The majority of the common as well as the severe movement disorders which usually affect individuals during their mid to later years rarely present during pregnancy. Currently, few studies of the interaction between hormonal changes associated with pregnancy and the course of the various movement disorders have been performed. In addition, most clinicians are unfamiliar with both the impact of medications used for the treatment of movement disorders in the course of pregnancy and the various medications’ potential for teratogenicity. Certain movement disorders such as chorea gravidarum occur exclusively during pregnancy, while others such as restless legs syndrome may initially present during pregnancy. A concise review of current knowledge about these disorders, as well as their treatment, during pregnancy will be presented. The authors hope that this chapter will assist the treating physician in making better decisions concerning management of the movement disorder patient during pregnancy.

Introduction

Co-occurrence of pregnancy and movement disorders is uncommon and poses a significant therapeutic challenge for the treating physician. The existing data regarding the effects of pregnancy on various movement disorders remains limited. Additionally, many medications that are used for the treatment of movement disorders should be stopped before pregnancy to avoid teratogenicity. Pregnancy may uncover a pre-existing movement disorder tendency such as for the development of chorea, or pregnant patients may develop chorea gravidarum (CG). Moreover, pregnancy can have variable effects on the clinical manifestations of such movement disorders as Parkinson’s disease (PD). A detailed review of the latest knowledge concerning pregnancy and movement disorders follows.

Parkinson’s Disease

PD was initially described by James Parkinson in his famous essay on the “shaking palsy.” PD is a progressive neurodegenerative disease that clinically presents with rigidity, resting tremor, bradykinesia, flexed posture, and loss of corrective postural reflexes. Certain clinical manifestations assist clinicians in differentiating PD from other parkinsonian syndromes. Prominent resting tremor, significant therapeutic response to levodopa/carbidopa, initial asymmetry of the basal ganglia manifestations, and minimal imbalance at the early stages of the disease favor a diagnosis of PD. Among the salient clinical features of PD, resting tremor is the most common and affects up to 70% of patients. Other prominent motor symptoms consist of bradykinesia and cogwheel rigidity. Postural instability associated with loss of corrective postural reflexes occurs at later stages of the disease and is a significant cause of falls. Gait disorder is another significant PD feature and is often associated with falls; and gait dysfunction constitutes one of the most disabling features of PD. Postural instability in PD patients is the end product of a number of basal ganglia manifestations including rigidity, akinesia, loss of corrective reflexes, and impairment of postural adjustment.

Patients with PD suffer from neurobehavioral abnormalities such as depression, sleep disturbances, dementia, and drug-induced hallucinations. Other abnormalities such as restless legs syndrome (RLS), sensory complaints, and akathesia also occur. Autonomic dysfunction including orthostatic hypotension, erectile dysfunction, constipation, urinary incontinence, and thermal dysregulation frequently affect these patients . Other PD nonmotor impairments include fatigue, seborrheic dermatitis, and weight loss. PD patients also develop expressionless facies (“masked facies”), hypophonia, and drooling.

Males with PD outnumber females by a ratio of 2:1, and the disease typically develops in the sixth or seventh decade. A small group of patients develop PD before the age of 50. Women usually develop PD at an older age than men, and usually the milder tremor form predominates. The etiologic pathophysiology and curative treatment remains elusive. Neuropathologic examination of the brains of PD patients has revealed selective and severe loss of melanin-containing neurons with intraneuronal Lewy body formation primarily occurring in the ventrolateral section of the pars compacta of the substantia nigra. Lewy bodies contain alpha-synuclein, ubiquitin, and Torsin A .

Treatment of PD involves symptomatic management of motor and nonmotor manifestations. The available medications include levodopa/carbidopa, dopamine agonists, amantadine, catechol- O -methyl transferase (COMT) inhibitors, a combination of levodopa/carbidopa with COMT, and anticholinergics. The dopamine agonists (bromocriptine, pergolide, pramipexole, and ropinirole) are used as either monotherapy in early PD especially in younger patients or as adjunctive therapy with levodopa formulations. COMT inhibitors are used together with carbidopa/levodopa to extend levodopa’s half-life and to decrease serum level fluctuations. Anticholinergics are primarily used to reduce tremor.

Cases of pregnancy in the context of PD are rare, and there is not much data concerning the course of the disease through either the pregnancy or the postpartum period. The mechanisms of interaction between pregnancy and PD pathophysiology remain unknown. However, the alteration of medication pharmacokinetics secondary to volume and metabolic changes during pregnancy, as well as the physiologic changes in female hormone levels (i.e., estrogen and progesterone), have been proposed to explain the impact of pregnancy on PD . A number of studies have reported worsening of PD during pregnancy , while others report stabilization of the disease , or even improvement of the clinical picture . Based on the available literature, it appears that in most cases, PD progresses during pregnancy, and this is reflected by the increased severity of the clinical manifestations including deterioration of the Unified Parkinson’s Disease Rating Scale (UPDRS) score and the need to increase the dosage of symptomatic medication . Additionally, after pregnancy, the patient may not return to her prepregnancy PD symptomatic baseline .

Because cases of pregnancy in patients with PD are uncommon, there is not much data in the literature concerning the safety of antiparkinsonian drugs during pregnancy, and much of this data is controversial. Most of the medications that are used for the treatment of PD are denoted “pregnancy class C” because the animal or human data for their teratogenicity potential is not available. Among the medications used for the treatment of PD, amantadine definitely should not be administered during pregnancy. Deep brain stimulation (DBS) is used for the treatment of dystonia as well as PD (see treatment section under dystonia).

In conclusion, patients with PD who plan to become pregnant should be advised of the risk of progression, the possibility of the need to increase PD medication dosage, the possibility of not returning to the prepregnancy PD disease baseline, and the lack of scientific data regarding the impact of PD medications on fetal growth and development.

Chorea Gravidarum

Chorea (derived from the Latin word choreus meaning “dance”) is a form of movement disorder that consists of irregular, involuntary, brief, and unpredictable movements resulting from continuous flow of random muscle contractions from one body part to another. Pregnancy may uncommonly present with chorea or chorea may develop during pregnancy, a condition known as chorea gravidarum (CG). CG, originally described in 1661 by Horstius , is more common among pregnant women who have a prepregnancy history of Sydenham’s chorea. CG has been linked to other causes including the immune-mediated conditions of systemic lupus erythematosus and antiphospholipid antibody syndrome , as well as infectious diseases such as syphilis and encephalitis . Based on the available literature, in those pregnancies affected by CG, clinical manifestations occur after the first trimester in half of pregnant women , spontaneously remits in one-third before delivery, and in most cases resolves after delivery . The severity of chorea usually improves as the pregnancy advances . In most cases, CG is not a life-threatening condition; however, severe and unrelenting cases may cause hyperthermia, rhabdomyolysis, myoglobulinuria, and even death . Only the severe cases of CG that pose a serious threat to either the mother or the fetus require treatment.

In general, the symptomatic treatment of choreiform disorders in the absence of pregnancy consists of the use of dopamine receptor blockers (phenothiazines and butyrophenones), and dopamine-depleting agents such as reserpine. The use of these medications for the treatment of chorea stems from the hypothesis that increased dopaminergic activity in the striatum is etiologic. Dopamine receptor blockers are categorized as pregnancy class C and should not be administered during the first trimester. Despite such warnings, haloperidol and chlorpromazine are useful for the treatment of CG and are safe if used at low doses . The American Academy of Pediatrics recommends haloperidol over the other neuroleptics due to its less severe maternal anticholinergic, hypotensive, and antihistaminergic side effects . Reserpine is a teratogen and contraindicated in pregnancy. Tetrabenazine, which was approved recently in the United States for treatment of chorea in Huntington’s disease (HD), is designated pregnancy class C. Therefore, in summary, treatment of CG is indicated only in severe cases, and haloperidol is the neuroleptic of choice during pregnancy.

Huntington’s Disease

HD is an autosomal dominant progressive neurodegenerative disorder with complete penetrance. It is clinically characterized by the triad of movement disorder (mainly chorea), cognitive decline, and psychiatric disorder including depression, apathy, irritability, and personality changes. HD is linked to an unstable polymorphic trinucleotide repeat unit (CAG that codes for the amino acid, glutamine) in the Huntington gene, and was identified in 1983 . The Huntington gene is located on chromosome 4, and huntingtin is the gene protein product although its function is unknown. The number of CAG repeats is an important determinant of the age of onset, and patients with the Westphal variant (juvenile onset disease with rigidity) carry a high number of CAG repeats. Except for this group of patients, the clinical symptoms appear in the fourth and fifth decades. Therefore, most patients with HD manifest symptoms well beyond their childbearing years, and currently, most neurologists are more concerned about genetic counseling and antenatal exclusion testing for pre-symptomatic, at-risk individuals who can potentially become pregnant. A major reason for genetic counseling is the fact that the ability of HD patients to provide ongoing care for their children can be a significant problem. Therefore, this needs to be discussed with at-risk individuals when the issue of pregnancy is raised. There are no significant concerns about the impact of HD on the actual pregnancy or delivery.

Currently, HD is incurable and its treatment is individualized and only symptomatic. Chorea is treated with antidopaminergic agents or dopamine depletors, and depression is managed with antidepressants. In general, neuroleptics are contraindicated during pregnancy; however if the clinical manifestations are severe, high-potency agents are recommended . For treatment of HD-associated depression, tricyclic antidepressants, for example, nortriptyline and desipramine, are the preferred agents .

Dystonia

Dystonia is a hyperkinetic movement disorder characterized by involuntary repetitive motor contractions frequently causing twisting movements or abnormal postures. Dystonia is the product of co-contraction of agonist and antagonist muscles . Because dystonia is a heterogeneous condition, it can be classified based on the age of onset, anatomic distribution, and etiology (primary versus secondary). Dystonia demonstrates a bimodal age of onset with early onset cases (age 9) mainly in genetically inherited dystonias and late onset (age 45) in sporadic cases . Clinically, dystonia has a range of presentations from generalized and disabling contractions which are more frequent in those patients with childhood onset, to more localized and focal contractions which are usually observed with adult-onset forms mainly affecting cervical muscles (torticollis), the arm (writer’s cramp), or cranial muscles (blepharospam). Primary or idiopathic dystonia is a form of dystonia with no other additional neurological abnormalities of an underlying neurodegenerative or acquired disease. Secondary dystonia (also known as symptomatic dystonia) is associated with other illnesses and includes inherited forms such as dystonia plus syndromes, toxic and acquired causes (stroke, drugs), and dystonia associated with degenerative parkinsonian disorders.

Acute drug-induced dystonic reactions commonly occur during pregnancy as a number of medications (such as metocloperamide, promethazine, and prochlorperazine) used for treatment of nausea and vomiting associated with the first trimester of pregnancy (such as metocloperamide, promethazine, and prochlorperazine) are associated with such adverse reactions. In general, all dopamine antagonists may acutely generate extrapyramidal manifestations including dystonic-dyskinetic movement disorders. While most of these acute dystonic reactions last a short time and resolve spontaneously, cases of death after dystonic reactions have been reported . Dystonia gravidarum describes dystonia that arises during pregnancy without any obvious cause and usually resolves before or shortly after delivery .

A number of case reports have addressed the impact of pregnancy on existing dystonia . Gwinn-Hardy et al. assessed the effect(s) of female hormonal variations on the severity of dystonia. The investigators surveyed 279 women with dystonia at Mayo Clinic Scottsdale over a 6-year period, of whom 204 responded. The participants were asked questions about their reproductive and menstrual histories and dystonia severity with emphasis on deteriorating or relieving factors. Most of the women did not report any consistent effect on dystonia severity. However, of the 62 premenopausal women with dystonia, 27 reported at least one pregnancy since the dystonia onset. Only four women described alterations in their clinical manifestations during pregnancy.

Dopaminergic agents, principally levodopa, are used for treatment of cases of dopamine-responsive dystonia. While levodopa has not been formally assigned to pregnancy class, levodopa/carbidopa has been assigned to pregnancy class C by the Federal Drug Administration (FDA).

Botulinum toxin A (Botox) and B (Myobloc) injections are used for treatment of focal dystonias. Currently, there is not sufficient clinical data from controlled human clinical trials regarding the treatment of pregnant patients with these forms of botulinum toxins. So far, Myobloc has not been connected to fetal harm in humans but is assigned as pregnancy class C. Botox has been given to pregnant mice and rats during organogenesis and at high doses was associated with low birth weights and delayed ossification.

DBS is used for the treatment of dystonia and PD. Paluzzi et al. reported three patients with dystonia who became pregnant after insertion of bilateral globus pallidus internus stimulators and completed the pregnancies successfully with vaginal delivery of healthy children. DBS does not pose any risks to pregnant women during investigation by routine ultrasound or fetal monitoring.