Authors:Elizabeth A.M. Frost, MD
Professor of Anesthesiology
Mount Sinai Medical Center
New York, New York
von Hippel-Lindau Disease
What Is It?
von Hippel-Lindau (vHL) disease, named after Eugene von Hippel (1904) and Arvid Lindau (1927), is an autosomal dominant inherited systemic cancer syndrome that results in cysts and hemangiomas in many organs, especially involving the eye and central nervous system (CNS).1-3 It is also known by other names, such as angiomatosis retinae, familial cerebello-retinal angiomatosis, cerebello-retinal hemangioblastomatosis, Hippel disease, Hippel-Lindau syndrome, Lindau disease or retino-cerebellar angiomatosis. Mutations of the von Hippel-Lindau tumor suppressor gene on the short arm of chromosome 3 (3p25-26) appear to be responsible. However, over 1,500 germline mutations and somatic mutations have been associated with vHL disease. Associated conditions include pheochromocytoma and other, usually benign tumors that may occur in all systems.
vHL disease has an incidence of about one in 36,000 births. The disease may be diagnosed from early childhood to 60 to 70 years. Average patient age at diagnosis is 26 years. Males and females as well as all ethnic groups seem to be equally affected. De novo mutations occur in about 1:4.4 million live births and account for 20% of cases.
vHL disease is a multiple-organ disease with considerable variation in clinical presentation. The criteria for diagnosis include multiple hemangioblastomas in the CNS or eye; a single hemangioblastoma in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts; pheochromocytoma; or renal cancer); a positive family history plus any one of the above clinical manifestations; or the finding of a deleterious mutation in the vHL gene. Hemangioblastomas of the retina are found in 60% to 70% of vHL patients, resulting in poor vision, and hemangioblastomas of the CNS (usually cerebellum or spine) are found in about 40%. Less commonly, erythrocytosis, pancreatic and renal cysts, and renal cell carcinoma (hypernephroma) are seen. Multiple endocrine neoplasias (i.e., MEN I, IIA, IIB) also may be part of the disease. Pheochromocytoma occurs in about 20%, and is more likely to be bilateral and to recur. Strokes, heart attacks and cardiovascular disease are common additional symptoms. Genetic testing for mutations in the vHL gene is available at 48 different laboratories in the United States (www.genetests.org). In hereditary vHL, techniques such as Southern blotting and gene sequencing can be used to analyze DNA.
There is currently no known means to reverse vHL mutations. Early recognition and treatment of specific manifestations of vHL can decrease complications and improve quality of life. Routine screening for retinal angiomas is recommended. They can be treated with photocoagulation or cryotherapy. Surgical removal of other tumors should be performed when the diagnosis is made, as renal cysts may develop carcinomatous changes.
Patients with MEN IIA often have asymptomatic hypercalcemia. Abnormal EKG findings include a shortened QT interval and prolonged PR interval. Cardiac dysrhythmias are frequent. Management of hypercalcemia requires IV fluid administration with sodium-containing solutions, which dilute the calcium and inhibit renal reabsorption. Urine output must be monitored closely to assess renal dysfunction. Consideration also must be given to muscle relaxant dosing, positioning and the potential for airway compromise. Muscle relaxant effects may be enhanced by hypercalcemia. Preoperative assessment of muscle weakness must be documented to record baseline and tailor muscle relaxant administration. Careful positioning of the patient with appropriate padding is important to avoid pathologic fractures from osteoporosis. Medullary thyroid cancer and other tumors may compress the airway. The diagnosis of pheochromocytoma should be suspected even if the patient is asymptomatic. Patients who have had a resected pheochromocytoma should be screened for recurrences and/or for pheochromocytoma on the unresected side. A subset of pheochromocytomas known as adrenal incidentalomas is clinically silent but may be hormonally active at low levels. Orthostatic hypotension suggests pheochromocytoma. Preoperative optimization with an alpha-adrenergic blocker is first-line therapy. Medications that trigger catecholamine release should be avoided, including metoclopramide, pentazocine (Talwin, Hospira), droperidol, morphine, atracurium, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, imipramine and curare. Anesthetic agents may include fentanyl, remifentanil (Ultiva, Mylan), rocuronium, vecuronium and low-dose inhaled agents. Arterial cannulation is indicated for larger cases. Adequate pain control postoperatively is important to avoid catecholamine release from an undiagnosed incidentaloma.
Tunthanathip T, Rattanalert S, Oearsakul T, et al. Spinal capillary hemangiomas: two case reports and review of the literature. Asian J Neurosurg. 2017;12:556-562.
Signorelli F, Piscopo G, Giraud S, et al. von Hippel-Lindau disease: when neurosurgery meets nephrology, ophthalmology and genetics. J Neurosurg Sci. 2017 Jul 26. [Epub ahead of print]
Haddad NM, Cavallerano JD, Silva PS. von Hippel-Lindau disease: a genetic and clinical review. Semin Ophthalmol. 2013;28:377-386.
What Is It?
Sjögren’s syndrome (SS), first described by Henrik Sjögren in 1933, is a complex systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva.4-8 It is a disorder primarily of the salivary gland with unknown etiology. Mikulicz’s disease, once considered to be a subtype of SS, is now considered an immunoglobulin G4–related disease and distinguishable from SS by Th2 and regulatory immune reactions that play key roles in IgG4 production. SS is associated with other autoimmune or rheumatic disorders, such as celiac disease, fibromyalgia, systemic lupus erythematosus, scleroderma, primary biliary sclerosis, autoimmune thyroiditis, multiple sclerosis, spondyloarthropathy and several malignancies, mainly non-Hodgkin lymphoma. SS is usually classified as either “primary” or “secondary.” Primary SS occurs by itself and secondary SS occurs together with another connective tissue disease (e.g., rheumatoid arthritis).
SS affects about 4 million people in the United States, usually people older than 40 years of age. Women are afflicted nine times more frequently than men.
Signs and symptoms include dry eyes and mouth, chronic bronchitis, myositis, peripheral neuropathies, dental caries, gastroesophageal reflux disease and general fatigue. Biopsy of moisture-producing glands and blood sampling can reveal specific antibodies. Typically, lymphocytic infiltration is found within glands. The syndrome is also associated with increased levels of interleukin-1 receptor antagonist in the cerebrospinal fluid.
Treatment is symptomatic, including artificial tears, medications to reduce inflammation, saliva substitutes and insertion of punctal plugs. Antihistamines, diuretics and birth control pills should be avoided, as they increase dryness.
Because most body systems may be affected, several areas must be addressed. Consent may be difficult because of blurred vision or partial blindness. Dental caries, oral sores, parotid swelling and dry mouth may impair intubation. Difficulty swallowing, acid reflux and esophagitis should require preemptive antacid treatment. Review of the respiratory system should rule out active pulmonary diseases, such as bronchitis, pneumonitis and interstitial lung disease. The presence of nephritis and chronic renal insufficiency should be assessed, as well as evidence of pancreatitis, primary biliary cholangitis and hepatitis. Finally, CNS involvement can cause lack of concentration, depression, anxiety and neuropathies, all of which should be documented. No anesthetic technique has been shown to be superior, including neuraxial blocks. Antisialagogues should not be used. Muscle relaxants should be used with caution, especially if the patient has a main complaint of weakness or muscle fatigue.
Thorne I, Sutcliffe N. Sjögren’s syndrome. Br J Hosp Med (Lond). 2017;78:438-442.
Bayetto K, Logan RM. Sjögren’s syndrome: a review of aetiology, pathogenesis, diagnosis and management. Aust Dent J. 2010;55:39-47.
Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol. 2014;6:247-255.
Qin B, Wang J, Yang Z, et al. Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:1983-1989.
Sjögren’s Syndrome Foundation. www.sjogrens.org. Accessed August 11, 2017.
What Are They?
Mitochondrial diseases (MitoD) are a clinically heterogeneous group of disorders caused by defects in the mitochondrial metabolism.9-15 The mitochondrion is a group of subcellular organelles that convert energy from food molecules into adenosine triphosphate (ATP), the main source of energy for most cell functions, produced through the Krebs cycle, fatty acid oxidation and oxidative phosphorylation (OXPHOS). OXPHOS is the principle means for the formation of ATP. Some disorders only affect one organ (e.g., the eyes in Leber hereditary optic neuropathy) while others involve many systems and present with neurologic and myopathic features. Several discrete clinical syndromes are described—although often with considerable overlap—such as Kearns-Sayre syndrome; chronic progressive external ophthalmoplegia; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged red fibers; and neurogenic muscle weakness, ataxia and retinitis pigmentosa, or Leigh syndrome. The model most frequently used to study mitochondrial diseases as a group is MELAS. Of the 200 disease-causing points in the mitochondrial genome, at least 30 are associated with MELAS.
The estimated incidence of mitochondrial myopathies is about 1:4,000, but variable symptomatology makes this number most probably low. MitoD usually are diagnosed by 10 years of age. However, an increasing number are first diagnosed in adolescents and adults.
As MitoD have multisystem involvement and are progressive, diagnosis depends on history and physical examination as well as laboratory findings. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, deafness, optic atrophy, retinopathy and diabetes mellitus. CNS findings include encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia and spasticity. Other symptoms include poor growth, loss of muscle coordination, muscle weakness, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, autonomic dysfunction and non–insulin-dependent diabetes mellitus. The triad of lactic acidosis, seizures and stroke-like episodes is central to the diagnosis of MELAS, occurring in over 90% of patients. Lactic acidosis is determined either from serum or cerebrospinal fluid. Other tests include pyruvate, creatinine phosphokinase, plasma amino acid levels and urine for organic acids. Analyses of skin and muscle samples may detect the presence of organelles and red ragged fibers.
Electrolyte perturbations are common and may be severe. Correction must be made for acid–base imbalance, hyponatremia, hyperkalemia and hyperglycemia. Coagulation parameters should be within normal limits. Cardiac conduction abnormalities (Wolff-Parkinson-White syndrome) and cardiomyopathies are not infrequent. Patients are at higher risk for aspiration because of bulbar muscle weakness and gut dysmotility, and are in danger of a metabolic crisis due to prolonged fasting and inadequate glucose balance. Lactated Ringer’s solution may increase the lactate load and should not be used. Vision, hearing and speech may be impaired, and cognitive dysfunction is common, including language and memory difficulties, making the ability to give informed consent difficult. Peripheral neuropathies and myodegenerative disorders are common. Renal involvement may manifest as de Toni-Debré-Fanconi syndrome, nephrotic proteinuria or focal segmental glomerulosclerosis, Bartter-like syndrome, hypercalciuria or tubulointerstitial nephritis. Skin changes may make IV placement difficult. Arterial cannulation allows frequent electrolyte monitoring. Normothermia decreases additional metabolic stress. Depending on hepatic and renal insufficiency, muscle relaxants should be used cautiously. Although there are few data regarding succinylcholine (Anectine, Sandoz; Quelicin, Hospira) and MitoD, their association with malignant hyperthermia in two case reports and a possible hyperkalemic response should be considered. Although no anesthetic technique has been shown to be superior, volatile anesthetics have been found to impair OXPHOS by inhibition of complex I. Also, isoflurane (Forane, Baxter) may induce caspase activation and apoptosis, part of Alzheimer’s degeneration. A safer, nontriggering anesthetic technique may be total IV anesthesia. However, the safety of propofol has been questioned because of its lipid component, possibly affecting fatty acid oxidation and directly affecting the mitochondrial respiratory chain. A propofol infusion-like syndrome is characterized by lactic acidosis, bradycardia, rhabdomyolysis, and cardiac and renal failure, and although diagnosed mainly with longer duration infusions (>48 hours), in susceptible patients even short-term infusions may cause symptoms. Ketamine has not been implicated as a deleterious agent. Although regional anesthesia may be an alternative, local anesthetics have been shown to impair OXPHOS and may lead to inefficient ATP synthesis. Tactics to postoperatively minimize metabolic stress and increases in metabolic demand include avoiding shivering and providing adequate analgesia. Opioids should be used at low doses to decrease the risk for respiratory depression.
Jancic J, Stojanovic S, Stojanovic A, et al. Leber’s hereditary optic neuropathy: the shift from an ophthalmologic disease to a multi-systemic paradigm. CNS Neurol Disord Drug Targets. 2017 Jul 24.
Enns GM. Pediatric mitochondrial diseases and the heart. Curr Opin Pediatr. 2017;29:541-551.
Zheng Q, Wei P, Zhou J, et al. Case report: perioperative management of caesarean section for a parturient with mitochondrial myopathy. BMC Anesthesiol. 2017;17:94.
Gordon TR, Montandon RJ. Anesthetic management of a child with unspecified mitochondrial disease in an outpatient dental setting. Anesth Prog. 2017;64:33-38.
Humeidan ML, Dalia J, Traetow WD. Anesthetic considerations for renal transplant surgery in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome: a case report. J Clin Anesth. 2016;34:344-347.
Parikh S, Goldstein A, Karaa A, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017 Jul 27. [Epub ahead of print]
Gurrieri C, Kivela JE, Bojanic K, et al. Anesthetic considerations in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome: a case series. Can J Anaesth. 2011;58:751-763.