Review Article Address correspondence to Dr E. Wayne Massey, Division of Neurology, Department of Medicine, Duke University Medical Center, DUMC 3909, Durham, NC 27710, [email protected]. Relationship Disclosure: Drs Massey and Guidon report no disclosure. Unlabeled Use of Products/Investigational Use Disclosure: Drs Massey and Guidon report no disclosure. * 2014, American Academy of Neurology.

Peripheral Neuropathies in Pregnancy E. Wayne Massey, MD, FAAN; Amanda C. Guidon, MD ABSTRACT Purpose of Review: This article provides an overview of the most common peripheral neuropathic disorders in pregnancy with a focus on clinical recognition, diagnosis, and treatment. Recent Findings: The literature on this topic consists primarily of case reports, case series, and retrospective reviews. Recent work, particularly in carpal tunnel syndrome, brachial neuritis, and inherited neuropathies in pregnancy, has added to our knowledge of this field. Awareness of diabetic polyneuropathy with associated autonomic dysfunction in pregnancy has grown as the incidence of diabetes mellitus increases in women of childbearing age. Summary: Women may develop mononeuropathy, plexopathy, radiculopathy, or polyneuropathy during pregnancy or postpartum. Pregnancy often influences consideration of etiology, treatment, and prognosis. In women of childbearing age with known acquired or genetic neuromuscular disorders, pregnancy should be anticipated and appropriate counseling provided. An interdisciplinary approach with other medical specialties is often necessary. Continuum (Minneap Minn) 2014;20(1):100–114.

INTRODUCTION Disorders affecting peripheral nerves, plexus, or nerve roots are generally rare in pregnancy and the postpartum period. However, they may be commonly encountered in both inpatient and outpatient neurology practice. Acquired and inherited peripheral nerve dysfunction affects the mother and fetus in various ways. This article reviews the most commonly encountered peripheral nerve disorders in pregnancy (Table 5-1) with the goal of facilitating rapid recognition, treatment, symptom management, appropriate counseling, and interdisciplinary collaboration. After initial history and focused symptom-specific neurologic examination, the clinician should strive to localize the problem to one nerve, multiple nerves, plexus, or nerve root. Electrodiagnostic studies, consisting

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of EMG and nerve conduction studies (NCS), both safe in pregnancy, further refine the clinical localization and provide additional information about severity, chronicity, and prognosis. In some cases, further laboratory or imaging evaluation is warranted. When choosing therapy, clinicians should consider potential effects on the fetus during pregnancy and whether the patient is breast-feeding postpartum. UPPER EXTREMITY Median Neuropathy at the Wrist (Carpal Tunnel Syndrome) Carpal tunnel syndrome (CTS) is the most common mononeuropathy during pregnancy. Estimates of the incidence of pregnancy-related CTS vary from 1% to 60% depending on study methodology. Incidence is approximately 17% in prospective studies describing

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KEY POINT

h Carpal tunnel syndrome

TABLE 5-1 Most Common Peripheral Neuropathic Disorders in Pregnancy

is common in pregnancy. Treatment is typically conservative, particularly when symptoms start during the third trimester.

b Upper Extremity Mononeuropathies (median, ulnar, radial) Brachial neuritis/neuralgic amyotrophy b Lower Extremity Mononeuropathies (femoral, obturator, lateral femoral cutaneous, fibular) Lumbosacral plexopathy Lumbosacral radiculopathy b Facial Neuropathy (Bell Palsy) b Intercostal Neuralgia b Polyneuropathy Immune-mediated neuropathies (eg, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy) Diabetic polyneuropathy Polyneuropathy due to nutritional deficiency Genetic causes of polyneuropathy (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies)

only electrodiagnostically confirmed pregnancy-related CTS.1 EMG and NCS can distinguish pregnancy-related CTS from other forms of pregnancyrelated hand pain. Key presenting features include nocturnal or activity-related hand paresthesias, which can be painful. Sensory disturbance classically occurs in a median distribution in the hand; however, more widespread hand and arm symptoms are commonplace. Patients often describe hand stiffness and clumsiness, and in severe cases, weakness of the abductor pollicis brevis may occur.2 Although it is a common disorder in pregnancy, the etiology of pregnancyrelated CTS is poorly understood. In general, CTS is caused by compression of the median nerve at the wrist due to reduced space in the carpal tunnel. Pregnancy-induced fluid retention may Continuum (Minneap Minn) 2014;20(1):100–114

cause edema in the tissues of the carpal tunnel. Most women with pregnancyrelated CTS develop symptoms in the third trimester when they have more generalized edema, which supports this hypothesis. Other hypotheses include the effect of relaxin and other hormones on ligamentous laxity, changes in sleep position, and increased adipose tissue in pregnancy. Although diabetes mellitus is a known risk factor for CTS in the general population, an association between gestational diabetes mellitus and pregnancy-related CTS is not known. Pregnancy-related CTS may occur postpartum and is most typically associated with breast-feeding, possibly due to altered hand positioning.3 Given the high likelihood that pregnancy-related CTS will resolve in the postpartum period, management is typically conservative, as illustrated by Case 5-1. Pregnancy-related CTS www.ContinuumJournal.com

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Peripheral Neuropathies in Pregnancy KEY POINTS

h While carpal tunnel syndrome in pregnancy is often less severe than nonYpregnancy-related carpal tunnel syndrome, a significant percentage of women may have ongoing symptoms postpartum. Electrodiagnostic studies are recommended to support the diagnosis in cases of severe, atypical, or persistent symptoms.

h Carpal tunnel syndrome may present or worsen postpartum.

Case 5-1 A 35-year-old right-handed woman developed severe bilateral hand pain and paresthesia during her third trimester. Her symptoms intermittently extended to her forearms and were particularly severe at night. She described hand clumsiness and swelling. Carpal tunnel syndrome (CTS) was suspected. A trial of wrist splints recommended by her obstetrician provided no relief. Neurologic examination was notable for normal strength, decreased sensation in a median distribution in the right hand, and a Tinel sign over the median nerve at both wrists. Electrodiagnostic studies showed mild, bilateral, right greater than left median neuropathies at the wrist. No evidence of more widespread polyneuropathy was present. Given the symptom severity and failed trial of wrist splints, the option of injections for CTS was discussed. The patient declined but stated that she was relieved to know the cause of her symptoms, which resolved 3 months postpartum. Comment. This patient was diagnosed with pregnancy-related CTS. By electrodiagnostic criteria, pregnancy-related CTS is typically mild, although patients may describe severe symptoms with significant functional impairment. As this case illustrates, symptoms often resolve postpartum, particularly when they first appear in the third trimester. Recent longitudinal data, however, suggest that a larger percentage of women than previously suspected may have persistent symptoms after delivery, particularly when symptom onset occurs early in pregnancy. Conservative measures and anticipatory guidance are typically recommended for pregnancy-related CTS.

is typically less severe than nonY pregnancy-related CTS, thus justifying more conservative management. Initial recommendations include using wrist splints to maintain a neutral position and avoiding repetitive maneuvers that may worsen symptoms. Few data compare the effects of various nonoperative therapies (eg, analgesics, low-salt diet, rest, splinting, local steroid or lidocaine injections). The belief that symptoms resolve in 75% of patients in the first month postpartum was recently challenged. A 3-year longitudinal study that included a control group of age-matched, nonpregnant women showed that persistent symptoms were more common than previously estimated. Approximately 50% of all patients with pregnancy-related CTS had improvement of symptoms in 1 year, and between 60% and 70% improved in 3

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years. However, among women not treated surgically, at 3 years 50% of those with pregnancy-related CTS still had symptoms, in comparison with 83% of women in the control group.4 Patients with symptom onset earlier in pregnancy and with greater pregnancyassociated weight gain were more likely to have persistent symptoms. Surgical therapy should be considered if conservative measures fail, symptoms are severe, or progression occurs after delivery. Surgery can nearly always be postponed until after delivery. It is important to remember that surgery may restrict hand and arm use in the postpartum period, when newborns require handling and care. Ulnar and Radial Neuropathies Ulnar and radial neuropathies occur infrequently in pregnancy. If severe or

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atypical or if localization is uncertain clinically, electrophysiologic evaluation may be considered. Therapy for ulnar neuropathy first involves care not to traumatize the olecranon groove or other site of compression, such as the wrist.3 Radial neuropathy near the spiral grove associated with prolonged use and inappropriate positioning of a birthing bar during labor has been reported.5 A birthing bar attaches to the labor bed and creates a shelf on which a woman may rest her upper arms. It is sometimes used to facilitate a squatting position during the second stage of labor. Neuralgic Amyotrophy Neuralgic amyotrophy, also known as Parsonage-Turner syndrome or brachial neuritis, has both an idiopathic and autosomal dominant hereditary form. Both forms are characterized by attacks of severe neuropathic pain, typically in the shoulder, followed by multifocal upper limb weakness and atrophy. The upper trunk of the brachial plexus is usually affected, scapular winging is frequently present, and sensory symptoms can be patchy. However, the clinical presentation is often heterogeneous; it may be bilateral or involve nerves outside the brachial plexus, such as the phrenic or spinal accessory nerves. Progression is rapid initially, and recovery may take months to years. Altered immunity and resulting inflammation are thought to underlie both the idiopathic and hereditary forms of neuralgic amyotrophy. Hereditary neuralgic amyotrophy is genetically heterogenous, but mutations in the SEPT9 gene on chromosome 17q25 have been reported in the majority of affected families. Features suggesting hereditary rather than idiopathic neuralgic amyotrophy include repeated episodes (especially postpartum), family history, involvement of Continuum (Minneap Minn) 2014;20(1):100–114

nerves outside the brachial plexus, and the presence of mild dysmorphic features. Dysmorphic features in hereditary neuralgic amyotrophy include short stature, hypotelorism, epicanthic folds, redundant cervical skin folds, and dysmorphic ears.6 In one series of 246 patients, four of the 10 cases of neuralgic amyotrophy associated with pregnancy were hereditary, whereas the remaining six were idiopathic.7 The method of delivery (eg, vaginal or cesarean delivery) does not appear to influence the incidence of postpartum attacks in hereditary neuralgic amyotrophy, and no proven way to prevent episodes exists. Anecdotally, early treatment with corticosteroids in hereditary neuralgic amyotrophy and idiopathic neuralgic amyotrophy may stop progression, limit pain, or improve outcome.6

KEY POINTS

h Neuralgic amyotrophy has both idiopathic and autosomal dominant hereditary forms. Both forms may occur postpartum. The inherited variety can recur with subsequent pregnancies, and no known method exists to prevent attacks.

h Attention to positioning in labor helps prevent lower extremity mononeuropathies. Femoral, fibular, and (less commonly) obturator neuropathies may occur.

LOWER EXTREMITY During pregnancy or after delivery, women may develop lower extremity weakness or sensory loss. Postpartum peripheral nerve injuries are now uncommon as a result of prevention strategies during labor.8 In general, frequent leg position changes, shortened active labor time, and avoidance of prolonged hip flexion, extreme thigh abduction, or hip external rotation are protective. Particular attention is warranted in women receiving epidural anesthesia, which is associated with a longer second stage of labor. Sensory blockade makes women less likely to sense pressure and change their own position.9 Femoral and Obturator Neuropathies The femoral nerve is formed by the L2 to L4 nerve roots and arises from the lumbar plexus. The nerve passes between the psoas and iliacus muscles and under the inguinal ligament. During delivery, the femoral nerve may be compressed at the inguinal ligament www.ContinuumJournal.com

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Peripheral Neuropathies in Pregnancy KEY POINT

h The etiology of compression or stretch should be evaluated when women develop lower extremity mononeuropathies or plexopathy postpartum. Electrodiagnostic studies confirm localization and assist with assessment of severity and prognosis, which is typically favorable.

or stretched through hip abduction and external rotation.10 In femoral neuropathy, patients report difficulty standing and may describe a buckling sensation in the leg. This results from weakness of the quadriceps femoris and, in lesions proximal to the inguinal ligament, the iliopsoas. Sensory loss and paresthesia may be seen in the distribution of the femoral nerve over the distal anteromedial thigh and, if involved, the saphenous nerve over the anteromedial aspect of the lower leg. The patellar reflex can be diminished or absent. Weakness of both hip flexion and adduction suggests a plexus or root lesion instead of an isolated femoral neuropathy.11 Although obturator neuropathy is rare postpartum, it should be considered in a patient with isolated hip adduction weakness and numbness over the proximal medial thigh. The obturator nerve may be affected by the lithotomy position. A cadaver study suggested that hip abduction, as is used in the lithotomy position, increases strain on the obturator nerve to a degree that has been associated consistently with subsequent nerve dysfunction. This strain was lessened by using concomitant hip flexion.12 The nerve may also be compressed against the pelvic brim during forceps delivery or due to hematoma from pudendal nerve block.9 In both femoral and obturator neuropathy in the postpartum, pelvic imaging is often indicated if symptoms are persistent or compression from hemorrhage is suspected.13 If no cause is found, treatment is supportive. Symptoms often improve within 2 to 6 months.9 Fibular (Peroneal) Neuropathy Following reviewed terminology published in 1998 by the Federative Committee on Anatomical Terminology (FCAT), the peroneal nerve is known as the fibular nerve, to distinguish it from other nerves with similar

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names; both terms are still used interchangeably by many texts. During pregnancy or following labor, women who have a fibular (peroneal) neuropathy may report paresthesia along the lateral aspect of the leg and may notice foot drop; examination reveals weakness of ankle dorsiflexion and eversion, and toe extension. Sensory loss may involve the lateral aspect of the leg and dorsum of the foot. The deep or superficial branches of the fibular nerve may be affected together or in isolation. Mechanical injury, neuroma, fat, or cysts can compress the common fibular nerve at the fibular head. Cysts may enlarge during pregnancy. Electrodiagnostic evaluation can confirm fibular neuropathy and exclude lumbosacral plexopathy and L5 radiculopathy. Peripheral nerve ultrasound may further aid in localization or in identification of structural causes of focal compression. Prognosis for recovery from pregnancy-related lower extremity nerve injury is typically good; however, the number of patients with peroneal neuropathy in one study of postpartum nerve injuries was small.9 The potential etiology of injury and severity of deficits should be considered in each case to help guide assessment of prognosis. Patients should be counseled to avoid pressure at the fibular head from activities such as prolonged squatting or crossing the legs. Ankle-foot orthoses may be required to assist with ambulation if severe ankle dorsiflexion weakness is present.3 Lateral Femoral Cutaneous Neuropathy (Meralgia Paresthetica) Meralgia paresthetica is a sensory mononeuropathy that occurs from injury to the lateral cutaneous nerve of the thigh (also called the lateral femoral cutaneous nerve). The course of the nerve is highly variable, and locations

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of trauma include the psoas or tensor fascia lata muscles, the iliacus compartment in the pelvis, the inguinal ligament, or the thigh. No cause is identified in many cases. Symptoms may be bilateral. Physical examination reveals sensory loss in the anterolateral thigh in the distribution of the lateral cutaneous nerve of the thigh. Importantly, because the lateral cutaneous nerve of the thigh is an exclusively sensory nerve, strength and deep tendon reflexes are normal. Standing, walking, and flexion or extension maneuvers of the hip can exacerbate symptoms.11 During pregnancy and delivery, the lateral cutaneous nerve of the thigh can be stretched or compressed. This nerve is unlikely to be damaged during regional anesthesia because it originates more caudal and lateral than the site typically used for epidural placement.2,14 Presence of meralgia paresthetica should not preclude the use of regional anesthesia. Management of meralgia paresthetica in pregnancy focuses on symptom management. Most cases resolve spontaneously within several months of delivery. Avoiding aggravating positions and tight-fitting clothing is recommended.15 Tricyclic antidepressants or anticonvulsants, which are first-line medications in nonpregnant patients, are all FDA pregnancy category C or D.10 These are not recommended for use in pregnancy because the risk to the fetus outweighs potential benefit to the patient with meralgia paresthetica. Lumbosacral Plexopathy Injuries to the lumbosacral plexus can occur during the third trimester or delivery, due to compression from the fetal head or forceps. The plexus is relatively unprotected at the pelvic brim. Therefore, fetal macrosomia Continuum (Minneap Minn) 2014;20(1):100–114

and malpresentation are risk factors.9 Symptoms include pelvic and proximal leg weakness and pain with associated weakness in ankle dorsiflexion, inversion, and eversion. Muscles innervated by L4 and L5 roots are most affected. Sensory impairment predominates in an L5 distribution. The Achilles (S1) reflex is often spared. Electrodiagnostic studies show a plexus lesion (ie, sparing the paraspinal muscles).3 Outcome data are limited, and after excluding an ongoing compressive lesion, management is typically conservative. Low Back Pain and Lumbosacral Radiculopathy Low back pain from musculoskeletal causes is reported in approximately 50% of pregnancies. However, low back pain due to herniated disc is rare and occurs in an estimated 1 in 10,000 pregnancies. Pregnancy does not increase the risk of disc herniation.16 Back pain without neurologic deficits can be managed symptomatically. Changes in sensation, strength, or reflexes, however, should prompt investigation for radiculopathy with noncontrasted MRI and electrodiagnostic studies. Most common causes of radiculopathy can be investigated without contrast. Gadolinium agents are FDA pregnancy category C and should only be used if the potential clinical benefit outweighs the risk (for more on this topic, see ‘‘Neuroradiology in Women of Childbearing Age’’ by Drs Riley Bove and Joshua ). Klein in this issue of Contrast is typically indicated only if concern exists for infection, inflammation, or malignancy causing radiculopathy.17 Conservative measures such as rest, physical therapy, postural education, and lumbar support are generally recommended.18 Surgery is typically avoided in pregnancy except

KEY POINT

h Meralgia paresthetica involves sensory loss and paresthesia of the anterior and lateral thigh. While symptoms are bothersome to the patient, it is typically a benign disorder, which is diagnosed clinically. Electrodiagnostic studies can be performed if the localization is in question. Normal strength and deep tendon reflexes help distinguish this from other causes of sensory disturbance of the thigh.

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Peripheral Neuropathies in Pregnancy KEY POINTS

h Back pain with focal neurologic deficits should prompt further investigation for radiculopathy, which occurs only rarely in pregnancy.

h Epidural anesthesia very uncommonly results in neurologic complications, including radiculitis, arachnoiditis, or epidural hematoma.

h Women have an increased risk of Bell palsy in the third trimester and postpartum. Pregnancy-related Bell palsy may be more severe than nonYpregnancyrelated Bell palsy. The risks versus benefits of treatment with steroids should be considered for each patient.

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in cases of significant progressive neurologic deficits or cauda equina syndrome.18 The risk of neurologic complication from epidural anesthesia is low, estimated at 0.1%. Potential complications include epidural hematoma, drug toxicity, chemical radiculitis, arachnoiditis, and direct needle injection injury into the nerve root. Therefore, urgent MRI is recommended in women who develop radiculopathy or myelopathy after epidural anesthesia.19 Although electrodiagnostic studies have limited ability to detect abnormalities in the acute setting, studies may be performed to establish a baseline for future comparison if symptoms persist. Idiopathic Facial Nerve Palsy (Bell Palsy) Bell palsy is the most common disorder of the facial nerve. Pregnant women, particularly in the third trimester and in the first 2 weeks postpartum, have 3 times the risk for developing Bell palsy over their nonpregnant counterparts. The pathophysiology of Bell palsy in pregnancy is poorly understood. Relative immunosuppression hypothetically may lower the threshold for reactivation of herpes viruses in the geniculate ganglion. Increased extracellular volume, hypertension, hypercoagulable states, and changes in hormonal levels have also been suggested. Retrospective studies have shown a significant association with chronic or gestational hypertension, preeclampsia, and diabetes mellitus.10 Bell palsy presents identically in pregnant and nonpregnant women, but the course may be more severe in pregnant women. Although most patients regain normal or near-normal function, retrospective data suggest that pregnant women are more likely to have complete facial paralysis,

which is a poor prognostic factor.20 Whether this difference is due to the disease process or treatment-related factors is unknown. Pregnant and breast-feeding women have traditionally been excluded from corticosteroid and antiviral trials for Bell palsy. The decision to treat pregnant women or not involves consideration of the potential risks and benefits. Recent evidence-based guidelines published by the American Academy of Neurology (AAN) recommended using corticosteroids for Bell palsy in the general population when started within 3 to 7 days of symptom onset to maximize the chance for facial nerve recovery.21 Steroids are FDA pregnancy category C and probably safe during lactation. As in the general population, comorbid conditions need to be considered when making the decision to start these agents in pregnancy or postpartum. If the patient has poorly controlled hypertension or hyperglycemia, the risk may outweigh the benefit. The same AAN guidelines found that antiviral agents have not conclusively shown efficacy in Bell palsy, and their benefit may only be modest. These agents are FDA pregnancy category B and considered generally safe in breastfeeding. No clear evidence-based guidelines for treating pregnant or breast-feeding patients who have Bell palsy have been published. Typically, in an otherwise uncomplicated pregnancy, the potential benefit of treatment with corticosteroids after the first trimester is likely to outweigh the risk, in the authors’ opinion. Because of the uncertain benefit and possible risk, antiviral agents can probably be forgone in pregnancy when no additional manifestations of viral infection are present. In all patients, the eye should be lubricated to prevent corneal abrasion. Patients can be

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reassured that recurrence of Bell palsy in future pregnancies is rare.3 Intercostal Neuralgia Intercostal neuralgia occurs rarely in pregnancy (when it is also called thoraconeuralgia gravidarum). Patients experience mild to severe pain and sensory change in the distribution of one to two thoracic roots, typically in the lower thoracic region. Pain can worsen with palpation of the paraspinal muscles or radiate to the abdomen. The etiology is unknown and may relate to stretch injury. Because symptoms typically remit within hours of delivery, a physiologic rather than structural cause of nerve injury has been hypothesized. EMG may reveal abnormal spontaneous activity in the paraspinal muscles of the corresponding symptomatic level. This abnormality is not required for diagnosis.22 Intra-abdominal and spinal (spinal cord or radicular) etiologies should be considered in the differential diagnosis, and imaging of the thoracic spine may be considered. Herpes zoster should be considered in the presence of a skin rash. Treatment with topical lidocaine patches, FDA pregnancy category B, may be considered after a discussion of the risk of treatment to the fetus versus potential benefit to the patient. Extended epidural anesthetic until delivery has been reported in a severe case.23 POLYNEUROPATHY The general approach to the evaluation of polyneuropathy is not significantly changed by pregnancy. Clinicians use the history, physical examination, and electrodiagnostic studies to characterize the polyneuropathy systematically and narrow the differential diagnosis of potential etiologies. A series of questions helps focus the evaluation (Table 5-224). With this framework in mind, the authors focus this discussion on several forms of Continuum (Minneap Minn) 2014;20(1):100–114

polyneuropathy with particular relevance to pregnancy and the postpartum period. AUTOIMMUNE NEUROPATHIES Acute Inflammatory Demyelinating Polyradiculoneuropathy Acute inflammatory demyelinating polyradiculoneuropathy (AIDP), or Guillain-Barre ´ syndrome, is an acute neuropathy that may affect women during pregnancy or the postpartum period. The incidence of AIDP is approximately 0.75 to 2 in 100,000 per year and increases with age. During pregnancy, the age-adjusted incidence is identical to that of the general population. Nearly all of these cases, however, occur in the second or third trimesters or the first month postpartum.25 The clinical presentation of AIDP and approach to therapy in pregnancy is the same as in the general population. Patients develop progressive weakness, sensory disturbance, and loss of deep tendon reflexes that often follow an ascending pattern. Extraocular movement abnormalities, facial weakness, ataxia, respiratory compromise, and autonomic dysfunction may occur. Diagnosis is made based on the clinical history, the presence of cytoalbuminologic dissociation in CSF, electrodiagnostic studies that support an acute neuropathy, and the exclusion of mimic diagnoses. Importantly, CSF and electrodiagnostic studies may be normal very early in the disease course. AIDP is most frequently demyelinating; however, some autoimmune polyneuropathy variants are axonal. Pregnant women may be less likely than the general population to have serologic evidence of associated Campylobacter jejuni infection. The 10% incidence of cytomegalovirus infection in pregnant women with AIDP mirrors the general population. Testing for these agents is

KEY POINTS

h Intercostal neuralgia results in pain and sensory change in the distribution of one or two thoracic roots. The etiology in pregnancy is unknown, and symptoms typically resolve within hours of delivery.

h The approach to evaluation of polyneuropathy is not significantly changed by pregnancy.

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Peripheral Neuropathies in Pregnancy KEY POINT

h Acute inflammatory demyelinating polyradiculoneuropathy can be treated with plasma exchange or IV immunoglobulin in pregnancy and does not appear to have adverse perinatal or neonatal outcomes. Testing for cytomegalovirus should be performed because cytomegalovirus can be transmitted to the fetus.

a TABLE 5-2 Characterization of Polyneuropathy

b What is the time course? Acute or chronic Progressive or relapsing/remitting b What is the distribution? Length-dependent or independent Multifocal b What types of nerve fibers are affected? Motor and/or sensory Large and/or small Somatic and/or autonomic b What portion of the nerve is affected? Axon, myelin, or both b Is there a family history or other features that would suggest a hereditary neuropathy? Lack of positive sensory symptoms Associated skeletal abnormalities (eg, scoliosis, high-arched feet) Early age at onset or very slowly progressive course a

Data from Alport AR, Sander HW, Continuum (Minneap Minn).24 journals.lww.com/continuum/ Fulltext/2012/02000/Clinical_Approach_to_Peripheral_Neuropathy_.6.aspx.

recommended because their presence is often associated with more severe disease and residual disability. Cytomegalovirus is also important to identify because it may be transmitted to the fetus.26 The treatment for AIDP is either a course of plasma exchange or IV immunoglobulin. One review of a small series of treatment outcomes and complications in pregnant patients with AIDP found no treatmentrelated complications with either therapy.25 Termination of pregnancy because of AIDP is not recommended, as it has no proven benefit in shortening disease course or improving maternal outcome. Additionally, perinatal and neonatal outcomes appear reasonable, without defined risk due to AIDP. In this review,25 35% of patients had preterm delivery; however, in most

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of the patients, labor was induced for maternal neurologic decline. Sixty-one percent of patients delivered via cesarean delivery. However, vaginal deliveries were achieved even in patients with severe weakness and ventilator dependence. Therefore, in general, AIDP does not appear to affect uterine contractility, and operative delivery can be reserved for obstetric indications. General anesthesia has been used without complication but may be complicated by autonomic instability. One report of succinylcholine precipitating severe hyperkalemia and maternal death in AIDP has been published27; depolarizing neuromuscular blocking agents should be avoided in patients with AIDP. Epidural anesthesia has generally been used in this group without complications, although one

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case of worsening weakness has been reported.28,29 The authors recommend communication with the obstetrician and anesthesiologist regarding method of delivery in AIDP. Additional important treatment considerations include deep vein thrombosis prophylaxis and prevention of secondary infections, such as pneumonia or urinary tract infection. Chronic Inflammatory Demyelinating Polyradiculoneuropathy Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a group of immune-mediated neuropathies with a relapsing or progressive course. Because they usually present in older adults, with a peak incidence between the ages of 40 and 60, information about pregnancy is limited. In case reports and a small series of nine women with CIDP who became pregnant, an increased risk of relapse during the third trimester and postpartum period was observed.30 A similar pattern of worsening has been reported in multifocal motor neuropathy (MMN), another uncommon disease in pregnancy. Risk to the fetus is not well established in either disorder. Interestingly, one case of neonatal transmission of MMN associated with anti-ganglioside M1 (antiGM1) antibodies and monoclonal gammopathy has been reported.31 METABOLIC AND NUTRITIONAL NEUROPATHIES Diabetic Polyneuropathy Diabetic polyneuropathy is estimated to affect 50% of patients with either type 1 or type 2 diabetes mellitus. Risk factors include duration of disease and poor glycemic control. Other vascular risk factors, such as obesity and hyperlipidemia, may play a role. The most common form of diabetic polyneuropathy is a length-dependent, small and large fiber, sensory greater than motor Continuum (Minneap Minn) 2014;20(1):100–114

polyneuropathy. This neuropathy is often painful and may be accompanied by autonomic abnormality. Manifestations of autonomic neuropathy include gastroparesis, vomiting, constipation, diarrhea, urinary frequency or retention, and postural hypotension. Many of these symptoms are common during pregnancy in nondiabetics and thus may go unrecognized as related to diabetic neuropathy by women and their doctors. Diabetes mellitus also predisposes patients to cranial, nerve root, and focal entrapment neuropathies. Limited information, mostly from case reports, exists about whether symptoms of diabetic polyneuropathy or autonomic neuropathy worsen with pregnancy. Moreover, the effect of diabetic polyneuropathy on pregnancy outcomes is difficult to separate from other known risk factors, such as poor metabolic control, hyperemesis, inadequate nutrition, or coexisting vascular disease. Pregnancy does not appear to increase the risk for development or progression of diabetic polyneuropathy or autonomic neuropathy. Adjustments in pharmacotherapy for painful diabetic neuropathies may be indicated during pregnancy. Particular attention to positioning and padding during delivery may help avoid superficial nerve injuries at sites of compression.32 Gastroparesis and cardiac complications from autonomic neuropathy pose significant challenges during pregnancy. Gastroparesis exacerbates nausea and vomiting in pregnancy, resulting in inadequate absorption of nutrients and erratic blood glucose control. Patients with gastroparesis may benefit from treatment with metoclopramide or erythromycin, both FDA category B medications in pregnancy. Total parenteral nutrition may be necessary in cases of severe gastroparesis with nausea and vomiting. Diminished counter-regulatory response to hypoglycemia may be present.33 This

KEY POINTS

h Communication with the obstetrician and anesthesiologist regarding the method of delivery in women with acute inflammatory demyelinating polyradiculoneuropathy is recommended.

h Autonomic dysfunction in diabetic polyneuropathy may cause gastroparesis or cardiac complications during pregnancy and delivery. Diabetes also predisposes pregnant women to focal compressive neuropathies.

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Peripheral Neuropathies in Pregnancy KEY POINTS

h Deficiency of B vitamins should be considered as a cause of polyneuropathy in pregnancy, particularly in women with hyperemesis gravidarum.

h In women presenting with polyneuropathy postpartum, a detailed history of emesis, diet, and supplementation during pregnancy is essential.

may result in inadequate release of glucagon, norepinephrine, epinephrine, and cortisol, which would typically restore normoglycemia.34 Patients should be assessed for this and educated on strategies to minimize the occurrence of hypoglycemia.33 Cardiac autonomic neuropathy is estimated to affect 11% to 33% of young adults with diabetes mellitus and depends on the quality of glycemic control. It may be accompanied by left ventricular hypertrophy and diastolic dysfunction. Cardiac autonomic neuropathy manifests as exercise intolerance, orthostatic hypotension, cardiac arrhythmias, silent myocardial ischemia, or intraoperative cardiovascular lability and increased cardiac events.33 Hypotension may worsen as a result of blunting of the normal compensatory response of increased heart rate. Volume expansion in pregnancy, however, may also reduce baseline orthostasis. Obstetric anesthetists should be aware of the possibility of labile blood pressures in response to general anesthesia.32 Neuropathy due to Nutritional Deficiency When evaluating pregnant or postpartum patients with symptoms of polyneuropathy, it is important to consider nutritional etiologies. Nausea and vomiting are common and affect 50% of pregnancies. In approximately 0.3% to 1% of pregnant women, these symptoms are severe and meet criteria for hyperemesis gravidarum. In these settings, women are at risk for polyneuropathy related to nutritional deficiency, particularly thiamine (vitamin B1), pyridoxine (vitamin B6), and cobalamin (vitamin B12).35 This is a point well illustrated by Case 5-2. Polyneuropathy due to nutritional deficiency typically follows a lengthdependent, axonal, and sensory greater than motor pattern. In thiamine defi-

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ciency, patients may have ophthalmoparesis or nystagmus or other features of Wernicke encephalopathy. Vitamin B12 deficiency can be manifested by myelopathy (including posterior column and corticospinal tract abnormalities). Neuropathy due to B12 deficiency may also manifest as a large fiber sensory neuropathy or small fiber neuropathy with normal nerve conduction studies.36 In addition to low serum B12 levels, assessing for increased methylmalonic acid and homocysteine levels increases the diagnostic yield. B6 supplementation has sometimes been used to treat nausea and vomiting in pregnant women. Therefore, both B6 toxicity and B6 deficiency should be considered potential causes of polyneuropathy in this group. B6 intoxication manifests as a sensory neuropathy or neuronopathy; strength is preserved, although significant sensory ataxia may be present. Serum B6 and whole blood thiamine can be reliably measured. In patients with presumed thiamine deficiency, one should emergently provide thiamine re p l a c e m e n t t o t r e a t p o ss i b l e Wernicke encephalopathy and not delay treatment while the results of the blood level are pending. HEREDITARY DISORDERS OF PERIPHERAL NERVE Charcot-Marie-Tooth Disease Hereditary motor and sensory neuropathies, which is a term used interchangeably with Charcot-Marie-Tooth disease (CMT), are the most common inherited polyneuropathies. Symptoms often begin in the first to third decades and progress slowly. Symmetric distal limb weakness, pes cavus, sensory loss without positive sensory symptoms, and imbalance are typical. Significant genetic and phenotypic variability exists. In some forms of CMT, postural tremor, dysphonia from vocal cord paralysis, respiratory insufficiency, pupillary dysfunction, or

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KEY POINT

Case 5-2

h Treatment of

A 30-year-old woman was seen 3 months postpartum for numbness and painful paresthesia in her distal lower extremities, which started during the second trimester of pregnancy. Pregnancy was complicated by hyperemesis gravidarum and 30-pound weight loss. Physical examination was notable for loss of pinprick and light touch sensation distal to the ankles with intact vibration, proprioception, and strength. Deep tendon reflexes were brisk throughout. Plantar responses were flexor. EMG and nerve conduction studies, including autonomic testing of R-R interval variability with deep breathing and posture, were normal. Laboratory evaluation demonstrated normal whole blood thiamine, vitamin E, vitamin B6, copper, erythrocyte sedimentation rate, extractable nuclear antigens, angiotensin-converting enzyme, antinuclear antibody, serum protein electrophoresis, and thyroid function testing. Hemoglobin A1C and 2-hour glucose tolerance testing were normal. Zinc levels were mildly low. Vitamin B12 was 199 pg/mL and had decreased from 600 pg/mL 2 months earlier. Methylmalonic acid was elevated due to B12 deficiency. HIV and hepatitis C testing had previously been negative. She was treated for small fiber neuropathy in association with B12 deficiency with oral B12 supplementation. Follow-up B12 and methylmalonic acid levels were normal, and the patient’s symptoms greatly improved. Comment. This patient was diagnosed with small fiber neuropathy due to B12 deficiency. While B12 deficiency typically causes a myeloneuropathy with findings of a large fiber sensory and motor axonal neuropathy, it may also cause small fiber neuropathy. Routine electrodiagnostic studies are normal in small fiber neuropathy. In this case, B12 deficiency developed due to hyperemesis gravidarum. In her evaluation, it was important to exclude other significant nutritional deficiencies and other non-nutritional, common causes of small fiber neuropathy. She was not breast-feeding, and gabapentin was successfully used for symptomatic relief. In the postpartum period, breast-feeding status may influence the clinician’s decision to treat symptomatically and the choice of medications.

scoliosis may be manifest.37 Classification of the CMT variant as axonal or demyelinating, combined with any available clues regarding pattern of inheritance, directs genetic testing. Inheritance is mainly autosomal dominant, although X-linked and autosomal recessive forms exist. Life expectancy is normal. Patients rarely (approximately 5%) become wheelchair dependent. Care is focused on maintaining function and mobility. Important areas for discussion regarding pregnancy for women with CMT, as with other preexisting peripheral neuropathic disorders, are outlined (Table 5-3).10 Retrospective data on pregnancy outcomes in CMT are generContinuum (Minneap Minn) 2014;20(1):100–114

Charcot-Marie-Tooth disease is heavily focused on adaptive equipment. Functional needs or abilities may change during pregnancy or postpartum, and reassessment is warranted.

ally favorable. In the most recent review, which included 33 patients undergoing a total of 63 pregnancies, pregnancy outcomes were good. No increase in the rate of miscarriage, pregnancy complications, preterm delivery, delivery by cesarean delivery or instrumentation, abnormal presentation, or adverse neonatal outcome was documented.38 This study did not replicate prior data on increased risk of presentation abnormalities, instrumentation, cesarean delivery, or postpartum bleeding. As with prior studies, however, transient worsening of CMT symptoms was reported in approximately 32% of pregnancies, and persistent worsening in an additional www.ContinuumJournal.com

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Peripheral Neuropathies in Pregnancy KEY POINT

h Pregnancy outcomes are typically favorable in Charcot-Marie-Tooth disease. Transient worsening of Charcot-Marie-Tooth disease occurs in approximately 30% of pregnancies, while persistent worsening is seen in an additional 22% of pregnancies.

in Women With TABLE 5-3 Key Considerations for Pregnancy Preexisting Neuropathya b Will the course of maternal disease change with pregnancy? b Will treatment need to be adjusted, and, if so, how? b What are the potential effects of therapy on the fetus? b Will there be complications during labor and delivery? b Are there additional implications for the fetus? a

Data from Guidon AC, Massey EW, Neurol Clin.10 www.sciencedirect.com/science/article/pii/ S0733861912000199.

22% of pregnancies.38 Worsening may be more common with earlier-onset disease. Deterioration in one pregnancy generally predicts deterioration in subsequent pregnancies. Women with CMT who are ambulatory before pregnancy, however, typically remain ambulatory. Case reports have documented safe use of regional anesthesia during delivery.39 The authors recommend optimizing functional status before pregnancy and reevaluating patients for any new needs during pregnancy and postpartum. It is important to address the generally good pregnancy outcomes and to allow the opportunity for genetic counseling. Carrier and prenatal testing and preimplantation genetic diagnosis are available for some forms of CMT. Fatigue and excessive daytime sleepiness are common in CMT. Physicians should be mindful of potential worsening of baseline fatigue in pregnant and postpartum patients with CMT.37 The authors recommend that patients work with physical and occupational therapists to anticipate the challenges of holding, feeding, and carrying the newborn. Hereditary Neuropathy With Liability to Pressure Palsies Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder, which is allelic to

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CMT1A: 85% to 90% of cases are due to a PMP22 gene deletion and 10% to a PMP22 point mutation. It is a multifocal demyelinating neuropathy that presents as recurrent painless mononeuropathies. These mononeuropathies occur at typical sites of compression (eg, fibular neuropathy at the knee, ulnar neuropathy at the elbow) and with everyday activities such as leg crossing, squatting, or leaning on an elbow.37 Although HNPP mononeuropathies generally recover spontaneously, fixed deficits may occur. Women with HNPP may develop such neuropathies during pregnancy or delivery: axillary and fibular neuropathies have been reported.40,41 Women with HNPP should take particular precautions to avoid compression. A personal or family history of multiple prior compression neuropathies prompts consideration of HNPP. EMG/NCS is utilized to confirm the mononeuropathy and site of compression. CONCLUSION Although rare, acquired peripheral neuropathic disorders in pregnancy are seen in practice. Neurologists can greatly assist the patient and often the rest of the medical team by facilitating localization of the problem, treatment, symptom management, and appropriate counseling. Diagnostic evaluation and treatment may be

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influenced in key ways by pregnancy and consideration of fetal outcomes. For neurologists who see women with preexisting disorders, an early and open dialogue about pregnancy can allow for anticipatory guidance and planning. Current data in this field are limited, and additional study of peripheral neuropathies in pregnancy is needed. REFERENCES 1. Padua L, Aprile I, Caliandro P, et al. Carpal tunnel syndrome in pregnancy. Neurology 2002;59(10):1643Y1646. 2. Stewart JD. Focal peripheral neuropathies. 4th ed. West Vancouver, Canada: JBJ Publishing; 2010:224Y225, 556. 3. Massey EW, Stolp KA. Peripheral neuropathy in pregnancy. Phys Med Rehabil Clin N Am 2008;19(1):149Y162. 4. Mondelli M, Rossi S, Monti E, et al. Prospective study of positive factors for improvement of carpal tunnel syndrome in pregnant women. Muscle Nerve 2007;36(6):778Y783. 5. Roubal P, Chavinson A, LaGrandeur R. Bilateral radial nerve palsies from use of the standard birthing bar. Obstet Gynecol 1996;87(5 pt 2):820Y821. 6. van Alfen N. Clinical and pathophysiological concepts of neuralgic amyotrophy. Nat Rev Neurol 2011;7(6):315Y322. 7. van Alfen N, van Engelen B. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006;129(2):438Y450. 8. Pridjian G. Safe maternal positioning during labor and delivery. Obstet Gynecol 2011; 118(2 pt 2):413Y414. 9. Wong C, Scavone B, Dugan S, et al. Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 2003;101(2):279Y288.

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Peripheral neuropathies in pregnancy.

This article provides an overview of the most common peripheral neuropathic disorders in pregnancy with a focus on clinical recognition, diagnosis, an...
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