Pathology

Parkinson disease is characterized by the pathologic degeneration of brainstem nuclei, especially dopaminergic cells of the substantia nigra. It is also due to hyperactivity of the cholinergic neurons in the caudate nuclei.¹

Clinical Presentation

The classic features of Parkinson disease include resting tremor, rigidity, postural instability, and bradykinesia. The resting tremor is the most common presenting symptom. It typically appears as a “pill-rolling” motion of the hand at 3 to 5 Hz. The resting tremor is suppressed by activity or sleep, and is intensified by stress or fatigue.

The rigidity of Parkinson disease can take two forms: “lead pipe” and cogwheeling. Lead pipe rigidity is frequently described as a smooth resistance to passive movement that is independent of velocity (in contradistinction to spasticity, which is velocity dependent). The lead pipe tone of one limb increases if another limb is involved in a voluntary motion or a mental task. Cogwheel rigidity is a ratcheting through the range of motion. It is caused by a subtle tremor superimposed on the rigidity.²⁵

Posture is also affected, as patients with Parkinson disease frequently assume a position that is slumped over and forward with protracted shoulders, and flexed hips and knees. In older texts this was referred to as a simian posture. Postural reflexes are commonly affected in Parkinson disease, which can result in an increased tendency to fall backward or to the side.

Bradykinesia refers to slowness of motion. It can be reflected in an inability to change direction while walking, difficulty walking around an object, or just difficulty standing. When the bradykinesia affects the muscles of facial expression, a masked facies can be apparent (also known as hypomimia).⁵⁴

Diagnosis

The diagnosis of Parkinson disease is primarily clinical. Casual observation of the patient typically reveals the tremor or paucity of spontaneous movements. Resistance to movement of the limbs can be assessed during the range-of-motion examination. Motor examination often shows that Parkinson disease findings are asymmetric in the early stages of the disease. Gait observation should include linear motion as well as changes in direction. If a patient uses more than five steps to complete a 180-degree turn, the diagnosis of Parkinson disease should be considered.⁶⁸ Fatigue in patients with Parkinson disease is common.⁵ Gait dysfunction contributes to the increased energy cost of walking.⁶ This can add to the elevated level of fatigue that is characteristic of individuals with Parkinson disease. Bedside cognitive evaluation can be normal early in the disease process, with neuropsychologic evaluation usually reserved for problematic cases. Routine electrodiagnostic studies do not aid in the diagnosis of Parkinson disease, except for exclusion of other neurologic processes. Investigational use of electrodiagnostic studies in Parkinson disease can be done in a research setting. The use of laboratory or neuroimaging investigations is for exclusionary indications and for atypical cases. At present, functional neuroimaging techniques such as positron emission tomography and single-photon emission computed tomography scanning are mainly experimental techniques. Both of these have emerged as significant investigational tools in some clinical trials.

The initial diagnosis of Parkinson disease can be delayed, depending on which symptoms predominate. The rigidity of Parkinson disease can be mistaken for the stiffness of arthritis. The postural changes can be attributed to osteoporosis or degenerative spine disease. The bradykinesia and masklike facies can be mistaken for depression. The differential diagnosis is wide (Box 51-1), as one should consider that the symptoms could also be induced by a drug, toxic, metabolic, or other neurologic process.

It is also helpful to watch for certain cardinal symptoms, such as early vertical eye movement abnormalities (progressive supranuclear palsy), early autonomic failure (Shy-Drager syndrome) or hyperreflexia, Babinski’s sign, ataxia, and peripheral neuropathy (multisystem degeneration).

Parkinsonism can manifest itself in multiple ways that can lead to disability. Patients with Parkinson disease have a high prevalence of both obstructive and restrictive pulmonary disease. This impairment is clinically relevant, in that Parkinson disease patients with respiratory disease have a decrement in activities of daily living compared with those with normal pulmonary function.⁵² The loss of muscle flexibility combined with the kyphotic posture is thought by some to contribute to the respiratory difficulty.⁵⁷ The speech in a patient with Parkinson disease can be rapid and monotonous, and have low volume with poor articulation and inappropriate periods of silence. Handwriting can become small and cramped (micrographia). As Parkinson disease advances, dementia and depression can occur.³ Autonomic dysfunction with increased salivation, drooling, orthostasis, increased perspiration, constipation, hyperreflexic bladder with incontinence, dysphagia, and erectile dysfunction can also be present.⁴

Prognosis

From a prognostic point of view, tremor-predominant patients tend to progress at a slower pace than those individuals with gait or postural instability as a primary complaint.⁴³ Tremor in general is not considered as disabling as bradykinesia. Akinesia can portend a more rapidly progressing disease process.³¹ Positive prognostic indicators include early tremor, rigidity, and a family history of Parkinson disease. Negative prognostic indicators include bradykinesia, akinesia, postural instability, gait dysfunction, cognitive deficits, and late age of onset. Laboratory, radiologic, or physiologic studies to date have not improved our prognostic acumen. Medical treatment, such as with levodopa, can affect quality of life.⁶⁷ Treatment with carbidopa-levodopa can improve quality of life in the short-term, but long-term use can be associated with the reemergence of symptoms, which adversely affects the quality of life. Life expectancy is variable,⁴³ but significantly improved with medical management.⁴⁷ Dysphagia is considered the most important risk factor associated with early death.

Medical Management

Pharmacologic treatments of Parkinson disease intervene with three different aspects of the disease: slowing of disease progression, symptomatic relief of motor symptoms, and amelioration of nonmotor manifestations. At times, additional medications are required to address the adverse effects of antiparkinsonian treatments.

Several agents have been touted as neuroprotective agents in Parkinson disease, but no single drug is universally accepted as disease modifying. The antioxidant vitamin E failed to demonstrate benefits in a large multicenter trial. Another antioxidant, coenzyme Q10, was shown to delay the onset of the need for levodopa treatment in one multicenter study involving 80 patients. The investigators of this study cautioned that their results needed replication in larger studies. Selegiline, a selective monoamine oxidase B inhibitor, was purported to be a neuroprotective entity, but it is currently considered more of a symptomatic agent. Similarly, although dopamine agonists have demonstrated some positive neuroprotective effects on functional neuroimaging examinations, their effect on clinical progression is controversial. Recent research with pramipexole and ropinirole has shown the most promise. Small trials using an infusion of glial cell line–derived neurotrophic factor into the central nervous system have shown conflicting results.⁵⁶

Symptomatic treatment of motor dysfunction has been the traditional medical intervention of Parkinson disease. The two main classes of drugs are dopamine replacements and dopamine agonists. Amantadine has weak antiparkinsonism effects. Anticholinergic medications are occasionally used in younger patients with tremor-predominant disease. Both amantadine and anticholinergic agents are relatively minor contributors to the Parkinson disease armamentarium. Levodopa is a keystone of Parkinson disease treatment. It is decarboxylated to dopamine. Levodopa is typically administered with a peripheral decarboxylase inhibitor such as carbidopa. This combination therapy results in less peripheral availability of dopamine (with a concomitant decrease in peripherally based side effects such as nausea) and increased central nervous system dopamine penetration.

Long-term levodopa treatment is complicated by two challenging clinical entities: motor fluctuations and dyskinesias. Motor fluctuations are a wearing-off phenomenon in which patients notice increased tremor and bradykinesia at the end of a dosing cycle. The predictability of these drop-off periods lessens as the disease progresses.⁵⁹ Younger patients seem particularly vulnerable to motor fluctuations. Treatment strategies for motor fluctuations include dietary interventions and variable dosing schedules. Dyskinesias usually take the form of chorea, but painful dystonias and myoclonus can also occur. Psychiatric symptoms, including florid psychosis, can be observed with levodopa use. Levodopa usually demonstrates high usefulness initially, but when used chronically it tends to have reduced therapeutic effectiveness.³

Because of the potential problems with levodopa therapy, some clinicians choose to use a dopamine agonist as an initial treatment strategy. Agents in this class include pergolide, pramipexole, and ropinirole. Although these medications often have less therapeutic efficacy than levodopa, they rarely cause dyskinesia. As noted, there is some suggestion that these agents might have a neuroprotective effect on disease progression. Side effects of dopamine agonists include nausea, vomiting, orthostatic hypotension, and psychiatric symptoms. Because patients can have individualized responses to these agents, switching between medications in this class is commonly done. Another factor that might have clinical relevance is that these agents are more expensive than levodopa therapy. Because of their potential disease-modifying effects and their enhanced utility in mild disease, these agents might be also the preferred drugs in younger and healthier individuals. One randomized trial supported either levodopa or pramipexole as a reasonable option for initial therapy in Parkinson disease, but each drug was associated with different efficacies and adverse effect profiles.²¹

Nonmotor symptoms of Parkinson disease, such as orthostasis, sphincter dysfunction, and depression, are also targets for pharmacologic intervention. Treatment options for orthostasis include increased salt and water intake, or the use of midodrine or fludrocortisone. Neurogenic bowel function in Parkinson disease usually presents as constipation, and is amenable to treatment with increased hydration, bulk-forming agents including dietary fiber, stool softeners, and chemical or mechanical rectal stimulation. Hyperreflexive bladder activity can be treated with anticholinergic agents or α-adrenergic blocking agents, although both classes can exacerbate orthostasis. Depression is usually addressed with selective serotonin reuptake inhibitors, but therapy needs to be carefully monitored, because there are reports that these agents have worsened Parkinson disease symptoms. Venlafaxine might be particularly useful because this agent can increase blood pressure. Tricyclic antidepressants can be considered, but one should choose one with low anticholinergic side effects, such as desipramine. Differences in effectiveness between the classes of antidepressants for patients with Parkinson disease have yet to be demonstrated.⁶¹

Rationale for Rehabilitation

Although rehabilitation services are often given to the patient with Parkinson disease, this occurrence is based more on common practice rather than clear research data.^22,34,64 There is a paucity of well-designed research studies looking at specific rehabilitation techniques. The existing literature is both sparse and fraught with confounding variables such as changes in medication regimens. A recent review examined 11 studies involving various physical therapy techniques in Parkinson disease. The authors found insufficient evidence to support or refute the efficacy of any form of physical therapy over another form.¹⁰ There was also insufficient evidence found to support the efficacy of any therapy compared with no therapy. Perhaps the best designed study was a prospective randomized crossover investigation of 4 weeks of outpatient physical therapy, in which medication changes were not allowed. This study demonstrated significant improvement in activities of daily living and motor function, but no improvement in tremor, mentation, and mood. These improvements returned to baseline 6 months after termination of the intervention. Long-term rehabilitation programs have been advocated, but the stability of the benefits gained in these programs has not been demonstrated.⁴²

Exercise and Muscle Physiology

When prescribing an exercise program, one has to take into account the patient’s underlying physical condition. Patients with Parkinson disease appear to exercise with decreased metabolic and mechanical efficiency.²⁶ This disadvantageous situation might be amenable to treatment with aerobic conditioning.⁵³ It appears that prescribing conditioning exercises to patients with Parkinson disease is useful only in the setting of an optimized medication regimen. The specific exercises have not been proven or agreed on. It might also be difficult for patients with Parkinson disease to exercise with sufficient intensity to achieve a training effect.⁴⁹ Careful attention to safety is needed when prescribing aerobic conditioning exercises, because patients with Parkinson disease are at high risk for falls. They typically require a supervised environment when using moving equipment such as a treadmill. Improvements in mood and dyskinesias have been reported with the use of aerobic conditioning.⁵⁰ Neck tone has been found to play a significant role in the patient’s functional mobility,¹⁷ and abnormal postural tone is an important contribution to balance and mobility disorders in patients with Parkinson disease. Therapy geared toward this tone could be a key to treatment.

Psychosocial and Cognitive Concerns

Depression is common in patients with Parkinson disease, with an estimated prevalence of 47%.⁷⁰ Some authors feel that depression significantly contributes to the cognitive dysfunction.³³ Depression can be related to a deficit in serotonergic transmission²⁵ or to diminished cortical levels of noradrenaline (norepinephrine) and dopamine.⁵⁵ The presence of depression adds significant disability beyond that attributed to motor dysfunction.⁷¹

No individual psychologic technique appears to have superiority over another with respect to improvements of mood status. As discussed further below, mental imagery and biofeedback can play a part in improving motor performance during rehabilitation. Some of the techniques reported for mood dysfunction in patients with Parkinson disease include individual, group, and family counseling. Social impairments include loss of autonomy and isolation. Many centers have support groups that are useful in educating patients and their families. Antidepressants such as the serotonin reuptake inhibitors have also been used.

Declining cognitive ability often adds to the challenge of treating a patient with Parkinson disease.⁹ As the disease progresses, thought processes become more rigid and preservative. Dementia occurs in 10% to 15% of patients with Parkinson disease and has an increasing incidence with age. Subtle changes in cognition begin to occur even early in the course of Parkinson disease. Decline in motor function and cognitive decline often occur on a parallel course. Deficits in visual perception and verbal fluency have also been reported in some patients with Parkinson disease.⁴⁴

There is little evidence supporting the therapeutic benefit of specific cognitive retraining techniques. The use of the mental imagery of a planned motor task has been purported to improve execution of function tasks, but this has not been fully validated.

Practical Approach to the Treatment of a Patient With Parkinson disease

Parkinson disease is a multifaceted entity that is conceptually amenable to treatment by an interdisciplinary team. This approach allows various disciplines to be involved with the patient, family, and community. The ideal treatment team includes consultation with a neurologist to optimize pharmaceutical therapies while rehabilitation is ongoing.

Formulation of a treatment plan requires that patients with Parkinson disease have an initial assessment of their impairments. A treatment plan should be formulated that addresses these impairments either directly or with compensatory strategies. Assistive devices can be used to improve the patient’s efficiency, independence, and safety. Wheeled walkers might have added benefit over standard walkers.⁸ Education regarding the disease process must be done for patients and their families. Maintenance programs are executed to prevent additional functional loss. Support groups, counseling, education, and the inclusion of the available community resources can be helpful in maintaining function and for avoiding depression and social isolation. Occupational therapy can evaluate the activities of daily living.³⁵ The utilization of lightweight utensils for meals can facilitate smoother and higher velocity arm movements than weighted utensils in patients with Parkinson disease.³⁰

Specific Therapy Approaches for Impairments in Patients With Parkinson Disease

Patients with Parkinson disease tend to assume a stereotypic pattern of gait, station, and posture. Gait tends to be rigid, with few extra motions and reduced arm swing. In some patients a festination phenomenon occurs, in which the short, shuffling steps become more rapid, accompanied by additional trunk flexion. Formal gait analysis has demonstrated that some of the stiffness seen in the gait of patients with Parkinson disease is caused by the pelvis and thorax rotating together en bloc, rather than in the normal reciprocal pattern.

Multiple physical therapy studies have been done that attempt to improve the abnormal gait features of patients with Parkinson disease. The results, however, are limited and controversial.¹⁰ The most commonly used technique is the addition of external sensory cues that are timed with step initiation or step maintenance. These prompts have taken the form of tactile, auditory, or visual modalities, and both single and multiple cues are being explored.^13,23,65 It is likely that strength training alone is insufficient to improve gait or to have any significant additive benefit to the cuing techniques.²¹ Preliminary investigation using body weight–supported treadmill training has shown promise, but long-term benefit has yet to be observed.^35,36 Compensation strategies for overcoming obstacles improved with programs that emphasized whole-body movement and trained anticipation obstacles.²⁶

The disability impact of the tremor of Parkinson disease is variable but is often mild. This is partly because the tremor is usually at rest, and is frequently reduced or eliminated by voluntary movement. Severe tremor can be addressed with medication as well as rehabilitative techniques. The method most often used is behavioral intervention, including both biofeedback and relaxation techniques. This strategy capitalizes on the observation that tremor is worse during anxious periods. Surface electromyography can be added to the biofeedback paradigm.²⁹

Orthostatic hypotension is a frequent complaint among patients with Parkinson disease, and many have orthostasis without being symptomatic.⁵⁸ This is caused by autonomic dysfunction that probably results from a relative sympathetic denervation.¹⁸ Tilt table training is necessary in some patients with severe orthostasis. Milder cases can be treated with measures such as arising slowly, pausing in a sitting position before arising from a supine position, and performing isometric contraction before changing positions. Pressure garment stockings and abdominal binders can also be used to mechanically control the drop of blood pressure. The use of pharmacologic agents might be indicated if these measures fail.

Many patients with Parkinson disease can benefit from a referral to a speech and language pathologist. Speech abnormalities observed in these patients include hesitancy, hypophonia, hyperfluency, stuttering, palilalia (rapid and involuntary word repetition), extended pauses, and trailing off. The strategy most commonly cited as being of utility in the dysarthria of Parkinson disease is the phonatory–respiratory effort model or Lee Silverman Voice Treatment.⁴⁸ This technique uses the “think loud, think shout” approach, although this method has been criticized for causing a strained or pressed voice. Other techniques that might be of use include breath control, oral-motor exercises, and imagery. Surface electromyography is occasionally added as a biofeedback device in voice therapy.⁶⁶

Patients with Parkinson disease can have problems in all three phases of swallowing. The videofluoroscopic swallowing study remains the criterion standard for the diagnostic evaluation of dysphagia.³⁷ Many patients report difficulty in attaining appropriate oral intake because of prolonged chewing. Other oral-phase abnormalities observed in these patients include excessive postswallow residuals, poor bolus control, and repetitive tongue motions. In the pharyngeal phase, vallecular and piriform pooling, delayed triggering of the swallow reflex, and delayed laryngeal elevation have been observed on videofluoroscopic swallowing studies. There is insufficient evidence to support or refute the utility of dysphagia training in patients with Parkinson disease, although smaller studies have demonstrated some benefit.¹⁰ Dysphagia training techniques typically include using foods mechanically altered with the use of viscous liquids, chin-down positioning, oral-motor exercises, electromyography, biofeedback, and verbal prompting.¹¹ Clinicians might also choose to administer antiparkinsonian medications before meals, so that maximal benefit of drugs occurs during mastication. Patients with severe or rapidly progressive dysphagia should be counseled on the use of enteral feedings in advance of the need for them. This allows the patient to make an informed decision before the onset of a swallowing-related medical emergency (see Chapter 27).⁴⁵

It is also important for the patient with Parkinson disease to maintain an independent lifestyle, whether at home or at work. An occupational therapy evaluation is often very helpful to patients in helping them maintain as independent a lifestyle as possible. The use of exercise and activities of daily living equipment is usually critical to lifestyle maintenance. Equipment such as raised toilet seats and grab bars can assist in making movement more fluid and more efficient, and safe. Home exercise programs are key in maintaining activity. The patient’s home environment should be studied, and obstacles such as throw rugs and excessive or bulky furniture might need to be removed to permit improved mobility. During and after periods of illness, it is important to fight off the effects of deconditioning by maintaining range of motion, deep breathing, and as much activity as possible.

Huntington Disease

Huntington disease is a relentlessly progressive, adult-onset, autosomal dominant disorder that is associated with cell loss within a specific subset of neurons in the caudate nucleus and putamen. It was first described by George Huntington in 1872. The cardinal features of Huntington disease include involuntary movements, dementia, and behavioral changes.

The estimated prevalence of Huntington disease in the United States is from 4.1 to 8.4 per 100,000 people. A few isolated populations worldwide have an unusually high prevalence of Huntington disease. The disease is typically diagnosed in the third and fourth decades of life, and the mean life expectancy after diagnosis is 20 years. Pneumonia and cardiovascular disease are the most common primary causes of mortality. The molecular underpinnings of Huntington disease are still being elucidated. Repeats of the trinucleotide CAG (cytosine-adenine-guanine) result in a polyglutamic expansion within the protein huntingtin. Although the normal function of huntingtin is not known, mutant huntingtin clearly leads to a neurodegenerative cascade.^15,20

Chorea, defined as excessive, abrupt, irregular, spontaneous, involuntary movements, is the hallmark of Huntington disease. This movement disorder might initially appear as an exaggeration of gestures or expressions. This appearance can progress to an unstable “dancing,” and ultimately to a continuous barrage of generalized movements. At times, large-amplitude, flinging, proximal movements of a limb (ballism) can be observed. Alternatively, chorea can be intermixed with slow distal writhing movements called athetosis. In late-stage disease, chorea is gradually replaced by more classic Parkinson-like features including bradykinesia, rigidity, and postural instability.

The cognitive-behavioral aspects are widely variable. The cognitive decline can mimic subcortical dementia, with initial manifestations of intellectual decline and memory dysfunction. As the disease progresses, patients can develop disorders of attention, and decreases in visual-spatial processing and executive function. Language abilities are typically preserved until the final stages of disease.

Depression is the most common psychologic dysfunction encountered, with mania, psychotic personality, and obsessive-compulsive disorders also possible.

Medical treatment for Huntington disease is somewhat limited. Although there are ongoing early clinical trials of neuroprotective agents, most treatments are aimed at symptom relief. In August 2006 the Food and Drug Administration approved tetrabenazine (Xenazine) for the treatment of jerky, involuntary movements associated with Huntington disease. It is the first medication to be specifically approved for this use in the United States. It promotes the early metabolic degradation of dopamine.^41,60,72 Side effects include drowsiness, nausea, restlessness, dizziness, and depression. It should not be taken by patients with diagnosed depression, especially those with suicidal thoughts. Other medication options for chorea include benzodiazepines, valproic acid, dopamine-depleting agents, and neuroleptics. The last two classes of medication have the possibility of worsening other aspects of the disease, such as the bradykinesia or rigidity. Antidepressant therapy is commonplace in Huntington disease, with selective serotonin reuptake inhibitors being the most frequently used. Other psychotropic medications can be used for the various behavioral abnormalities observed. Current research efforts are focused on therapeutic strategies to strengthen antioxidant defenses to prevent the progression of the disease, and gene therapy.

Although the potential for benefit for rehabilitative therapy in Huntington disease would appear reasonable, recent studies suggest that these patients are typically not referred to allied health professionals. One study reported referral rates of 8% to physical therapy, 25% to occupational therapy, and 0% to speech and language pathology. A survey of physical therapists showed that only 16% of physical therapists have ever treated a patient with Huntington disease, and only 6% have treated more than one. Multiple studies have described specific therapy techniques, but most are observational studies with few participants and do not use valid or reliable outcome measures.

Chorea itself appears resistant to rehabilitative techniques. Perhaps the rehabilitation problem with the greatest body of data is Huntington disease–related dysphagia. The methodology of the dysphagia treatment studies is somewhat problematic, but there is a suggestion that some positive training effects can be observed. Although it is reasonable to extrapolate that other impairments of Huntington disease are amenable to modification by rehabilitation, there is a paucity of literature to support specific recommendations.²

Hereditary Ataxias

Another class of motor neurodegenerative diseases includes the hereditary ataxias. The most common syndrome in this category is Friedreich ataxia, and it will be used as a model for discussion in this section. Other neurodegenerative processes can have ataxia as a predominant feature, including the spinocerebellar ataxias, Wilson disease, and Refsum disease. Accurate diagnosis is fundamental because some treatable abnormalities can also present with ataxia as the principal characteristic (including tumors, vascular malformations, and vitamin E deficiency).

Friedreich ataxia is a progressive disorder with the presentation of limb and gait ataxia with diminished muscle stretch reflexes, joint position sense, and vibratory appreciation. Comorbidities of Friedreich ataxia can include impaired glucose tolerance, cardiomyopathy, dysarthria, dysphagia, scoliosis, foot deformities, lower limb weakness, and optic atrophy. The disorder typically presents in the teens, with loss of ambulation occurring 20 years after disease onset. More than 95% of patients are wheelchair users by the age of 45 years. Premature mortality occurs because of aspiration or complications from diabetes. This disease also has a trinucleotide expansion in the FRDA gene, which encodes the protein frataxin. The prevalence of Friedreich ataxia is estimated at between 2 and 5 per 100,000, with a higher incidence in the white population compared with Asians or Africans. The hereditary pattern is classically autosomal recessive. As with many of the neurodegenerative diseases, medical treatment of Friedreich ataxia is inadequate. Comorbid diseases such as diabetes should be treated aggressively. Small clinical trials with 5-hydroxytryptophan and coenzyme Q have shown some partial success in slowing the progression of the disease.

Similar to many of the movement disorders, the evidence basis for rehabilitative interventions in the hereditary ataxias is sparse. Anecdotal reports describe the use of such techniques as weighting of the ataxic extremities, functional strengthening, and tension-controlled gait aids.¹⁹ As the paraparesis of Friedreich ataxia progresses, wheelchair prescription and family teaching are needed. Psychologic support is certainly indicated, as it is with all progressive diseases. Psychotherapy and comprehensive genetic counseling should be made available to the entire family.

Hereditary Spastic Paraparesis

Hereditary spastic paraplegia, also known as familial spastic paraplegia and Strumpell-Lorrain syndrome, describes a group of inherited disorders in which the primary symptoms are progressive bilateral lower limb spasticity and weakness. These disorders were first described by Strumpell in 1883, and later in more detail by Lorrain. They are characterized by clinical and genetic heterogeneity, and occur in an estimated 1.5 to 2.7 per 100,000 people worldwide when strict clinical criteria are used. Hereditary spastic paraparesis is caused by axonal degeneration in the spinal cord, maximally at the terminal portions of the corticospinal tracts in the thoracolumbar region and dorsal column fibers in the cervicomedullary region.

Hereditary spastic paraparesis is classified according to clinical symptoms, age of onset, mode of inheritance, and genetic linkage. Clinical classification includes an uncomplicated (spastic paraparesis only) type and a complicated (paresis plus other neurologic findings) type. Spastic paraparesis is categorized as type 1 when the age of onset is before 35 years, and type 2 if the onset is after the age of 35. Classification by mode of inheritance includes three categories: autosomal dominant, autosomal recessive, and X-linked.⁶⁷

The classic presenting symptom in hereditary spastic paraparesis is progressive difficulty walking that occurs secondary to the principal clinical features of lower limb spasticity and weakness; however, considerable symptom variability can occur. It is estimated that 30% of those with genetically diagnosed hereditary spastic paraparesis remain asymptomatic throughout their lifetime. Life expectancy is typically unaffected.

The cardinal features are symmetric lower limb spastic paresis and extensor plantar responses. A common early symptom is leg muscle stiffness and “spasms” that occur more commonly at night, after exertion, or in cold weather. Hypertonicity, spasticity, and/or hyperreflexia can occur without weakness, especially early in the course. Weakness most commonly occurs in the tibialis anterior, hamstring, and iliopsoas muscles. These clinical findings can begin at any age from early childhood to old age, with variable progression of symptoms. Additional common clinical findings in uncomplicated hereditary spastic paraparesis include urinary symptoms in up to 50% of patients and sensory disturbances in 10% to 65%. Less common clinical features include pes cavus, sphincter dysfunction, upper limb dysmetria, and neurocognitive deficits. Uncommon clinical features in uncomplicated hereditary spastic paraparesis include paresis and hyperreflexia of the upper limbs and distal amyotrophy. Complicated hereditary spastic paraparesis can present with a host of neurologic features, including seizures, dementia, cataracts, adrenal insufficiency, extrapyramidal disturbances, optic neuropathy, retinopathy, deafness, mental retardation, ichthyosis, cutaneous abnormalities, peripheral neuropathy with or without atrophy of intrinsic hand and feet muscles, cranial nerve dysfunction, bulbar muscle weakness, and sensory impairment.

The diagnosis of hereditary spastic paraparesis is made clinically and is one of exclusion. Laboratory testing has focused on genetic analysis. Genetic analysis is used to confirm the diagnosis and assists in genetic counseling. Neuroimaging studies are also used to assist in excluding alternative diagnoses. Magnetic resonance imaging of the spinal cord might show normal findings or atrophy in the thoracolumbar regions. Magnetic resonance imaging of the brain usually shows normal findings. The results of electrophysiologic studies are usually normal in uncomplicated hereditary spastic paraparesis.

Treatment of hereditary spastic paraparesis is symptomatic only, with no current treatment available to prevent, retard, or reverse the underlying degenerative process. Modulation of the hypertonicity can be attempted pharmacologically with oral, neurolytic, or intrathecal interventions. The mainstay of therapeutic intervention is the implementation of physical therapy. Therapy treatments for spasticity include cold application, manual stretching techniques, splinting, serial casting, posture and body mechanics training, aerobic conditioning, and gait and dynamic balance training. Therapeutic exercise is helpful in retraining or improving muscle strength, minimizing muscle atrophy, increasing endurance, reducing fatigue, preventing spasms and cramps, and maintaining or improving range of motion (see Chapter 30).¹²

Gait training is best done after an evaluation for lower extremity bracing and assistive devices to facilitate mobility, independence, and prevention of falls. Given the progressive nature of the disease, an integral aspect of treatment is psychologic support and social services.^16,67

Dystonia

Dystonia is a movement disorder characterized by muscle contraction resulting in twisting, turning, and posturing. Dystonia can be generalized, focal, and segmental (affecting two or more adjacent parts of the body). Some patterns of dystonia have been defined as specific syndromes, such as cervical dystonia and blepharospasm. Dystonia can be primary (idiopathic or inherited) or secondary to another process (environmental or basal ganglia disease).

No specific treatment for dystonia has been universally successful. Focal cervical dystonia and blepharospasm are frequently treated with botulinum toxin. General dystonias have been responsive to such medications as those affecting γ-aminobutyric acid (baclofen and clonazepam) and those affecting dopamine (levodopa and bromocriptine). Physical therapy techniques such as therapy, massage, and biofeedback need to be individualized to address each patient’s specific problems and attributes. A continuing focus on range of motion and movement is of benefit.

Tourette Syndrome

Tourette syndrome is a constellation of symptoms including tic disorders and comorbid neurobehavioral problems. The precise pathophysiologic mechanisms for Tourette syndrome are yet to be determined, but most studies support a genetic component and describe it as an inherited developmental disorder of synaptic neurotransmission. Evidence supports an autosomal dominance inheritance pattern. There is a common prevalence across races and cultures, suggesting a common genetic basis. As the clinical criteria have evolved, the estimated prevalence is 0.7% to 4.2% based on observation studies.

The diagnosis of Tourette syndrome is based on clinical findings. Diagnostic studies have not demonstrated consistent findings. The diagnostic criteria for Tourette syndrome from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) include the following:

The diagnosis of Tourette syndrome is often delayed until adulthood. Because the diagnosis of Tourette syndrome can be challenging, diagnosis is delayed an average of 6.8 years.^5,7

Tics are defined as involuntary, sudden, rapid, repetitive, nonrhythmic, stereotyped movements or vocalizations. They vary in severity and duration, and typically wax and wane. Tics often diminish with distraction, relaxation, and when engaged in activities requiring selective attention. They often intensify with anxiety, anger, excitement, stress, and fatigue. Tics are categorized as simple or complex, motor or phonic. Tourette syndrome is the most common cause of inherited tics, but other more progressive neurodegenerative conditions can present with tics, including Huntington disease, neuroacanthocytosis, Wilson disease, and primary dystonia. Tics are the hallmark clinical feature of Tourette syndrome. Two thirds of children with Tourette syndrome can anticipate a significant amelioration of their tics.

The tic disorders in Tourette syndrome are often associated with emotional and behavioral dysfunction. These include obsessive-compulsive behaviors, hyperkinetic disorder (attention deficit–hyperactivity disorder), impulsive and self-destructive behavior, sleep abnormalities, irritability, antisocial behavior, alterations in mood and sexual behavior, phobias, and anxieties. These often compound the overall morbidity of the disease and detract from quality of life. Hyperkinetic disorder occurs in 50% to 75% of those with diagnosed Tourette syndrome. Obsessive-compulsive disorder (OCD) occurs 20% to 60% of the time, in a variable degree of severity. A variety of mood disorders are also associated with Tourette syndrome. These include anxiety, phobias, depression, labile mood, panic disorder, and agoraphobia.

The management of Tourette syndrome is a multifaceted approach aimed at medical management of frequent or disabling tics, treatment of coexisting behavior symptoms, and patient and family education. Drug treatment of tic symptoms is limited to patients with disabling symptoms, because of the potential for side effects. It is frequently difficult to distinguish between medication response and the spontaneous waning of symptoms. The first choices of medications for tic suppression typically are α₂-adrenergic agonists (clonidine) or neuroleptics such as haloperidol or pimozide. Atypical neuroleptics such as risperidone are often used as second-line agents. They interact with both serotonin and dopamine receptors and have fewer extrapyramidal effects compared with neuroleptics or dopaminergic receptor blocking agents. Other pharmacologic options include pergolide, baclofen, and botulinum toxin injections. The use of psychostimulants in the treatment of hyperkinetic disorder in Tourette syndrome is controversial because there is concern that these medications can exacerbate tic behavior. More recent studies dispute this and support the combined use of psychostimulants with α-adrenergic agents when hyperkinetic disorder is associated with tic behaviors. Other pharmacologic agents that have been used include desipramine and bupropion. The most effective treatment of OCD symptoms in Tourette syndrome is with the selective serotonin reuptake inhibitors.

A wide variety of behavioral treatment strategies are used in conjunction with pharmacotherapeutic intervention in the treatment of tic symptoms. There is no clear indication for the utilization of one specific type of behavioral treatment strategy. The most commonly used technique is “massed (negative) practice.” This strategy involves repeated, rapid, voluntary, and effortful performance of an identified tic for a specific period, interspersed with brief periods of rest.^27,46,62,63 Other psychotherapeutic techniques include assertiveness training, cognitive therapy, and self-monitoring.