential to prompt discontinuation of the offending medication or administration of specific symptomatic treatments in select cases. A high index of suspicion is needed to arrive at the correct diagnosis promptly, initiate a treatment plan, limit unnecessary testing, and reduce overall health care cost burden.

KEY POINTS

  • All beta-lactam antibiotics can potentially cause encephalopathy and seizure by reducing γ-aminobutyric acid A activity, leading to neuronal excitotoxicity. Imipenem and cefepime carry the highest risk of seizure.
  • Prolonged metronidazole treatment can precipitate a subacute cerebellar syndrome that can start several weeks following treatment discontinuation. MRI shows T2-hyperintense lesions in the dentate nuclei.
  • Metronidazole, fluoroquinolones, linezolid, and chloramphenicol can cause peripheral neuropathy. Symptoms are dose dependent and usually improve after medication withdrawal.
  • Fluoroquinolones, macrolides, and aminoglycosides slow neuromuscular transmission by inhibiting presynaptic acetylcholine release and binding postsynaptic acetylcholine receptors. These medications are contraindicated in patients with myasthenic syndromes.
  • In contrast to direct sympathomimetic agents, indirect sympathomimetic agents readily penetrate the central nervous system and have widespread neurotoxic effects, including agitation, insomnia, euphoria, delirium, psychosis, seizure, and addiction.
  • Patients who are elderly, especially those with neurodegenerative diseases, are vulnerable to anticholinergic side effects. Limiting the use of anticholinergic agents, prescribing the lowest possible doses, and selecting quaternary amines are safer for patients who are elderly.
  • The anticholinergic toxidrome is characterized by confusion, mydriasis, hyperthermia, tachycardia, anhidrosis, and urinary retention. Neurologic symptoms can include delirium with hallucinations and seizures. Serotonin syndrome is distinguished from anticholinergic toxicity by the presence of diaphoresis.
  • Fluoxetine and other selective serotonin reuptake inhibitors can be very effective in the treatment of steroid-induced depression. Tricyclic antidepressants have been reported to exacerbate symptoms.
  • Statin-associated necrotizing autoimmune myopathy is a rare condition characterized by slowly progressive lower extremity weakness, creatine kinase levels from 2000 IU/L to 20,000 IU/L, and antibodies to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase or signal recognition particle.
  • Nucleoside reverse transcriptase inhibitors cause mitochondrial toxicity by blocking mitochondrial DNA synthesis and DNA polymerase inhibition, ultimately leading to myopathy and painful peripheral neuropathy. Symptoms and creatine kinase levels improve within 8 weeks of medication discontinuation.
  • Integrase strand transfer inhibitors can cause muscle weakness and creatine kinase elevations, especially when taken with statins and fenofibrates. Mitochondrial myopathy and rhabdomyolysis are rare.
  • Metformin treatment can cause cognitive symptoms and myeloneuropathy by depleting vitamin B12. It is important to screen vitamin B12 levels in a patient with diabetes mellitus presenting with new-onset neuropathic or cognitive symptoms. Some clinicians routinely monitor vitamin B12 levels at least every 4 years.

Article 10: Anticancer Drugs and the Nervous System

Bianca D. Santomasso, MD, PhD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):732–764.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the clinical features, prognosis, and treatment of neurotoxicity from anticancer drugs, including conventional cytotoxic chemotherapy, biologics, and targeted therapies, with a focus on the newer immunotherapies (immune checkpoint inhibitors and chimeric antigen receptor T cells).

RECENT FINDINGS

Whereas neurologic complications from traditional chemotherapy are widely recognized, newer cancer therapies, in particular immunotherapies, have unique and distinct patterns of neurologic adverse effects. Anticancer drugs may cause central or peripheral nervous system complications. Neurologic complications of therapy are being seen with increasing frequency as patients with cancer are living longer and receiving multiple courses of anticancer regimens, with novel agents, combinations, and longer duration. Neurologists must know how to recognize treatment-related neurologic toxicity since discontinuation of the offending agent or dose adjustment may prevent further or permanent neurologic injury. It is also imperative to differentiate neurologic complications of therapy from cancer progression into the nervous system and from comorbid neurologic disorders that do not require treatment dose reduction or discontinuation.

SUMMARY

Neurotoxicity from cancer therapy is common, with effects seen on both the central and peripheral nervous systems. Immune checkpoint inhibitor therapy and chimeric antigen receptor T-cell therapy are new cancer treatments with distinct patterns of neurologic complications. Early recognition and appropriate management are essential to help prevent further neurologic injury and optimize oncologic management.

KEY POINTS

  • Immunotherapy is associated with new patterns of neurotoxicity that are distinct from those associated with traditional chemotherapy and can affect both the central and peripheral nervous systems.
  • Neurologic immune-related adverse events have been reported throughout the course of treatment and even after treatment discontinuation; however, serious events tend to occur days to weeks after treatment initiation.
  • Neurologic immune-related adverse events are frequently associated with immune-related adverse events affecting other organ systems; this can be a clue alerting to the possibility of a given neurologic symptom being related to the therapy.
  • Early detection of neurologic immune-related adverse events is essential as prompt therapeutic intervention is likely to be associated with better recovery.
  • Chimeric antigen receptor (CAR) T-cell therapy induces oncologic responses but is associated with unique toxicities, cytokine release syndrome, and immune effector cell–associated neurotoxicity syndrome.
  • Neurotoxicity from anticancer drugs is a diagnosis of exclusion.
  • MRI and lumbar puncture for CSF evaluation can be particularly helpful for evaluating possible therapy-associated neurotoxicity by ruling out other causes.
  • Recognition of neurotoxicity is important to prevent further neurologic injury or the premature cessation of a necessary anticancer treatment.
  • Determination of immune effector cell–associated neurotoxicity syndrome from CAR T-cell therapy is usually more straightforward because classic symptoms are seen that typically follow a stereotyped progression within a defined time window (usually within the first 30 days) after CAR T-cell infusion.
  • Chemotherapy-induced peripheral neuropathy is typically dose dependent and cumulative.
  • With most chemotherapy drugs, chemotherapy-induced peripheral neuropathy has a symmetric, distal, stocking-glove distribution. Chemotherapy-induced peripheral neuropathy predominantly consists of sensory rather than motor symptoms, although motor symptoms can occur.
  • Autonomic neuropathy is rare in chemotherapy-induced peripheral neuropathy with the exception of vinca alkaloids, particularly vincristine. A typical presentation of autonomic neuropathy is constipation.
  • Unlike chemotherapy-induced peripheral neuropathy, which is often dose or duration related, neuropathy related to immune checkpoint inhibitors may develop very soon after treatment starts, even within the first one to three doses.
  • Neuropathy presentations from immune checkpoint inhibitors may be diverse.
  • Unlike chemotherapy-induced peripheral neuropathy, in which holding or discontinuing the drug is the mainstay of management, peripheral neuropathies from immune checkpoint inhibitors are managed by holding therapy plus initiating corticosteroids. For severe cases, other immunosuppressants may be used.
  • With several chemotherapies, such as cisplatin and paclitaxel, although initial symptoms usually begin during treatment, they can continue to progress for several months after completion of therapy or may worsen for several months following the discontinuation of therapy (coasting).
  • Vincristine primarily affects peripheral nerves but can also cause cranial neuropathies and autonomic nervous system dysfunction. Symptoms such as hoarseness, ptosis, vision loss, facial weakness, and hearing loss are suggestive of cranial neuropathy from vincristine. The major differential diagnosis is tumor recurrence in the central nervous system.
  • Unlike classic Guillain-Barré syndrome, in which albuminocytologic dissociation is seen, a lymphocytic pleocytosis is usually seen in the polyradiculoneuropathy resulting from immune checkpoint inhibitor treatment.
  • Unlike chemotherapy-induced peripheral neuropathy, immune-related neuropathies are more likely to have an acute or subacute and non–length-dependent presentation.
  • Immune-related neuropathies typically occur early in the treatment course but may occur many months after the start of immune checkpoint inhibitor therapy and may persist after the immune checkpoint inhibitor is discontinued.
  • Myalgia and muscle cramps are common in patients treated with cisplatin and vincristine but may also occur with several other agents, such as brentuximab, rituximab, imatinib, and the combination of BRAF and MEK inhibitors.
  • Myositis is a complication of immune checkpoint inhibitor therapy that usually occurs early in the course of treatment, most often triggered by anti-PD1/PD-L1–containing therapy. It may affect oculobulbar muscles and resemble myasthenia gravis.
  • Immune checkpoint inhibitor–induced myositis must be distinguished from immune checkpoint inhibitor–induced myasthenia gravis.
  • The diagnostic workup for myositis resulting from immune checkpoint inhibitor therapy often shows elevated creatine kinase or aldolase and a myopathic pattern on EMG. Antistriational antibodies may be present and appear to be associated with a more severe necrotizing myositis.
  • In severe cases of myositis, the immune checkpoint inhibitor should be discontinued and patients should be treated with IV corticosteroids with or without IV immunoglobulin or plasma exchange.
  • When myasthenia gravis occurs with immune checkpoint inhibitor therapy, it usually occurs within the first 3 months after treatment.
  • Since myasthenia gravis may overlap with myositis or myocarditis, immune-related adverse event management guidelines recommend that creatine kinase, antistriational antibodies, and troponin be tested and ECG obtained in cases of immune checkpoint inhibitor–associated myasthenia gravis regardless of cardiac symptoms.
  • Headache associated with immune checkpoint inhibitor therapy may suggest aseptic meningitis or hypophysitis.
  • Aseptic meningitis from immune checkpoint inhibitor therapy is typically very responsive to oral corticosteroids.
  • Immune checkpoint inhibitors may result in encephalitis at an incidence estimated to be 0.1% to 0.2%. Diagnosis is often challenging as patients may present with a wide range of symptoms, including altered mental status, confusion, short-term memory impairment, agitation, aphasia, and seizures.
  • Studies found that early treatment with tocilizumab decreased the incidence of severe cytokine release syndrome, but it was not associated with decreased incidence or severity of immune effector cell–associated neurotoxicity syndrome (ICANS); in fact, severe ICANS rates may have been slightly higher. Therefore, tocilizumab is not recommended for management of isolated ICANS.
  • ICANS is usually reversible but can be severe or even fatal.
  • Many centers use prophylactic levetiracetam or another antiepileptic drug starting on the day of infusion for CAR T-cell agents associated with high incidence of immune effector cell-associated neurotoxicity syndrome (ICANS).
  • A variety of inflammatory demyelinating syndromes have been reported following treatment with immune checkpoint inhibitors, including optic neuritis, transverse myelitis, and acute tumefactive demyelinating inflammatory lesions.
  • Patients with cancer have an increased risk of stroke and other cerebrovascular disease because of the underlying hypercoagulability of malignancy as well as the treatments they receive.
  • The most common chemotherapy to induce a cerebellar syndrome is high-dose cytarabine, usually at high cumulative dose.
  • Tremor or myoclonus associated with CAR T-cell therapy is typically mild and transient; it may begin with the onset of cytokine release syndrome and may be the last immune effector cell–associated neurotoxicity syndrome symptom to resolve, usually within a few days of the start of the symptom.
  • The risk of myelopathy in patients who have received an intrathecal chemotherapeutic agent is higher in those who have received prior spinal radiation.

Article 11: Drugs of Abuse and the Nervous System

Derek Stitt, MD; Neeraj Kumar, MD. Continuum (Minneap Minn). June 2020; 26 (3 Neurology of Systemic Disease):765–784.

ABSTRACT

PURPOSE OF REVIEW

This article discusses the neurologic complications of traditional, nontraditional, and emerging drugs of abuse.

RECENT FINDINGS

The manufacture, distribution, and use of so-called designer drugs are increasing. These agents can induce dramatic neurologic manifestations and can evade identification on conventional drug-screening assays. Additionally, gabapentinoids, drug agents that are very familiar to neurologists, are being abused in the general population at increasing rates to achieve euphoric highs and potentiate the effects of opiates. Furthermore, even well-known illicit narcotics such as heroin are posing dangers above their baseline because of “lacing” with additives or substitutes such as fentanyl and related compounds. These clandestine agents increase the potency of what are thought to be typical dosages to lethal levels, thus leading to more unintentional overdose deaths.

SUMMARY

The potential for short- and long-term nervous system injury from drug abuse is well established. However, it is important for the practicing neurologist to possess awareness of the features and observed sequelae of the toxidromes of both traditional and nontraditional drugs of abuse. This is because the use of both is widespread in our society and conventional drug screening can miss detection of some powerful agents, thus forcing us to maintain a high index of suspicion based on recognition of the clinical features.

KEY POINTS

  • Severe opioid overdose is characterized by the triad of coma, miosis, and respiratory depression. Treatment is rapid respiratory support and administration of an opioid antagonist (naloxone).
  • New synthetic opioid compounds are being used to lace common street drugs, such as heroin, to increase their potency, which leads to more unintentional overdoses.
  • Heroin abuse carries the risk of both acute and chronic central nervous system complications, including a toxic spongiform leukoencephalopathy and myelopathy.
  • Gabapentin and pregabalin are increasingly becoming abused substances. Their effects serve to potentiate the already dangerous effects of opioids.
  • Barbiturates have higher abuse, dependence, and withdrawal potential than benzodiazepines.
  • The manifestations of benzodiazepine and barbiturate withdrawal are similar to that of alcohol, with seizures being of highest concern.
  • The risk of bizarre behavioral adverse events from zolpidem use is quite low. Its abuse/dependence potential is also low but should not be ignored.
  • All psychostimulants have a similar pharmacologic effect of increasing dopaminergic, serotonergic, and noradrenergic neurotransmission.
  • Acute intoxication with most psychostimulants carries the risk of serious cardiovascular and cerebrovascular complications, as well as seizures.
  • “Bath salts” are synthetic cathinone derivatives and are often marketed as “legal highs.” They are not detected on standard drug-screening assays.
  • Cerebrovascular complications of stimulant abuse, such as abuse of methamphetamine and cocaine, are well known to include hemorrhagic and ischemic stroke as well as reversible cerebral vasoconstriction syndrome.
  • Synthetic cannabinoids are more potent than conventional cannabis and can induce greater stimulantlike effects, including severe agitation and psychosis.
  • Seizures are a known and concerning risk with the use of synthetic cannabinoids.
  • Marijuana use is not totally benign. Increased risk for neurologic injury exists due to acute cerebral vascular disease; people who use marijuana chronically are at risk for cannabinoid hyperemesis syndrome.
  • Hallucinogens cause psychedelic highs marked by distorted sensory perception.
  • Hallucinogen overdose is managed supportively. Pharmacologic agitation control may be indicated.
  • Withdrawal is a not a standard feature of even repeated psychedelic drug use.
  • Lysergic acid diethylamide and other hallucinogens can cause flashbacks of their effects even long after the last usage. Long-term use has been associated with a chronic hallucinogenic persisting perception disorder.
  • Phencyclidine is a dissociative drug that produces a syndrome similar to a marked schizophrenic episode.
  • Inhalant agents of abuse are volatile hydrocarbons with short euphoric highs lasting a few hours.
  • Toluene abuse can cause a chronic white matter dementia from toxic leukoencephalopathy.
  • n-Hexane is associated with a potentially severe axonal sensorimotor peripheral neuropathy that can persist after discontinuation.
  • Nitrous oxide abuse (often in the form of whip-its) can lead to a functional vitamin B12 deficiency.
  • Anticholinergic toxicity manifests with encephalopathy, dilated pupils, tachycardia, dry mouth, constipation, anhidrosis, and urinary retention. Seizures, myoclonus, and coma are risks in severe cases.
  • Recreational use of purple drank is a means of opioid and anticholinergic toxicity due to the combination of codeine-containing antitussive agents mixed with promethazine.
  • IV physostigmine is used as a reversal agent for anticholinergic toxicity because of its central nervous system penetrance.
  • A possible link exists between e-cigarette use (vaping) and risk of seizures.
  • Chronic abuse of alcohol is toxic to the nervous system in many ways, including cerebellar toxicity, peripheral neuropathy (small fiber predominant), and chronic cognitive impairment that may not resolve after cessation.
  • People who chronically abuse alcohol are at risk for developing nutritional deficiencies that lead to neurologic injury (thiamine, vitamin B12, and vitamin B6 deficiency).
© 2020 American Academy of Neurology.