Pathophysiology and Diagnosis

HMSN type 1, or CMT-1, is a demyelinating disorder of peripheral nerves that most often presents in the first or early-second decade of life, although infants can also be affected. Significant family history is typical. Diffuse slowing of nerve conduction velocity and gradually progressing distal muscle weakness with early loss of coordination characterize CMT-1. It is associated with loss of reflexes, talipes (pes) cavus, and hammer toe. Later, distal calf atrophy develops (classic “stork leg” deformity), in combination with gradual loss of proprioception and sense of vibration. Abnormal concentric myelin formations are called “onion bulbs” and are found around the peripheral axons. These are a characteristic feature of CMT-1, usually revealed by sural nerve biopsy. The CMT-1A subgroup of patients may present with proximal muscle wasting and weakness. Dematteis et al. also observed obstructive sleep apnea (OSA) in this subtype of patients, with a high degree of correlation between the severity of neuropathy and degree of obstruction. Even later changes include atrophy of the intrinsic hand and foot muscles, footdrop, palpable hypertrophy of the peripheral nerves, and possible scoliosis and kyphosis. Disease exacerbation may occur in pregnancy. Life expectancy is unaffected.

Type 2 HMSN, or CMT-2, also called axonal CMT, is a heterogeneous disorder with normal or borderline nerve conduction velocity. It is primarily an axonal, not a demyelinating, disorder, with neuropathy the result of neuronal death and wallerian degeneration (no onion bulbs on biopsy). The clinical course is similar to that of CMT-1, but sensory symptoms predominate over motor symptoms, and peripheral nerves are not palpable. Patients with CMT-2 C subtype display significant vocal cord and diaphragmatic weakness, resulting in OSA, which is of concern to the anesthesiologist. Onset is usually in the second or third decade of life, but can be seen in early childhood, with rapid clinical progression.

Type 3 HMSN includes two syndromes: Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy (CHM). Both are characterized by profound hypotonia, presenting in early infancy or at birth, in the case of CHM. Dejerine-Sottas syndrome is clinically similar to CMT-1, although its manifestations are more severe and appear in early childhood.

The preoperative evaluation and preparation of HMSNs may be complicated because of similarity in clinical presentation with other genetic or acquired polyneuropathies ( Box 8-1 ).

No specific treatments for HMSNs are available. Symptomatic supportive care consists of orthopedic corrective joint procedures for talipes cavus and scoliosis deformities and physical and occupational therapy. Orthopedic procedures are usually staged, ranging from soft tissue procedures and osteotomy to triple arthrodesis. Multiple administrations of general or regional anesthesia might be required.

Preoperative preparation of patients with HMSNs is dictated by the extent of clinical involvement and coexisting morbidities. The degree of motor neurologic involvement should be evaluated and affected muscle groups noted. Atrophic denervated muscles usually display significant resistance to nondepolarizing muscle relaxants and are unreliable for monitoring of neuromuscular blockade (NMB).

Patients with CMT-1 and CMT-2 C should be evaluated for restrictive pulmonary disease related to scoliosis and diaphragmatic weakness and potential OSA. Respiratory insufficiency has been described in patients with CMT. Careful planning for extubation and a possible need for postoperative respiratory support may be necessary in these patients. Patients with HMSNs may have undetected cardiac conduction abnormalities. Although this association is not strong, all patients with an HMSN should have a preoperative ECG. Pregnancy often leads to exacerbation of the symptoms of CMTD and, in combination with diaphragmatic splitting, can lead to respiratory compromise.

Pathophysiology and Diagnosis

Congenital insensitivity to pain with anhidrosis, or HSAN type IV, is a rare autosomal recessive neuropathy characterized by recurrent episodic fever, anhidrosis (absence of sweating), pain insensitivity, self-mutilating behavior, and mental retardation. Death from hyperthermia has been reported in infants with CIPA. Besides anhidrosis, it differs from FD by complete insensitivity to superficial and deep painful stimuli and normal lacrimation, much milder autonomic dysfunction, with absent postural hypotension or dysphagia. Self-inflicted multiple injuries are typical for these patients. This is often accompanied by accidental trauma, burns, wound infections, skin ulcers, joint deformities, and osteomyelitis.

There is only limited anesthetic experience in patients with CIPA. Okuda et al. suggest three important considerations in the anesthesia management of patients with CIPA: anxiety alleviation, temperature control, and adequate pain control. Despite congenital insensitivity to pain, general anesthesia was found to be necessary. Overall requirements of general anesthetics necessary for maintaining stable hemodynamics have been only slightly reduced. General anesthesia was used in all patients in these reports without any adverse reactions to the IV or inhalational anesthetic agents, opioids, or succinylcholine. In one report, a patient died after intraoperative cardiac arrest without clear cause, although the authors suspected that the high concentration of halothane used (2%) could have been responsible. Previous recommendations against the use of atropine (or other anticholinergic drugs) to avoid hyperpyrexia in these patients was not supported by the results reported in this series. Many patients received atropine without untoward effects.

Pathophysiology

Coordination of movement depends on a complex feedback loop in which the cortex sends information to the basal ganglia and cerebellum and in turn receives information from these structures through the thalamus. Because of their anatomic location, these pathways are often referred to as “extrapyramidal.” PD is characterized by neuronal loss, depigmentation, and gliosis in the substantia nigra pars compacta and pontine locus ceruleus, as well as degeneration of the putamen, globus pallidus, hippocampus, and brainstem nuclei. The result of this degeneration is a relative dopamine deficiency, particularly in the striatum and putamen, and unopposed cholinergic activation of inhibitory γ–aminobutyric acid (GABA) transmission from the striatum. The end result of this imbalance is excessive inhibition of the thalamus, which suppresses both the cortical motor system, leading to bradykinesia and tremor, and the brainstem motor areas, leading to gait and postural instability.

The precise mechanism of degeneration in PD has yet to be elucidated. Programmed cell death, protein misfolding and aggregation, abnormal proteosomal degradation, oxidative stress, mitochondrial dysfunction, and immunomodulation and inflammation have all been proposed. Although no universally accepted pathologic criteria exist for the diagnosis of PD, one hallmark of the disease appears to be the presence of eosinophilic, intracytoplasmic inclusions known as Lewy bodies. Composed primarily of α-synuclein, in association with ubiquitin, complement, and numerous cytoskeletal proteins, Lewy bodies are found in the substantia nigra, locus ceruleus, cerebral cortex, and sympathetic ganglia of PD patients, as well as in the cardiac sympathetic plexus, dorsal vagal nucleus, and myenteric plexus of the intestines. Importantly, Lewy bodies are not specific for PD and are found in other neurodegenerative diseases (e.g., MSA, progressive supranuclear palsy, Lewy body dementia), in Down syndrome, in amyloidopathies (e.g., Alzheimer’s disease), in tau -protein–associated diseases (e.g., frontotemporal dementia), and even in a small percentage of normal elderly brains. It remains unclear whether Lewy bodies represent a pathologic neurotoxic process, or as recent evidence suggests, play a neuroprotective role.

Medical Management

Pharmacologic management of PD patients seeks to balance dopaminergic and cholinergic effects in the striatum and thus preserve motor function and quality of life while minimizing medication-related side effects. Current therapies attempt to achieve these goals by blocking acetylcholine transmission, enhancing dopamine production, or stimulating central dopamine receptors ( Table 8-3 ). Motor symptoms generally respond better to treatment than extramotor symptoms, but effectiveness diminishes in later stages. Although several agents have shown possible neuroprotective effects in human and animal studies, currently no treatment significantly reverses or delays PD progression.

Surgical Management

Surgical treatment of PD began in the early 20th century and was originally based on the intentional lesioning of deep brain structures. Thalamotomy was performed to ameliorate tremor and pallidotomy to control both parkinsonism and levodopa-induced dyskinesias. Although the introduction of stereotactic localization improved outcomes and reduced complications from these surgeries, the continued risk of permanent paresis, visual field cuts, gait disturbances, dysarthria, and hypersalivation, combined with the development of deep-brain stimulation techniques, have led to a pronounced shift away from permanent surgical lesioning.

Drawing on the intraoperative observation that focal electric stimulation of the brain induced a functional but reversible “lesion,” implantable deep-brain stimulation of the subthalamic nucleus (STN), globus pallidus (GPi), and ventralis intermedius (Vim) have all been successful in ameliorating PD symptoms. Vim stimulation appears to be most effective for tremor-predominant cases. Evidence from randomized controlled trials (RCTs) suggests that both STN and GPi are effective for treatment of motor symptoms and bradykinesia. STN stimulation appears to provide a greater dose-sparing effect in terms of future medication use, and GPi may provide superior control of dyskinesias as well as fewer alterations of mood, cognition, and behavior.

In addition to its reversibility, deep-brain stimulation appears safer than lesioning, even when bilateral. The treatment effect may be modulated; it causes less permanent collateral damage to the surrounding brain, without ruling out the possibility of new medical or surgical therapies as they become available. Drawbacks include increased time and expense, including specialized intraoperative and postoperative device management, the infection risk of indwelling hardware, potential magnetic resonance imaging (MRI) incompatibility, and the need for periodic battery replacement. Anesthesia for deep-brain stimulation is discussed later.

Future directions for surgical management include neural transplantation of dopaminergic cells, targeted infusion of glial cell line–derived neurotrophic factor (GDNF), gene therapy, and continuous duodenal levodopa infusion.

Preoperative Concerns

A thorough history of the patient’s symptoms, disease severity, and medication regimen should be obtained. The patient’s prescribed medication regimen should be optimized before scheduling surgery. Because several medications used to treat PD have a relatively short half-life, doses should be continued through the morning of surgery, and until as close to induction of anesthesia as feasible for afternoon or unscheduled procedures ( Box 8-5 ).

Preoperative Evaluation

Cognitive impairment may predispose patients to postoperative delirium, and baseline mental status should be assessed. Neurologic symptoms, including tremor, muscle rigidity, and bradykinesia, should also be assessed. Patients with PD are particularly vulnerable to respiratory complications, and the preoperative evaluation should elicit evidence of swallowing dysfunction, retained or excessive oropharyngeal secretions, dyscoordination or rigidity of accessory muscles of respiration, and recent or active respiratory infection. From a cardiovascular standpoint, patients should be evaluated for arrhythmia and hypertension, as well as evidence of hypovolemia and orthostatic hypotension, which are common medication side effects. Autonomic dysfunction, including abnormal micturition, salivation, GI function, and temperature regulation should be considered. Seborrheic dermatitis of the face, ears, and skin folds is common in PD patients and should be recognized as a manifestation of underlying autonomic dysfunction. Weight loss and malnutrition are also common in patients with more advanced disease, and GI dysmotility and esophageal reflux disease can increase the risk of aspiration. Glucose utilization is often disrupted, and preoperative serum glucose should be measured.

Intraoperative Management

As suggested, intraoperative challenges in the management of patients with PD include increased aspiration risk, potential for autonomic instability and arrhythmia, and relatively high incidence of orthostatic hypotension. Tremor and rigidity may make positioning and cooperation difficult for patients undergoing sedation or preinduction vascular access or monitor placement. On the other hand, regional anesthesia may reduce the risk of aspiration and respiratory complications, minimize the risk of postoperative nausea and vomiting, and facilitate earlier ability to resume enteral medications. When tremor is a serious impediment to the safe performance of a procedure (e.g., ophthalmologic surgery), diphenhydramine may be a useful adjunct for reducing tremor in the awake or sedated patient.

In the absence of hypovolemia or cardiac dysfunction, propofol is a good choice for induction of general anesthesia because of its rapid metabolism and predictable offset. Although case reports have linked propofol to dyskinesias, it has also been noted to diminish tremor in the postoperative period. Thiopental has been associated with dyskinesias in several reports. Although ketamine may increase oral secretions and is relatively contraindicated because of its potential to cause hypertension through an exaggerated sympathetic response, it has been used without incident. Inhaled anesthetics have been associated with an increase in postoperative rigidity.

Nondepolarizing neuromuscular blockers may mask tremor, but patients with PD appear to have normal sensitivity to these drugs. Hyperkalemia has been reported in one patient with presumed denervation from chronic PD who received succinylcholine. However, a subsequent case series found no evidence of hyperkalemia in PD patients exposed to succinylcholine. Anticholinesterase agents have been used in the treatment of some parkinsonian symptoms and are presumed safe to use for the reversal of NMB. Because it does not cross the blood-brain barrier, glycopyrrolate is the preferred anticholinergic, particularly in patients with cognitive deficits.

Opioid medications should be used with caution in patients who are unlikely to tolerate respiratory depression. Fentanyl and remifentanil may exacerbate muscle rigidity, although this effect is amenable to treatment with neuromuscular blockers and may be blunted by coadministration of propofol. At low doses, morphine has been reported to decrease dyskinesias, but at high doses it may actually precipitate them. NSAIDs may be beneficial as part of an opioid-sparing strategy.

Medications that may precipitate extrapyramidal symptoms or dystonic reactions, including phenothiazines (promethazine), butyrophenones (droperidol), and metoclopramide are contraindicated in patients with PD. Benzodiazepines may diminish tremor, but may also exacerbate delirium and should be avoided in patients with significant dementia. Vasodilators should be used with caution in patients at risk for hypovolemia, and hypotension should be treated with volume resuscitation and direct-acting agents such as phenylephrine rather than ephedrine.

Postoperative Concerns

Patients with PD should be watched closely for postextubation respiratory failure. These patients are at increased risk of laryngospasm, inability to handle oral and respiratory secretions, and aspiration pneumonia. Respiratory reserve is likely to be diminished, especially in patients with preoperative muscle rigidity and dyscoordination. Intraoperative atelectasis and medication effects are likely to impair respiratory function further. Oral secretions may be a contraindication to noninvasive ventilation. In patients who fail to meet criteria for extubation or who are reintubated for respiratory failure, antiparksinonian medications should be continued via gastric tube to maximize chances of successful extubation.

Anesthesia for Deep-Brain Stimulator Placement

Deep-brain stimulation (DBS) surgery is generally accomplished using two separate procedures. In the first stage, a stereotactic head frame is placed with the patient in a semi-upright position, and leads are then placed through burr holes using stereotactic guidance and patient cooperation. Several techniques have been used to facilitate lead placement; all share the goal of protecting the airway, providing adequate patient comfort, and allowing patient cooperation with intraoperative neurologic examination to optimize lead positioning. Monitored anesthesia care, scalp block, IV sedation, and general anesthesia using an asleep-awake-asleep technique have all been described. Maintenance of airway patency and ventilation are particularly important, given the difficulties of airway management once the head frame is in place. In addition to their potential for disinhibition or confusion in patients with cognitive deficits, the effects of GABAergic medications on electrophysiologic brain monitoring and their tendency to suppress tremor and rigidity may contraindicate their use.

Intraoperative risks include an increased potential for venous air embolism in the semi-upright position and intracerebral hemorrhage (2%-4% of DBS cases). Maintenance of systolic BP less than 140 mm Hg has been suggested in an effort to reduce the risk of hemorrhage. Stimulator implantation is usually performed 1 to 4 weeks after lead placement. Because neuromonitoring is not required, DBS is usually performed under general anesthesia and carries risks similar to permanent pacemaker implantation.

Anesthesia for Patients with Implantable Deep-Brain Stimulators

Anesthesia for patients with implantable deep-brain stimulators has not been well studied. MRI compatibility varies slightly by device, and the manufacturer should be consulted before proceeding with MRI in these patients. Electrocautery has the theoretic potential to cause generator malfunction and inappropriate electrode activation or CNS burns, but a recent review found no evidence of such complications. If possible, bipolar diathermy eliminates this concern. Scant evidence is available to guide intraoperative device management. Turning off the device intraoperatively seems a safe approach, but whether it is necessary is unclear. Postoperative akinesia may respond to levodopa, but some recommend turning the generator back “on” before emergence from anesthesia.

Etiology

Primary dystonias are generally characterized by a gradual onset and progression of symptoms, and occur in the absence of other neurologic, imaging, or laboratory abnormalities. Early-onset dystonias present in childhood or young adulthood, often beginning in one leg, and become generalized in a majority of patients. Late-onset dystonias (occurring in adulthood) typically present in the neck, arms, or face, and are likely to remain focal or segmental (involving contiguous body areas).

Cervical dystonia, also referred to as “spasmodic torticollis,” is the most common primary focal dystonia. Dystonia may involve rotation, lateral flexion, or anterior flexion of the head and is painful in 50% of patients. Dystonic contractions may lead to finer movements of the head that may resemble tremor. Oromandibular and facial dystonias involve the muscles of the jaw, tongue, and larynx and may cause difficulty with speech and swallowing. Spasmodic dysphonia refers to a focal dystonia of the laryngeal muscles, most often involving the adductor muscles, and therefore causing difficulty with vocalization rather than airway occlusion. Blepharospasm involves the periocular muscles and may impact vision when severe enough to cause prolonged involuntary eye closure. Blepharospasm may also occur in conjunction with oromandibular and facial dystonias, a constellation referred to as Brueghel’s or Meige’s syndrome. Focal or segmental dystonias of the upper extremity are also common. These are generally unilateral, are often absent at rest, and may produce an apparent tremor in addition to abnormal posturing. Repetitive performance of specific muscular tasks may produce occupational dystonias, such as writer’s cramp or the embouchure dystonia that has affected players of woodwind or brass instruments. An interesting feature of many focal dystonias is the presence of a geste antagoniste, or specific maneuver, such as a light touch to the overlying skin, which will relieve the dystonic contractions.

Several hereditary dystonias have been identified, and genetic predisposition or vulnerability likely plays a role in many cases. Mutation of the TOR1A gene, which encodes torsinA, an ATP-binding protein, may account for as many as half of all cases of early-onset primary dystonia. Other hereditary dystonias include dopa-responsive dystonia, an early-onset form often associated with parkinsonian features and notable for its responsiveness to levodopa therapy; various forms of dystonia plus parkinsonism; several types of paroxysmal dyskinesia; and myoclonus dystonia, an autosomal dominant condition involving myoclonic upper body jerks with dystonic features.

Secondary dystonias occur as a result of an alternative primary process. In these cases, dystonia is generally associated with additional neurologic, laboratory, or imaging abnormalities. Stroke, medication effects, and musculoskeletal or CNS trauma are common causes. Atypical presentations should also prompt further investigation. Numerous degenerative, genetic, and metabolic disease processes have been associated with dystonia; notable examples include Wilson’s, Huntington’s, and Leigh’s diseases; corticobasal degeneration; and cyanide or manganese toxicity.

Pathophysiology

Primary dystonias are not associated with specific neuropathology and do not appear to involve neuronal cell degeneration. They have also been difficult to localize anatomically. PET and functional MRI studies have suggested abnormal metabolic activity in the motor cortex and supplementary motor areas, the cerebellum, and the basal ganglia. DBS recordings have implicated abnormal function of the globus pallidus. Functionally, electrophysiologic studies suggest that dystonia involves loss of normal inhibitory signals, abnormal plasticity of the motor cortex, and subtle abnormalities of sensory function. The neurochemistry of dystonia remains poorly understood. The overlap between dystonia and parkinsonism, as well as the acute dystonic reactions that can accompany pharmacologic antagonism of dopamine receptors, suggest the importance of dopaminergic pathways in the neurochemistry of dystonia. The clinical observation that anticholinergic therapy can be effective in treating childhood dystonia suggests the importance of cholinergic pathways as well.

Treatment

Treatment of dystonia is symptomatic. Appropriately, dopa-responsive dystonia can be almost completely abolished with levodopa therapy. This response is generally sustained, and required doses are often small enough to prevent motor side-effects. Up to 15% of other dystonias will also respond to levodopa therapy. Anticholinergic drugs, including trihexyphenidyl and tetrabenazine, have also been widely used in the treatment of dystonia, but evidence for their efficacy is equivocal. Anecdotal evidence also suggests that some patients may benefit from benzodiazepines, baclofen, carbamazepine, zolpidem, or dopamine receptor blockers. Injection of affected muscle groups with botulinum toxin (BoNT-A and BoNT-B) has proved safe and effective and is now considered a first-line therapy for patients with cervical dystonia, blepharospasm, focal upper limb dystonias, and spasmodic dysphonia. Although sustained benefits are possible using botulinum toxin, not all patients will respond, and some will develop resistance to BoNT-A. These patients may respond to the alternate serotype BoNT-B, but some patients will fail treatment with either type. In patients with medication-resistant segmental or generalized primary dystonia, DBS of the globus pallidus has been effective in controlling symptoms for a majority of patients. Long-term follow-up data are limited. Although some evidence indicates a benefit in focal dystonia treated with DBS, data for the treatment of secondary dystonia are mixed.

Treatment

Current therapies for MS are not curative but attempt to ameliorate acute or chronic symptoms and disability and reduce the number of future exacerbations. Most MS relapses respond to glucocorticoid therapy in the early phases, but many patients fail to respond to corticosteroids as their number of exacerbations increases. Patients with optic neuritis respond to oral and IV adrenocorticotropic hormone (ACTH) and prednisone in the acute phases and experience fewer relapses. Other immunosuppressive agents, such as cyclophosphamide, cytarabine, and azathioprine, have shown intermittent success at preventing the number and severity of relapses, but do carry side effects. Patients with severe motor spasticity and bladder dysfunction are treated with antispastic medications, which provide some relief. Alternative therapies not clinically proven but tried in severely resistant cases include plasmapheresis, hyperbaric oxygen therapy, linoleate supplementation, and interferons. The most recent, controversial development is related to the “vascular hypothesis,” suggesting that MS could be caused by the chronic cerebrospinal venous insufficiency frequently found in these patients. Cerebral venous balloon angioplasty result in significant improvement in the course of MS in preliminary reports. The results of these series are inconclusive until proper blinded randomized studies can be conducted. However, if this treatment were to gain a wider acceptance, administering anesthesia for this procedure may significantly increase exposure to patients with MS among anesthesiologists.