Neurologic Complications of Systemic Disease

What is the major neurologic complication of cardiac disease?

Stroke is the most common neurologic sequela of cardiac disease. The risks for embolic, thrombotic, and hemorrhagic strokes are elevated in the presence of cardiac disease. Nonvalvular atrial fibrillation, followed by ischemic heart disease and valvular heart disease, is the most common type of cardiac abnormality causing embolic ischemic strokes. Infective endocarditis is frequently associated with embolic strokes with hemorrhagic conversion. A patent foramen ovale may be a risk factor for stroke in some, especially younger patients, but it may be merely an incidental finding unrelated to stroke in other patients with other vascular risk factors.

What is the association between transient ischemic attack (TIA) and myocardial infarction (MI)?

Patients who suffer a TIA are more likely to suffer a fatal MI than a stroke, although the stroke incidence is three times higher in those who suffer from a TIA. Patients with a TIA are twice as likely to suffer an MI as the general population. Due to this increased risk, screening for cardiovascular disease and primary prevention of coronary artery disease are important in patients with a TIA.

What is the association between sleep, MI, and stroke?

Profound changes in centrally mediated sympathetic activity occur during rapid eye movement (REM) sleep, with small increases in blood pressure, heart rate, skin conductance changes, as well as momentary restorations in muscle tone, mesenteric and renal vasodilation, and skeletal muscle vasoconstriction. In the elderly, it is hypothesized that large fluctuations in sympathetic activity associated with REM sleep also cause increased rates of arrhythmia and increased risk for cardiac vasospasm and subsequent stroke and MI. The presence of heart rate abnormalities during sleep in normotensive patients is also reported to be a predictor of future cardiovascular disease. Sleep-disordered breathing (SDB) also contributes to increased stroke risk in multiple ways. In patients with obstructive sleep apnea, apneic episodes can cause increased sympathetic activation and increases in blood pressure. Compared to control subjects, atrial fibrillation is more common in patients with SDB. Finally, hypoxia due to apnea may activate inflammatory pathways. These pathways increase oxidative stress in blood vessels, leading to accelerated atherosclerosis.

What are the nonstroke-related neurologic complications of cardiac disease?

Cardiac arrhythmias (especially sick sinus syndrome) may produce decreased cardiac output, causing syncope, and, rarely, encephalopathy. Cerebral blood flow can be altered due to changes in cerebral autoregulation caused by abnormal autonomic vagal activity associated with cardiac disease. Persistent decreased brain perfusion, such as in the case of cardiac arrest or cardiogenic shock, may lead to laminar necrosis of the cerebral cortex or hippocampus.

What is the major cause of neurologic symptoms associated with gastrointestinal (GI) disease?

Most known neurologic complications of GI disease are the consequence of malabsorption of essential nutrients and vitamins. The consequences of some nutrient deficiencies have been well described, including those involving thiamine, folate, cyanocobalamin, niacin, vitamin D, vitamin E, and copper.

What are the neurologic manifestations of celiac disease?

Celiac disease, or gluten enteropathy, is an autoimmune disease of the small intestine that produces chronic small bowel malabsorption of vitamins and other nutrients often with iron deficiency anemia, osteoporosis and osteomalacia, and hypoalbuminemia. Individuals with the disease are intolerant to gluten proteins that are present in rye, wheat, barley, and in some adhesives, including that of stamps and envelopes. Ten percent of affected patients have neurologic complaints, the most notable being cerebellar dysfunction secondary to chronic fat malabsorption. Tremor, intranuclear ophthalmoplegia, encephalopathy, subacute combined degeneration, seizures, or myopathy are other features associated with the disease. The observed myopathy is often treatable by vitamin D replacement.

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Atanassova PA, Chalakova NT, Dimitrov BD: Major vascular events after transient ischaemic attack and minor ischaemic stroke: post hoc modelling of incidence dynamics. Cerebrovasc Dis 25:225-233, 2008.

Burns JD, Rabinstein AA, Roger VL, Stead LG, Christianson TJ, Killian J, Brown Jr. RD: Incidence and predictors of myocardial infarction after transient ischemic attack: a population-based study. Stroke 42(4):935-940, 2011.

Plante GE: Sleep and vascular disorders. Metabolism 55(10 Suppl 2):S45-S49, 2006.

Somers VK, Dyken ME, Mark AL, Abboud FM: Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 328:303-307, 1993.

Lipford MC, Park JG, Ramar K: Sleep-disordered breathing and stroke: therapeutic approaches. Curr Neurol Neurosci Rep 14:431, 2014.

Henri-Bhargava A, Melmed C, Glikstein R, Schipper HM: Neurologic impairment due to vitamin E and copper deficiencies in celiac disease. Neurology 71:860-861, 2008.

Baldassarre M, Laneve AM, Grosso R, Laforgia N: Celiac disease: pathogenesis and novel therapeutic strategies. Endocr Metab Immune Disord Drug Targets 8:152-158, 2008.

Beyenburg S, Scheid B, Deckert-Schluter M, Lagreze HL: Chronic progressive leukoencephalopathy in adult celiac disease. Neurology 50:820-822, 1998.

What is the triad of neurologic clinical features associated with Whipple’s disease?

Whipple’s disease is a multisystem granulomatous infection caused by Tropheryma whippelii . Neurologic complaints develop in 10% of afflicted patients. The common triad of findings includes ocular disturbance (often ophthalmoparesis), gait ataxia, and dementia. Other associated abnormalities include seizures, myelopathy, meningoencephalitis, autonomic dysfunction, and steroid-unresponsive myopathy. Effective treatment involves antibiotic therapy directed against the organism. Untreated, most patients die within 1 year of the onset of neurologic symptoms.

What is the triad of neurologic complaints associated with Wernicke’s encephalopathy?

Wernicke’s encephalopathy is associated with thiamine deficiency. Clinical symptoms include a triad of ophthalmoparesis, gait ataxia, and disturbances of mental function. An axonal sensorimotor neuropathy appears in half of patients with this deficiency state, and Korsakoff’s psychosis (dementia associated with profound amnesia and confabulation) is also variably present. The mortality associated with Wernicke’s encephalopathy is still greater than 10%, although this is more due to concomitant infections and malnutrition than to the neurologic disorders.

What is known about the etiology of nervous system impairment associated with vitamin B12 malabsorption?

The deficiency of methionine synthetase activity secondary to absence of its cofactor (B12) leads to accumulation of homocysteine. The resulting impairment in DNA synthesis is responsible for the megaloblastic anemia associated with vitamin B12 deficiency, while neurologic abnormalities are the result of failure to maintain methionine biosynthesis.

What are the neurologic manifestations of vitamin B12 deficiency?

Neurologic manifestations of vitamin B12 deficiency include cognitive, behavioral dysfunction, myelopathy, and peripheral neuropathy. Patients may manifest slowed cerebration, dementia, or delirium (with or without delusion), while others exhibit depression, amnesia, or acute psychotic states. Rare cases of reversible manic or schizophreniform states have also been reported. In addition to a sensorimotor neuropathy, vitamin B12 deficiency also can result in subacute combined degeneration of the spinal cord due to dorsal and lateral column involvement. Copper deficiency due to small bowel malabsorption or zinc overconsumption can produce a similar neurologic presentation.

Which vitamin deficiencies cause different neurologic syndromes in children from those in adults?

Lack of absorption of vitamin D from the intestinal tract leads to rickets in children and osteomalacia in adults. In children with rickets, neurologic sequelae include head shaking, nystagmus, and increased irritability that may evolve into tetany with a sufficient fall in serum calcium concentrations. Malabsorption of folate in infants leads to mental retardation, seizures, and athetotic movements, whereas in adults, polyneuropathy and depression are the primary complications. Pyridoxine deficiency leads to seizures in infants but a sensory polyneuropathy in adults.

Malabsorption of which vitamins will lead to an increased risk for subdural hematoma?

Malabsorption of vitamin C or vitamin K results in an increased tendency for hemorrhage, especially following trauma. Lack of thiamine, vitamin B12, or vitamin E all can result in ataxia, with an increased tendency for falls and head trauma.

Besides thiamine, malabsorption or dietary lack of which vitamin may produce a syndrome resembling Korsakoff’s dementia?

Nicotinic acid deficiency results in pellagra, whose major and often sole manifestation is psychiatric disturbance, sometimes mimicking Korsakoff’s psychosis.

So YT, Simon RP: Deficiency diseases of the nervous system. In Bradley WG, Daroff RB, Fenichel G, Jankovic J (eds): Neurology in clinical practice, 3rd ed. Boston, Butterworth-Heinemann, pp 1495-1509, 2000.

Winston GP, Jaiser SR: Copper deficiency myelopathy and subacute combined degeneration of the cord—why is the phenotype so similar? Med Hypotheses 71:229-236, 2008.

What are the five major neurologic syndromes associated with hepatic dysfunction?

• 1.

  Encephalopathy

• 2.

  Hepatocerebral degeneration

• 3.

  Wilson’s disease

• 4.

  Reye’s syndrome

• 5.

  Intracranial hemorrhage (ICH)

What causes hepatic encephalopathy (HE)?

This complication may occur with hepatic failure or with portal or hepatic circulatory dysfunction, as caused by acute or chronic hepatitis, hepatic necrosis, cirrhosis, or portocaval anastomosis. There are multiple theories about the pathogenesis of HE. Ammonia is thought to play an important role in the pathogenesis of HE. Patients with HE have been shown to have increased diffusion of ammonia through the blood–brain barrier. In the brain, cytoplasmic enzymes in the astrocyte medicate ammonia detoxification. Overloading of this system with excess ammonia generates free radicals in the mitochondria, causing cellular swelling and astrocytic dysfunction. Another important potential factor are nonpharmacologic ligands interacting with the gamma-aminobutyric acid (GABA) receptor. These ligands are normally occurring substances proposed to accumulate in brain tissue in HE. In addition, ammonia also plays a role in the affinity of GABA receptors to GABA itself. Reduction in the serum concentration of ammonia, or addition of centrally acting GABA antagonists, may temporarily improve hepatic encephalopathy, although correction of the precipitating causes of hepatic dysfunction is necessary for ultimate recovery.

How is HE treated?

Acute therapy for HE requires either removal or blockade of neurologically acting toxins produced in the gut. Reduction of protein intake along with lactulose therapy to enhance ammonia excretion and reduce ammonia absorption is the mainstay of therapy. Oral antibiotics, such as either neomycin or rifaximin, and amino acids l -ornithine and l -aspartate, are used as second-line agents to reduce gut bacterial levels and ammonia formation. Long-term treatment of HE with medical therapies has only limited success and depends on whether the hepatic damage is reversible, static, or progressive. Ultimately, the most effective therapy involves treatments directed at reversing the hepatic failure, including surgical shunting procedures and liver transplantation for selected individuals.

What is Reye’s syndrome?

Reye’s syndrome is a rare, acute noninflammatory encephalopathy that primarily affects children and adolescents. A correlation between the disease and a preceding viral infection (especially influenza and varicella) treated with salicylates has been reported, although other toxic, metabolic, or hypoxic insults may play roles in the pathogenesis. The clinical manifestations of Reye’s syndrome include hyperammonemia, hypoglycemia, coagulopathy, and cerebral edema. Treatment is supportive and includes administration of intravenous glucose to prevent hypoglycemia, and in severe cases, hyperventilation and intravenous mannitol to reduce intracranial pressure.

Defects in fatty acid oxidation, such as medium-chain acyl coenzyme A dehydrogenase deficiency, can also present as a Reye-like syndrome and may be more common than Reye’s syndrome, warranting a workup for inborn errors of metabolism in affected children.

In addition to HE, what other diseases cause asterixis?

Asterixis, or “flapping tremor,” is best elicited by the extension of outstretched, opened hands. It results from the acute loss of muscle tone or contraction associated with passive or active hand/wrist extension (“negative” myoclonus), most likely induced by pathologic coupling of the thalamus and motor cortex. This sign is encountered in many metabolic encephalopathies, including uremia, malnutrition, severe pulmonary disease, and polycythemia rubra vera.

What electroencephalographic (EEG) abnormality is associated with hepatic encephalopathy?

Slow triphasic waves are the abnormal EEG pattern reported with hepatic encephalopathy, and the pattern is commonly used to support the diagnosis. It can also be seen with encephalopathy associated with head trauma (especially with subdural hematoma), acute cerebral anoxia, uremia, electrolyte imbalance, and thyrotoxicosis.

Görg B, Qvartskhava N, Keitel V, et al.: Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo. Hepatology 48:567-579, 2008.

Lockwood AH: Hepatic encephalopathy. In Aminoff MJ (ed): Neurology and general medicine, 2nd ed. New York, Churchill-Livingstone, 1995.

Cordoba J: Hepatic encephalopathy: from the pathogenesis to the new treatments. ISRN Hepatology Vol 2014; Article ID 236368, 16 pages, 2014.

Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al.: Rifaxamin treatment in hepatic encephalopathy. N Engl J Med 362:1071-1081, 2010.

Dhiman RK, Chawla YK: Minimal hepatic encephalopathy: time to recognise and treat. Trop Gastroenterol 29:6-12, 2008.

Lockwood AH, Weissenborn R, Butterworth RF: An image of the brain in patients with liver disease. Curr Opin Neurol 10:525-533, 1997.

Gosalakkal JA, Kamoji V: Reye syndrome and Reye-like syndrome. Pediatr Neurol 39:198-200, 2008.

Smith TC: Reye’s syndrome and the use of aspirin. Scott Med J 41:4-9, 1996.

Timmerman L, Gross J, Butz M, et al.: Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling. Neurology 61:689-692, 2003.

What are the neurologic manifestations of Wilson’s disease?

Wilson’s disease is a rare disorder of copper metabolism resulting in accumulation of copper in the liver, kidneys, and central nervous system (CNS). In almost half of patients, neurologic manifestations are present, including tremors, dysarthria, clumsiness, drooling, and gait instability in order of decreasing frequency. Neuropsychiatric symptoms, including those of dementia, mania, depression, or psychosis, may dominate the presentation in up to 20% of patients. Kaiser–Fleischer rings, copper deposits in Descemet’s membrane of the cornea, are present in 98% of patients with neurologic manifestations and are visualized by slit-lamp examination. Neurologic manifestations invariably follow liver involvement, even in silent, unrecognized liver disease.

What is the treatment for Wilson’s disease?

Early diagnosis and copper chelation therapy are the mainstays of therapy. The chelation therapy of choice is oral d -penicillamine. d -Penicillamine should be administered concomitantly with pyridoxine to prevent vitamin B6 deficiency. Side effects include rash, fever, thrombocytopenia, relative eosinophilia with total leukopenia, and reversible lupus-like and myasthenia gravis-like syndromes. Trientene and zinc acetate are alternative agents with fewer side effects. Liver transplantation is recommended in patients with fulminant hepatic failure and end-stage liver cirrhosis but is not generally recommended for patients with neurologic disease without pronounced liver involvement.

What are the neurologic complications of hemochromatosis?

Hemochromatosis is a disorder of iron overload resulting in multiorgan fibrosis and dysfunction. Acquired causes result from excess total body iron due to multiple blood transfusions. Hereditary hemochromatosis is due to mutations in the HFE gene, which encodes for a protein involved in the regulation of GI iron absorption and uptake. Encephalopathy, truncal ataxia, and rigidity may all complicate hemochromatosis and invariably are due to liver disease (liver cirrhosis and failure) resulting from massive iron deposition in the liver. Neuritis is either a complication of the diabetes mellitus (DM) that accompanies most cases of hemochromatosis or is a result of local iron deposition.

Treatment requires serial phlebotomies four to six times per year. Lifetime treatment with phlebotomies is currently the treatment of choice, although newer therapies using growth factor control over red blood cell production are being tested.

Which porphyrias are associated with primarily neurologic manifestations?

Hepatic porphyrias, acute intermittent porphyria (AIP), and variegate (South African) porphyria can be distinguished from the rare “erythropoietic” forms that produce dermatologic symptoms without neurologic disease. In AIP, clinical symptoms develop during crises, most often precipitated by ingestion or administration of drugs that adversely affect porphyrin metabolism. These clinical symptoms include the following: (1) abdominal pain with vomiting, constipation or diarrhea, and often a previous history of exploratory abdominal surgery; (2) psychiatric disorder, with symptoms suggesting conversion reactions, delirium, or psychosis; (3) peripheral neuropathy, primarily motor, often with autonomic abnormalities, that may be severe or fatal and mimic Guillain–Barré syndrome; and (4) central abnormalities, such as syndrome of inappropriate antidiuretic hormone or convulsions.

Chronic ingestion of what substance may produce a condition similar to AIP?

Lead poisoning produces a condition (termed saturnism ) that closely resembles AIP clinically, and also appears to share heme synthetic dysfunction with accumulation of delta-aminolevulinic acid.

What is the treatment for neurologic crises in AIP?

Therapy is directed at modifying the biochemical abnormalities found in the disease, including overproduction of the neurotoxin delta-aminolevulinic acid and heme deficiency. Intravenous administration of hematin increases available heme and downregulates the patient’s abnormal heme biosynthetic pathway, thus reducing delta-aminolevulinic acid levels. Prevention of crises is the primary goal in treating patients with AIP. Education of patients to the many precipitants of acute attacks is necessary for their survival.

What are the most common neurologic complications of renal disease?

Typical neurologic complications of renal disease are peripheral neuropathy and metabolic encephalopathy.

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Graeme KA, Pollack CV Jr: Heavy metal toxicity. J Emerg Med 16:45-56, 1998.

Anderson KE, Bloomer JR, Bonkovsky HL, et al.: Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 142:439-450, 2005. Erratum in Ann Intern Med 143:316, 2005.

What are the characteristics of uremic neuropathy?

Uremic neuropathy appears as a symmetric distal sensorimotor axonal neuropathy and is almost invariably present in patients by the time they require dialysis. Other conditions that predispose to renal failure (e.g., diabetes and vasculitis) may also produce neuropathy, and thus symptoms can result from several different etiologies. Uremic neuropathy is at least partially reversible by repeated dialysis or by kidney transplantation.

What are the characteristics of uremic encephalopathy?

Patients with uremia often develop a metabolic encephalopathy. The mechanisms responsible for this encephalopathy remain unclear but presumably involve the retention of inorganic and organic acids, fluid alterations among cerebral cellular compartments, and abnormalities caused by hypertension, hypocalcemia, hyperkalemia, hypernatremia, hyperphosphatemia, and hypochloremia. Uremic encephalopathy is unusual because of the coexistence of signs of neuronal depression (lethargy, coma) with those of neuronal excitation (agitation, muscle cramps, myoclonus, tetany, asterixis, and seizures).

Name three neurologic complications associated with dialysis.

Dialysis disequilibrium syndrome, dialysis dementia, and ICH.

What is dialysis disequilibrium syndrome?

Dialysis disequilibrium syndrome is the name given to the cerebral edema produced by the rapid removal of urea and other osmoles and fluid and electrolyte shifts associated with dialysis. Dialysis disequilibrium is most likely to occur in patients either during or after their first treatment but can occur at any time in their treatment. The incidence appears to be decreasing, likely due to the earlier initiation of dialysis in the course of end-stage renal disease. The symptoms are nonspecific, but they are similar to those of ICH. They include persistent headache and fatigue. The syndrome may also be sufficiently severe to produce seizures, coma, and death. Due to the nonspecific nature of the symptoms, other causes of increased intracranial pressure must be ruled out. Recognition of this problem has led to newer protocols using more frequent, but less vigorous, dialysis.

What is dialysis dementia?

Dialysis dementia refers to reported cases in the 1980s of a rare but serious syndrome of irreversible progressive dementia with apraxias, dysarthria, hyperreflexia, myoclonus, and multifocal seizures. Clusters of patients with dementia presented from dialysis centers that used water contaminated with aluminum, and therefore the presence of aluminum in the dialysate was thought to be the primary agent causing CNS toxicity. Removal of aluminum with ion exchange resins prior to dialysis has significantly reduced the problem.

What causes ICH in patients undergoing dialysis?

Anticoagulation during dialysis and chronic hypertension associated with renal failure increases the incidence of ICH.

What neurologic complications are associated with renal transplantation?

Neurologic complications of renal transplantation can be due to either the renal disease necessitating transplantation or posttransplantation immunosuppression. Calcineurin inhibitors are the most common immunosuppressive medications in renal transplant patients and may cause tremors, paresthesia, a severe disabling pain syndrome, and posterior reversible encephalopathy syndrome. Reduction or discontinuation of the drug can either reverse or reduce the majority of the neurologic side effects. The monoclonal antibody OKT3 may induce severe neurologic syndromes such as aseptic meningitis. Stroke occurs in about 8% of renal transplant patients. End-stage renal disease due to diabetes and/or peripheral vascular disease are the strongest risk factors. Guillain–Barré syndrome may also develop, triggered in some cases by either cytomegalovirus or Campylobacter jejuni infection. Infection represents the most frequent neurologic complication in transplant patients on immunosuppression. Acute meningitis, usually caused by Listeria monocytogenes , and subacute and chronic meningitis, caused by Cryptococcus neoformans , account for more than 90% of nonviral CNS infections. Aspergillus fumigatus , Toxoplasma gondii , and Nocardia asteroides result in focal brain infection and JC virus, a polyoma virus, and cause progressive multifocal leukoencephalopathy. Lymphomas are the most frequent brain tumors. They are usually associated with an Epstein–Barr virus infection and are more frequent in patients who receive aggressive immunosuppressive therapy. The overall risk of developing cancer following renal transplantation is approximately 6%, or about 100-fold greater than that expected for the general nonimmunosuppressed population.

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Mudge DW, Johnson DW, Hawley CM, Campbell SB, Isbel NM, Van Eps CL, et al.: Do aluminum-based phosphate binders continue to have a role in contemporary nephrology practice? BMC Nephrol 12:20, 2011.

Amato AA, Barohn RJ: Transplantation and immunosuppressive medication. In Rolak LA, Harati Y (eds): Neuro-immunology for the clinician. Boston, Butterworth-Heinemann, pp 341-376, 1997.

Ponticelli C, Campise MR: Neurological complications in kidney transplant recipients. J Nephrol 18:521-528, 2005.

Potluri K, Holt D, Hou S: Neurologic complications in renal transplantation. Handb Clin Neurol 121:1245-1255, 2014.