Neurologic Disease and Anesthesia

Huntington’s disease

Huntington’s disease is a universally fatal neurodegenerative disorder affecting the central nervous system that results from an autosomal dominant mutation in the huntingtin gene. It is characterized by movement and psychiatric disorders as well as dementia and occurs in 4–10 per 100,000 population. The genetic defect is due to a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4, resulting in production of an abnormal form of huntingtin. Huntingtin is present ubiquitously in somatic tissues, and only recently have the pathological effects of mutant HTT been described outside of the CNS. ^, The mechanism by which the genetically altered protein induces the associated central nervous system changes is unknown, but prevailing theories suggest that huntingtin deposition enhances neuronal susceptibility to oxidative stress or glutamate mediated excitotoxicity. The brain of a patient with Huntington’s disease undergoes progressive atrophy and gliosis that is most prominent in the basal ganglia. Interestingly, striatal atrophy becomes apparent with some MRI techniques more than a decade before onset of clinical symptoms. These cerebral alterations, combined with loss of GABA-ergic neurons in the striatum, and skeletal muscle changes help explain the motor symptoms of Huntington’s disease, but the pathophysiology of the cognitive and psychiatric alterations remains unknown.

A patient with Huntington’s disease can develop symptoms at any time after infancy, but they usually become evident in the late 30s or early 40s. As such, the diagnosis is often not established until after reproduction, but genetic testing now allows for earlier diagnosis and the option of genetic counseling. The motor symptoms of Huntington’s disease typically begin with a lack of coordination and involuntary jerks. These uncontrollable, involuntary choreic movements (i.e., random jerking movements of the extremities, torso, face and truncal muscles) and athetosis (i.e., slower sinusoid writhing movements) peak after steady progression for 10 years and ultimately develop a rigid dystonic character. Dysphagia is common in advanced cases and most patients suffer from malnutrition at some stage.

All patients with Huntington’s disease eventually develop dementia that spares long-term memory, but impairs executive functions. Other psychiatric and cognitive changes occur before, after, or at the same time as motor abnormalities and may include irritability, apathy, emotional instability, impulsiveness, and aggression. Depression is frequent, as is suicide, which occurs at a rate up to 10 times that of the general population. Death usually occurs within 20 years of diagnosis due to falls, pneumonia, aspiration, malnutrition or suicide.

There are no specific treatments that prevent, cure, or slow the progression of Huntington’s disease. Symptomatic therapy aims to control the motor and psychiatric aspects of the disease. Drugs shown in clinical trials to be efficacious for the treatment of chorea include amantadine, remacemide, levetiracetam, and tetrabenazine. However, they can cause bradykinesia, rigidity, depression and sedation. The affective disorders associated with Huntington’s disease are often amenable to psychiatric treatment, such that polypharmacy is common in these patients. The prudent anesthesiologist will, therefore, be vigilant for the possibility of adverse drug interactions.

Anesthetic management for a patient with Huntington’s disease is driven mostly by theory because the literature is limited to anecdotal experiences and case reports. Because patients with Huntington’s disease are at increased risk of pulmonary aspiration due to pharyngeal muscle abnormalities and dysphagia, aspiration prophylaxis and precautions seem warranted, but whether administration of anesthesia to these patients further increases the risk of aspiration pneumonitis is unknown. Patients with Huntington’s disease are also alleged to be at risk for prolonged respiratory depression and delayed return to consciousness after general anesthesia and have reduced requirements for midazolam. Whether this is related to altered pharmacokinetics due to nutritional depletion and altered protein binding, increased central nervous system sensitivity, or altered pharmacodynamics is unknown. In any event, most patients with Huntington’s disease experience a normal anesthetic and postanesthetic course. ^{, ,}

Data concerning the response to muscle relaxants is similarly confusing. There is an increased incidence of abnormal plasma cholinesterase variants among patients with Huntington’s disease and a case report of prolonged muscle relaxation following administration of succinylcholine, but succinylcholine has been used uneventfully in other cases. There are, however, no case reports of succinylcholine-induced hyperkalemia. With respect to non-depolarizing muscle relaxants, both abnormal and normal responses have been reported. ^,

There are also reports of clinically significant, generalized, tonic muscle spasms related to shivering during emergence from anesthesia in patients with Huntington’s disease, suggesting maintenance of perioperative normothermia is especially important in these patients. Some authors even recommend avoiding inhalational anesthetics to decrease the risk of postoperative shivering, although the benefit of doing so is only theoretical and exacerbation of involuntary movements has been noted after propofol anesthesia. ^{, ,} Lastly, other than being technically difficult because of the continuous uncontrollable movements, there appears to be no contraindication to regional anesthesia in the patient with Huntington’s disease. ^,

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, untreatable, degenerative disease of the central nervous system that involves both upper and lower motor neurons. The disease affects 5–6 per 100,000 population with an average age at onset of 56 years. ALS is marked by loss of motor neurons in the anterior horn of the spinal cord, brainstem nuclei of cranial nerves V, VII, IX, X, XII, and degeneration of the corticospinal tracts secondary to loss of cortical motor neurons. This degeneration produces symptoms that include asymmetric muscle atrophy and weakness and bulbar abnormalities, such as dysarthria, dysphagia, drooling, and an ineffective cough. The clinical course ultimately ends in paralysis, but the type depends upon whether upper or lower motor neuron lesions are most prominent. If upper motor neuron lesions predominate, the paralysis is spastic whereas lower motor neuron lesions result in flaccidity. Both evolve over months to years and affect all striated muscles except that of cardiac and ocular origin. The disease leads to a restrictive pulmonary defect, with progressive decreases in FVC and FEV1 as a result of muscle weakness and skeletal deformities. These changes can occur rapidly but typically are slowly progressive and lead to hypercarbia, atelectasis, and a predisposition to pneumonia. Multiple studies suggest that survival and quality of life may be enhanced by the administration of riluzole, a glutamate release antagonist, and both respiratory and nutritional support in the form of noninvasive ventilation and placement of a gastrostomy tube. Death usually occurs within 3–10 years of diagnosis due to respiratory complications, such as pneumonia, atelectasis, and/or aspiration.

There are no laboratory tests to confirm the diagnosis of ALS, which is usually made on the basis of both upper and lower motor neuron abnormalities in association with progressive motor dysfunction. ^, Supporting laboratory evidence includes spontaneous fibrillations, positive sharp waves, fasciculations and decreased recruitment of motor units on EMG. Nerve conduction studies are normal or reflect denervation of motor neurons without sensory involvement.

Genetics may play a role in the etiology of some cases of ALS as mutations in superoxide dismutase 1, TAR DNA-binding protein, fused in sarcoma, and ubiquitin 2 are associated with the development of ALS, but there are suggestions that environmental factors such as central nervous system trauma, bacteria, and cigarette smoke may be involved. Ultrastructural changes in the motor neurons of patients with ALS include inclusion bodies and swelling in the proximal axon and cell body. Ultimately, these abnormal neurons are thought to undergo necrosis or apoptosis, leading to degeneration and neuronal cell loss.

Given the pathophysiology and clinical manifestations of ALS, anesthetic considerations include altered responses to muscle relaxants, ventilation impairment, bulbar dysfunction, and concerns about neurologic sequelae of regional anesthesia. Patients with ALS are predisposed to succinylcholine-induced hyperkalemia because of denervation and atrophy of skeletal muscles. Thus, succinylcholine is best avoided in these patients. Patients with ALS may also have increased sensitivity to non-depolarizing muscle relaxants, suggesting either that relaxants be avoided altogether or that shorter acting relaxants be used. ^, Although not currently clinically available in the US, the administration of Sugammadex to a patient with ALS with residual neuromuscular weakness after reversal of neuromuscular blockade has been successfully reported. Progressive impairment of ventilation is another serious problem and the degree of impairment is a useful predictor of anesthetic risk and the need for postoperative ventilatory support. While it would be easy to suggest that regional anesthesia is preferable to general in such high-risk patients, it has not been established that this is true. Although cases have been successfully conducted using both regional and general anesthesia, significant respiratory involvement may predispose patients with ALS to perioperative respiratory failure. Accordingly, it may be necessary to support ventilation in the ALS patient both during and in the immediate postoperative period regardless of anesthetic technique. ^,

The primary concern about bulbar dysfunction is dysphagia and the risk of recurrent pulmonary aspiration. For this reason, aspiration prophylaxis should be considered but there is no evidence that this reduces the perioperative risk of aspiration pneumonitis in the ALS patient. Moreover, because of the inability to swallow properly, many ALS patients will require placement of a feeding tube. This can typically be accomplished under regional anesthesia, but may require the use of noninvasive ventilation both during and after the procedure.

Lastly, there has been concern about the possibility that regional anesthesia may facilitate progression of neurodegenerative diseases such as ALS. Evidence for this is entirely anecdotal, however, and there are several case reports of uneventful neurologic recovery following epidural anesthesia and peripheral nerve blocks in ALS patients. Perhaps the most one can say is that regardless of the type of anesthesia, the proximate cause of neurologic deterioration is difficult to establish in a relentlessly progressive neurologic disorder.

Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease (after Alzheimer’s disease). Classically considered a movement disorder, secondary to degeneration of dopaminergic neurons in the basal ganglia and nigrostriatal system, it is now recognized that PD is a multisystem neurodegenerative process. It afflicts about 1 million Americans, or approximately 1% of patients over age 60, and its prevalence is projected to double in the next 15–20 years. Fifteen years after diagnosis, 40% of PD patients are living in long-term care facilities and mortality is almost twice the expected rate. Most cases of Parkinson’'s disease are idiopathic, but environmental factors, including exposure to volatile anesthetics, ^, and genetic predisposition have been implicated; a recent meta-analysis indicated that for those with a first-degree relative with PD the relative risk of developing PD is 2.9. The common feature of the disease is neuronal loss and gliosis of the substantia nigra, pars compacta. By the time motor symptoms develop, 70% of the dopamine producing cells in the striatum have degenerated, leading to a relative imbalance between the inhibitory properties of dopamine and the excitatory properties of acetylcholine within the striatum. However, pathology extends beyond the striatum and dopamine. The pathologic hallmark of PD is the Lewy body, an intracellular aggregate of abnormal proteins including α synuclein, which is present in nearly all forms of PD. This α synuclein pathology and concomitant neurodegeneration are seen in numerous areas of the central and peripheral nervous system including noradrenergic, serotonergic, and cholinergic neurons of the brainstem and in the amygdala, cingulate gyrus, and neocortex. Moreover, changes in these regions may actually precede the striatal degeneration. Therefore, it is overly simplistic to see PD only as a movement disorder.

Cardinal clinical features of Parkinson’s disease include a resting rhythmic tremor, muscular rigidity, and bradykinesia. These are often associated with a lack of spontaneous movement, masked facies, cogwheel rigidity, a monotonous voice, stooped posture, and a shuffling gait leading to postural instability and impaired locomotion. ^, Not surprisingly, given the widespread neurodegeneration, non-motor features of the disease represent important sources of disability and, in long-standing PD, are often the predominant problem. Autonomic dysfunction (postural hypotension), daytime sleepiness, depression, anxiety, hallucinations, and psychosis are common; dementia is almost universal in patients with long-standing PD, and can be as high as 90% in patients 90 years old or greater.

There is no cure for Parkinson’s disease. Therapy has focused almost exclusively on the motor aspects of the disease, and only recently have the cognitive and non-motor symptoms received attention. Given that the main deficit in PD is inadequate dopamine in the basal ganglia, pharmacologic therapy aims to increase the activity of dopamine relative to acetylcholine in this region. This is typically accomplished with dopamine receptor agonists, such as bromocriptine and pergolide or with levodopa (L-DOPA), a prodrug that undergoes decarboxylation in both the periphery and central nervous system to produce dopamine. Peripheral conversion of L-DOPA to dopamine produces side effects such as nausea, vomiting, and hemodynamic instability, so combined treatment with carbidopa, a decarboxylase inhibitor that does not cross the blood–brain barrier, is common. L-DOPA is the most potent, best-tolerated symptomatic therapy and may even slow disease progression, but dopamine agonists are often first-line therapy because L-DOPA is associated with a higher incidence of dyskinesias. Dopamine agonists have their own problems, however, including leg edema, hallucinations, somnolence, and development of impulse control disorders, such as binge eating or compulsive gambling. A variety of other drugs used to treat Parkinson’s disease also act by altering the dopamine/acetylcholine balance in the brain. Usually used as initial therapy of mild Parkinson’s disease or as an adjunct to levodopa therapy in patients with dose-related fluctuations, benztropine and other anticholinergic agents block cholinergic transmission and amantadine, an antiviral agent, alters the uptake and release of dopamine at presynaptic sites. Because monoamine oxidase (MAO) is the major enzyme involved in oxidative metabolism of dopamine in the striatum, type-B MAO inhibitors such as selegiline are often employed. Early concerns that the combination of L-DOPA and selegiline may lead to increased mortality have not been substantiated and selegiline has become a first-line treatment choice for many clinicians. ^,

When motor complications become disabling and medical therapy fails, deep brain stimulation (DBS) is recommended. DBS involves surgical placement of electrodes in the subthalamic nucleus and other brain regions, and stimulation at high frequencies. In this case stimulation leads to effects similar to lesioning of the same region, possibly by jamming or desynchronizing the region being stimulated. In a 4-year, multicenter trial of patients with bilateral DBS showed an improvement in activities of daily living and PD symptoms. Given the success of DBS in managing medically refractory PD, other surgical approaches for the control of PD, such as thallamotomy and pallidotomy have become increasingly less common as they involve destructive brain lessioning.

Transplantation of fetal midbrain or stem cells into human PD patients is another exciting alternative. The cells function and survive for up to 14 years, but begin to develop Lewy bodies and fail after about 10 years. ^, Indeed, some argue that pharmacologic and surgical treatments are inherently limited because they only address a late, specific event—loss of striatal dopamine neurons—in what is likely to be a widespread disease.

Perioperative management of the patient with Parkinson’s disease is challenging. Attention should be directed toward maintenance of perioperative drug therapy, potential adverse drug interactions, and the physiologic perturbations associated with the disease. It is also important to recognize that emotional stress, which is unavoidable and difficult to address in the perioperative period, can also exacerbate PD. One major problem is that the half-life of levodopa is short (about 60–90 min). Therefore, even brief interruptions in drug therapy are undesirable and can result in an acute exacerbation of the symptoms of Parkinson’s disease or the development of neuroleptic malignant syndrome, a potentially fatal disorder that presents as hyperthermia, akinesia, altered consciousness, muscle rigidity, and autonomic dysfunction. ^, Consequently, interruption of anti-Parkinson’s drug therapy should be as brief as possible. However, maintenance of therapy is difficult when the patient is unable to take medications per os for lengthy periods. Intravenous levodopa has been used successfully in the perioperative period but, without co-administration of a decarboxylase inhibitor (not yet available in intravenous form), cardiovascular side effects such as hypertension, hypotension, and arrhythmias can be anticipated. Levodopa and carbidopa are absorbed in the small intestine and thus must first traverse the stomach, making administration of tablets through a gastric tube suboptimal or ineffective because patients with Parkinson’s disease often have delayed gastric emptying. ^, One recent report involving six patients noted success in administering intravenous amantadine in the perioperative period without the adverse effects of amantadine administration or perioperative complications and this may, therefore, represent a viable alternative.

In addition, Parkinson’s disease takes a toll on body systems that are vitally important during and after surgery. Respiratory dysfunction is especially prominent. ^, Parkinson’s disease can produce restrictive lung disease secondary to chest-wall rigidity, but pulmonary function tests often reveal a obstructive pattern with a characteristic “sawtooth” pattern on flow volume loops, which are improved, but not normalized, with levodopa. ^, Upper airway abnormalities also occur. Involuntary movements of the glottis and supraglottic structures cause intermittent airway obstruction, a condition that can be exacerbated by levodopa withdrawl. ^, Upper airway obstruction, laryngospasm, and respiratory arrest are documented complications of Parkinson’s disease and may occur outside the setting of anesthesia and surgery. ^, Perhaps not surprisingly, therefore, laryngospasm has been reported postoperatively in awake patients hours after surgery. Direct visualization of the larynx during such episodes reveals complete apposition of the vocal cords requiring succinylcholine for relief. While some of these cases occurred despite maintenance of anti-Parkinson’s drug therapy, most followed withdrawal or pharmacologic antagonism of Parkinson’s medication. ^, Indeed, not only should interruption of drug therapy be minimized, but also the dosage may need to be increased if airway problems persist despite otherwise adequate therapy.

Parkinson’s patients are predisposed to aspiration because they often have severe, but asymptomatic, dysphagia and dysmotility which, combined with upper airway abnormalities, presents an especially troublesome situation. ^, In fact, pulmonary aspiration is a frequent cause of death among patients with Parkinson’s disease. As such, administration of antacids and pro-kinetic agents should be considered, but whether anesthesia actually increases the risk of aspiration in these patients is unknown. Metoclopramide must be avoided, however, because it is a dopamine receptor antagonist and could acutely exacerbate the disease. In contrast, prokinetic agents, such as cisapride or domperidone, have no effect on central dopaminergic balance and are reasonable alternatives.

Nervous system dysfunction is also common. Autonomic insufficiency affects the ability of Parkinson’s patients to respond to the hypovolemia and vasodilation sometimes associated with anesthesia and surgery. ^, Orthostatic hypotension and/or thermoregulatory or genitourinary dysfunction suggests preexisting autonomic insufficiency and should heighten awareness of the potential for perioperative hemodynamic instability and altered responses to vasopressors such as norepinephrine (noradrenaline). At the level of the central nervous system, psychiatric complications such as anxiety, confusion, and even frank psychosis occur more frequently in patients with Parkinson’s disease than the general population, and can be especially problematic in the perioperative period. Often related to or exacerbated by fluctuations in anti-Parkinson’s drugs, the first line of treatment is to look for and remedy reversible causes as one would in any patient with delirium. ^, Pharmacologic treatment is difficult, however, because the usual remedies (e.g., benzodiazepines for anxiety and antipsychotics for psychosis) can produce severe side effects, such as oversedation or acute exacerbation of motor symptoms in elderly patients with PD. ^, In the event such treatment becomes necessary, consultation with a specialist is recommended.

Anesthetics and a number of other agents used perioperatively may affect the disease process. Volatile anesthetics can alter dopaminergic balance in the brain but whether they exacerbate Parkinson’s disease is unknown. ^, In fact, provided the intraoperative electrophysiological approach is based on multi-unit recording, deep brain stimulation surgery has been performed successfully under general anesthesia with a volatile agent, suggesting activity in dopaminergic circuits are reasonably well maintained. Propofol produces both dyskinesias and ablation of resting tremor, suggesting that it has both excitatory and inhibitory effects in this patient population, but it also has been used successfully to sedate Parkinson’s patients during DBS surgery. ^, Dexmedetomidine also appears to be safe and, when used for deep brain lead implantation and stimulation, has the advantage of not interfering with motor symptoms. Ketamine should be used cautiously, if at all, because of potential interactions between levodopa and its sympathomimetic properties. However, in a single case report, ketamine temporarily stopped the motor symptoms of the disease. Butyrophenones (e.g., droperidol) and phenothiazines, which block dopamine receptors and exacerbate Parkinson’s disease and so should be avoided. In at least one case, droperidol may have induced parkinsonism in a normal patient. Ondansetron, a 5HT-3 serotonin receptor antagonist, appears to be a safe treatment or prevention of emesis in these patients and has been used successfully to treat the psychosis of chronic levodopa therapy. Although opioids are more likely to produce muscular rigidity in a patient with Parkinson’s disease, acute dystonia has been observed only rarely and enhancement of opioid neurotransmission during disease progression may be a compensatory mechanism that prevents motor complications. ^, Meperidine should be avoided in a patient taking an MAO inhibitor, however, because of the potential for the development of stupor, rigidity, agitation and hyperthermia. Responses to depolarizing as well as nondepolarizing muscle relaxants are thought to be normal in Parkinson’s disease, despite a single case report of succinylcholine-induced hyperkalemia.

Finally, with the advent and increasing popularity of DBS, issues arise about the safety of MRI or intraoperative electrocautery in PD patients with stimulator leads in place. ^, In theory, extraneous current can heat the electrode tip, causing brain tissue damage, but there is limited experience with this circumstance clinically. To reduce the risk of injury, the bipolar mode should be used if electrocautery is needed and the leads and generator should not be located between the surgical site and ground plate. In the case of an MRI, the neurostimulator should be switched off.