DIAGNOSIS.

No clinical sign or diagnostic test is unique to MS, but a typical clinical syndrome with typical MRI of the brain or spinal cord and exclusion of other similar illnesses can result in a correct diagnosis very rapidly. MRI of the brain and spinal cord is critical to the diagnosis of MS. It is, however, important to first exclude other potentially treatable causes of the presenting symptoms before making a diagnosis of MS. Box 31-8 show some examples of differential diseases for which screening should be done. The corpus callosum is usually involved in MS, whereas this is not as common in hypoxic-ischemic diseases. This is because this structure receives a unique double blood supply, and with short arterioles, perfusion deficits may be less likely to result in injury.

The whole spinal cord can be imaged with high resolution and phased-array coils, showing abnormalities in 80% to 90% of individuals with MS, usually without accompanying neurologic symptoms or signs. Hypoxic-ischemic disease does not present with spinal cord abnormalities. Incidental spinal cord lesions do not occur with aging and are rarely reported in other immune-mediated disorders. Most individuals with early MS have lesions within the spinal cord. But imaging may not be performed, so they may not be isolated. Spinal cord lesions tend to increase as the number of brain lesions rises; this is associated with higher risk for a second attack and a diagnosis of clinical MS. Ultimately, abnormal brain MRI scans are present in more than 90% of individuals with clinically definite MS. Normal brain MRI scans may represent disease that is relatively restricted to the spinal cord. Reductions in nerve fiber density are seen in the spinal cord, including in otherwise normal-appearing tissue, and are likely related to permanent disability. Axonal loss can be profound in later stages of disease.

Fig. 31-8 shows the plaques seen on MRI. The lesions do not always correlate with the clinical signs, and there can be evidence of focal lesions in the absence of disease. In fact, the vast majority of enhancing lesions are considered to be asymptomatic when they first appear on the brain scan. However, there is a correlation between periods of clinical worsening of the disease and increases in the total number of lesions, the number of new lesions, and the total area of enhancement on MRI.²³ Thus, a single brain MRI scan after a first event is highly prognostic of development of clinically definite MS.¹³⁷ Fig. 31-9 shows an example of aggressive MS over 2 years revealed in MRI imaging.

Contrast enhancement in CT and MRI suggests inflammation but is more accurately a measure of leakage of moderate-size molecules across the damaged tight junctions of the CNS endothelium. The enhancement pattern (size, shape, solid versus ring) may be variable within and more so between individuals, which reflects a heterogeneous pathology. Ring enhancement, for example, may suggest a more severe pathology. Fig. 31-10 demonstrates the development of a T2-weighted hyperintense lesion by serial MRI. The correlation between the pattern of enhancement, the underlying pathology, and the clinical course in given individuals may not be straightforward. Monitoring serial MRI studies with enhancement helps to identify agents that may be active against the early inflammatory stage of MS.¹⁷⁰

Individuals with MS have significant atrophy of both white matter and grey matter. Atrophy is considered an important measure in MS because it likely reflects in most cases irreversible injury, much of which is from axon loss, but with additional contributions from myelin loss and structural changes from astrogliosis. The demyelinated cortex contains apoptotic neurons. Cortical demyelination could affect neurons, dendrites, and axons, which may lead to disease progression. The cerebral cortex may be affected by tissue loss and atrophy, particularly in areas adjacent to severe white matter pathology. Neurons in such lesions may show signs of retrograde damage as described earlier. Fig. 31-11 shows changes related to progressive forms of MS.

Functional MRI maps the brain areas activated using a task paradigm. Functional disturbances have been the basis for hypotheses suggesting that compensatory mechanisms develop in early MS, which initially may mask injury and delay the appearance of dysfunction. Functional disturbance may only become apparent after exhaustion of these adaptive mechanisms. Fatigue severity is correlated with the reduction in thalamic and cerebellar activation. Although abnormal functional MRI patterns may be observed in given individuals with MS, their interpretation may not be straightforward. Functional MRI findings reflect functional adaptation, they do not necessarily serve as direct evidence for grey matter pathology.

Functional MRI appears to identify sensorimotor and cognitive disturbances in MS. The most consistent finding by functional MRI studies in populations of individuals with MS is impairment in sensorimotor activation indicated by abnormally increased contralateral blood oxygenation level and ipsilateral supplementary motor activation. Sensorimotor functional MRI is sensitive even in the early stages of disease.

Measures of regional brain atrophy are useful to determine neuropsychologic dysfunction. Imaging data suggest that neuropsychologic impairment in MS is related, in part, to atrophy of grey matter regions and in the juxtacortical areas. Grey matter atrophy has been associated with impairments in verbal memory, euphoria, and disinhibition.

Whole-brain atrophy reflects the destructive aspects of the disease. The data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is a major determinant of disease progression, whereas white matter lesion activity has less correlation. The strongest correlations between MRI measures and disability may be those provided by atrophy measures. Confounding factors must be considered when assessing whether loss of brain volume directly indicates tissue atrophy. Secondary progressive disease causes significantly more atrophy of both white matter and grey matter and a significantly higher lesion load than relapsing-remitting disease.¹⁷⁴ Primary progressive disorders show decreased numbers and volume of enhancing lesions, related to the less intense inflammation. Spinal cord pathology has been hypothesized to be an important factor in disease progression in primary progressive MS but is not always predictive (see Fig. 31-11).

Cellular imaging based on superparamagnetic iron oxide–tagged cells is a more specific probe of the migration occurring at the level of the blood-brain barrier basic to the inflammatory process. The superparamagnetic iron oxide particles are used to follow macrophages as they pass into the CNS. The particles exert a strong influence on the local magnetic field, which is detected as signal loss on T2-weighted and T2-weighted pulse sequences. The location of lesions and their time course based on superparamagnetic iron oxide imaging does not correlate strongly with that based on conventional contrast-enhanced MRI, suggesting that it provides different quantitative and qualitative information. Studies of fiber degeneration and connections between lesions and fiber pathways are becoming feasible in the clinical imaging environment through diffusion tensor MRI.

Although the mechanisms that contribute to brain atrophy are unclear, degenerative processes that underlie brain atrophy will hopefully provide novel therapeutic targets to help individuals. Several initiatives are under way to define criteria for successful or acceptable treatment versus treatment failure, based on both clinical and MRI activity. MRI monitoring may increase confidence in a clinical impression of stable disease or help discount borderline symptoms or signs, supporting maintenance of the current therapy. MRI activity may support a clinical impression or uncover a need to initiate aggressive and more risky therapy with immunosuppressive agents.

CSF analysis often shows increased mononuclear cell pleocytosis, an elevation in total immunoglobulins, and the presence of oligoclonal bands. These responses suggest an inflammatory response in the CNS. In 85% to 95% of individuals with clinically definite MS, these values are abnormal. In people with suspected MS, the number is much lower. Abnormal values, including oligoclonal bands, also may be seen in a smaller percentage of those with a variety of disorders, especially other inflammatory or infectious disorders that may affect the CNS. Metabolites from the breakdown of myelin may also be detected in CSF but are very nonspecific. Measurement of these myelin basic proteins in CSF is more useful as a predictor of response to steroids used during acute exacerbations than as a diagnostic tool.

Evoked potential response testing may detect slowed or abnormal conduction in visual, auditory, somatosensory, or motor pathways. These tests employ computer averaging techniques to record the electrical response evoked in the nervous system following repetitive sensory or motor stimuli. Evoked potentials are abnormal in up to 90% of individuals who have clinically definite MS. Testing can provide evidence of a second lesion in an individual with a single clinically apparent lesion, or it can demonstrate an objective abnormality in a individual with subjective complaints and a normal examination.

Myelography and CT are both insensitive to the pathologic changes in MS and should not be used where the diagnosis of MS is a possibility. Both may still be used to rule out other disorders that mimic MS symptoms.

TREATMENT.

Keeping an activated immune system from getting to the central myelinated fibers slows the process of demyelination in MS. Therefore, the principle of treatment in MS today revolves around immune modulation. Different steps of the pathologic cascade in MS may eventually be targeted therapeutically for optimal treatment of MS. Understanding the inflammatory process in MS is important, because it is becoming clear that inflammation includes destructive components that should be targeted for inactivation and potentially beneficial mechanisms that should be enhanced or not disturbed by treatment. Despite earnest research efforts, there is no cure for or immunization against MS.

Current drug therapy can diminish approximately one third of the attacks in the actively affected MS population 2 years beyond onset. The “ABC” drugs are used. A is for interferon beta-1a (Avonex, Biogen Idec), and B is for interferon beta-1b (Betaseron, Berlex Laboratories). The higher the dose of interferon, the more potent is the response. Rebif, another interferon beta-1a drug, is used in higher doses. Rebif is given subcutaneously at a 46% higher dose three times weekly, for a total of 4.4 times as much drug as Avonex. The potent antiinflammatory effects of interferons have a dramatic effect on the MRI scans, with a decrease in contrast-enhancing lesions.^101,106 Interferon beta-1a also has been shown in relapsing individuals to slow progression of disability, brain atrophy, and cognitive dysfunction.⁸⁸ The treatment effect can be delayed by at least several months. This delay might indicate the fact that the atrophy occurring in the first months is the culmination of a cascade of events that began before the onset of therapy. Alternatively, the ongoing loss of brain volume might be the result of “pseudoatrophy,” such as that due to treatment-related resolution of brain edema and inflammation. Proposed mechanisms by which interferon might limit brain atrophy include increasing nerve growth factors, limiting immune-mediated destructive inflammation, and limiting toxic mechanisms such as pathologic iron deposition.¹²² Thus, the question remains as to whether controlling acute relapses and inflammation will ultimately be adequate. Other factors may have an influence on demyelination and axon injury.¹³⁴

The C drug, glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) is a polypeptide that appears to fool the immune system. It seems to decrease the attack by blocking immune cells headed toward myelin and thereby preventing damage. It also has a partial and delayed but significant effect of limiting the rate of brain atrophy in relapsing-remitting MS. Glatiramer acetate has gained wide acceptance as one option for the treatment of relapsing-remitting MS as there is less occurrence of the flulike symptoms that are associated with the interferons. Although its precise immunologic mechanisms continue to be investigated, current views suggest that its principal effect may be mediated by a shift from a proinflammatory cell bias to an antiinflammatory cell bias. Ongoing studies are exploring the possibility that glatiramer acetate confers neuroprotection and are seeking novel ways to use the agent alone or in combination with other medications.¹²⁰ Localized panniculitis or inflammation of lipid stores at the sites of subcutaneous injections seems to be a rare but characteristic side effect.

Mitoxantrone (Novantrone, Immunex) is used to modify relapsing and secondary progressive MS. Mitoxantrone is the only drug approved for treatment of secondary progressive MS. It presumably works by depression of T-cell counts and removal of activated T cells from the immune repertoire. Because of potential side effects, its use is being limited at present to individuals whose MS is clearly advancing in spite of aggressive ABC therapy or who already are in a secondary progressive phase. The ABC drugs have not yet been found conclusively to be helpful in secondary progressive disease, and no drugs have been found effective in primary progressive disease.¹⁶⁹

Natalizumab (Tysabri) is a monoclonal antibody that prevents immune cells from moving from the blood to the CNS. It was originally approved by the FDA based on a dramatic lowering of relapse rate and a 50% reduction in the development of a sustained increase in disability. This treatment is a once-monthly intravenous infusion. Unfortunately, shortly after approval of the treatment by the FDA, there were two fatal cases of progressive multifocal leukoencephalopathy (PML) when it was used in conjunction with interferon beta-1a. As a result, the distribution of natalizumab was halted, pending further evaluation. Studies continue, and it may emerge again for use in treating MS, perhaps as a monotherapy.¹⁸⁷

Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing MS. Its final effect is also to reduce the normal circulation and trafficking of leukocytes. It also nears the 50% mark for decreasing the mean cumulative number of lesions. A phase III trial is under way to definitively assess clinical efficacy. Encephalopathy is a risk, and fin golimod is also associated with an initial reduction in the heart rate.⁹²

Despite the time and effort given to slow the disease, the bulk of current intervention is devoted to symptomatic management. Improvement in the ability to control symptoms through therapy and medications can enhance quality of life in the individual with MS. Amantadine, pemoline, modafinil, and other medicines can reduce fatigue. Depression and sleep disorders may contribute to fatigue and must be recognized and treated appropriately. Centrally acting and peripherally acting muscle relaxants, such as baclofen (Lioresal), tizanidine, and dantrolene, decrease hypertonicity and leg spasms. Anticonvulsants and antidepressant medicines are used to treat pain. Intrathecal baclofen pumps reduce severe spasticity. Oxybutynin and tolterodine diminish bladder hyperactivity. Focal injections of BTX can be helpful in decreasing muscle spasticity.¹ Repetitive transcranial magnetic stimulation may improve spasticity in MS. The antiepileptic agents and antidepressant treatments often are effective in modulating the painful symptoms. Gabapentin in relatively high doses often is necessary for the desired effect. Spasms occurring during the day usually are handled best by the addition of the antiepileptic medications, including gabapentin and topiramate.

Amitriptyline is helpful, especially at night as it can sedate and provide pain relief. Clonazepam, given at bedtime, can aid in sleep initiation and decrease spasms with minimum side effects. Diazepam has a similar effect. Dose escalation should be avoided. Dopamine agonists and dopamine itself also decrease nocturnal spasms reasonably effectively at low dosages.

All of these treatments require adjustment from time to time to maintain some relief. All medications currently available to control symptoms of MS have potential side effects and therefore must be used judiciously. Careful monitoring of systems affected by MS is essential to medical management.¹⁵⁷

Both corticosteroids (prednisone, cortisone, methylprednisolone) and adrenocorticotrophic hormone (ACTH) are known to shorten the recovery period after an acute MS attack. There appears to be no consensus about the optimal form, dosage, route, or duration of corticosteroid therapy, but there is now a consensus statement from the American Academy of Neurology regarding treatment of acute optic neuritis with methylprednisolone. Oral prednisone should not be used. Corticosteroids can alter almost every aspect of the immune system. Corticosteroid-induced restoration of the blood-brain barrier, which becomes less effective during active demyelination or plaque formation, has an antiedema benefit and may prevent circulating toxins, viruses, or immunoactive cells from entering the CNS. Decreased activity of the macrophages and lymphocytes results in less damage to the myelin in response to steroid therapy.⁶¹ Individuals with severe demyelination who do not respond to corticosteroids may improve with plasma exchange.^95,194

Based on the rapid advances in our understanding of the immunopathogenesis of MS, a variety of experimental approaches presently are under study. These include the hormonal agent estriol, matrix metalloproteinase inhibitors, statin drugs, adhesion molecule antibodies, T-cell peptides, combination therapies (especially ABC drugs with other types of agents), intravenous immunoglobulin, and stem cell transplantation. All these are preventive, not restorative of previously damaged CNS function. Growth factors that enhance CNS remyelination are being studied as a method to restore the loss of oligodendrocytes in MS.¹³⁹ Findings of neural stem cells in the adult CNS and the potential of blood-derived stem cells to become neural cells offer the possibility of transplanting cells into the CNS that will restore function. Studies on intense immunosuppression with bone marrow transplantation (autologous and stem cell) continue, but results are not positive enough to recommend its use.

PROGNOSIS.

The average frequency of attacks of MS is approximately 1 per year. The attacks vary in severity; therefore close observation is required to reliably track the attack frequency. Attacks tend to be most common in the early years of MS and become less frequent in later years, regardless of the disability. The risk for rapid development of moderate disability may be greater in persons in whom the frequency of attacks is higher than average.

Multiple factors may predict a severe course, such as motor and cerebellar symptoms, disability after the first attack, and short time interval between attacks. Numerous relapses within the first year negatively influence the clinical course. Conversely, sensory symptoms, infrequent attacks, full neurologic recovery after a relapse, and a low level of disability after 5 to 7 years may be associated with an improved prognosis.

Burden of disease on MRI scans may be the strongest predictor of clinical outcomes. Over 14 years, there was no significant disability accrued in individuals with normal MRI findings at the time of diagnosis, whereas MRI scans with greater than 10 lesions predicted that individuals would require a cane for walking within that same time frame. A change in lesion load within the first year also is a negative predictor of outcome. Late-onset MS is not necessarily associated with a worse outcome. Progression of primary progressive and relapsing MS differed little between late-onset and early-adult-onset disease. The individuals with late-onset disease were older when reaching an Expanded Disability Status Scale score of 6.¹⁸³

Because disability is often significant in individuals with MS, lifestyle changes are frequently necessary. Movement impairment is frequently associated with MS, and difficulty in walking is a major disability. If MS is untreated, 15 years after diagnosis 50% of individuals with MS will require the use of an assistive device to walk, and at 20 years 50% will be wheelchair bound. About one fourth of persons with MS will require human assistance with ADLs.⁹⁴

It is the coexistence of physical and cognitive impairments together with emotional and social issues in a disease with an uncertain course that makes MS rehabilitation unique and challenging. Individual rehabilitation improves functional independence but has only limited success in improving the level of neurologic impairment. Severely disabled people derive as much as or more benefit than those who are less disabled, but cognitive problems and ataxia tend to be refractory. Cost and utility are significantly correlated with functional capacity.⁹⁷ There is now good evidence that exercise can improve fitness and function for those with mild MS and helps to maintain function for those with moderate to severe disability. Several different forms of exercise have been investigated. For most individuals, aerobic exercise that incorporates a degree of balance training and socialization is most effective. Time constraints, access, impairment level, personal preferences, motivations, and funding sources influence the prescription for exercise and other components of rehabilitation. Just as immunomodulatory drugs must be taken on a continual basis and be adjusted as the disease progresses, so should rehabilitation be viewed as an ongoing process to maintain and restore maximum function and quality of life.²⁷

Life expectancy is reduced by a modest amount in MS; the risk of dying of MS is strongly associated with severe disability. The death rate in persons who are unable to stand or walk is more than four times that in persons the same age without MS. In mildly disabled individuals, the death rate is approximately 1.5 times that of the age-matched population. Persons with more frequent initial episodes with rapidly developing disability have a poorer long-term outcome. Individuals with primary progressive disease also have decreased life expectancy. Suicide is more than seven times more common than in age-matched controls, and depression must be treated aggressively.

DIAGNOSIS.

The classic triad of major signs of PD is made up of tremor, rigidity, and akinesia.¹⁷⁹ The combination of asymmetry of symptoms and signs, the presence of a resting tremor, and a good response to levodopa best differentiates PD from parkinsonism due to other causes. Diagnostic problems may occur in mild cases. Other movement disorders that do not fall under the category of parkinsonism need to be recognized by clinicians to establish a differential diagnosis. See Box 31-11 for features of parkinsonism due to causes other than PD.

Depression, with its associated expressionless face, poorly modulated voice, and reduction in voluntary activity, may be difficult to distinguish from mild parkinsonism. Olfaction is frequently impaired in PD, suggesting that deficiencies in smell may be a potentially useful test to distinguish PD from related disorders.

CT or MRI is not helpful in diagnosis of PD but can identify other causes of symptoms, such as Wilson’s disease, or mass effects causing disruption of the basal ganglia function, such as stroke or hydrocephalus.

Functional imaging through PET is highly sensitive to regional changes in brain metabolism and receptor binding associated with movement disorders. SPECT shows differences in the posterior putamen, contralateral to the predominantly affected limb. Asymmetric scan findings have been observed in individuals with mild, newly recognized symptoms. Unilateral disease produces a significant difference in striatal uptake between the ipsilateral and contralateral sides in both the caudate and putamen nuclei. One explanation is that there is a preceding unequal functional reactivity of the basal ganglia, which results in an asymmetrical clinical response.

Altropane (a close cousin of cocaine), a component of radioactive technetium 99m, is a compound that can measure the concentration of dopamine transporters imaged by SPECT. This may lead to diagnosis of PD based on identifying decreasing levels in the brains of persons when only mild symptoms appear.

Assessing progression of PD using clinical rating scales such as the United Parkinson’s Disease Rating Scale (UPDRS) is a common way to track progression. However, the progression may be masked by medication, and because of the multitude of symptoms that may change at different rates, it is hard to determine a change in the course of the disease.

TREATMENT.

The current therapeutic approach to PD is symptomatic; major studies to determine possible thera- peutic neuroprotection are under way, but no single intervention has proven to be disease modifying. Drug therapy is adapted to the person’s needs, which may vary with the stage of the disease and the predominant manifestations.⁵ When mobility becomes affected to the degree that walking and self-care activities become difficult, medications improve the control of movement. As the disease progresses over time, the effectiveness of medication changes, leaving the individual with a shorter “on” time during which symptoms are reduced and more rigidity during “off” times when symptoms are active. Long-term use of medication can also increase the dyskinesia or chorea-like movement resulting from the change in activity in the basal ganglia. Side effects can become more problematic as the dosages needed to control symptoms are increased. The management of these medications becomes the focus of intervention.⁵⁹

Levodopa (l-dopa), which is taken up by remaining dopaminergic neurons in the basal ganglia and converted to dopamine, improves most of the major features of parkinsonism, including bradykinesia. Initially it leads to nearly complete reversal of symptoms, with effects lasting up to 2 weeks, known as long-duration levodopa response. As the disease progresses, the length of the effect becomes shorter, it takes longer for the effect to be noticed after dosing, and symptoms increase during the end of the dose period. Eventually there is dose failure or lack of any effect at all. Levodopa can cause dyskinesias that produce chorea, athetosis, dystonia, tics, and myoclonus. Predictable fluctuations include a wearing-off effect and early-morning akinesia. The duration of effect of each dose becomes shorter and will often match the drug’s half-life of less than 2 hours. Although levodopa is the most effective drug for PD, the time to start taking it is controversial. Early use may contribute to greater activity levels and employability but cause more disability at later stages when the effect fluctuates and ultimately decreases. Protein in food uses the same mechanism as levodopa for crossing the blood-brain barrier. When levodopa is given with protein, the protein blocks the ability of the levodopa to cross the blood-brain barrier. This is usually managed by having the individual eat most of the daily protein in the evening, when immobility will cause the least inconvenience. Caffeine administered before levodopa may improve its pharmacokinetics in some individuals with parkinsonian symptoms.⁴⁸ Infusion of levodopa directly into the intestines gives a more stable response but is expensive and invasive. Levodopa should be avoided in persons with malignant melanoma and in persons with active peptic ulcers, which may bleed.

Carbidopa inhibits the breakdown of levodopa and is often used in combination with levodopa. Carbidopa reduces the amount of levodopa required daily for beneficial effects and is often combined with levodopa in a single preparation (Sinemet).

Catechol-O-methyl transferase (COMT) inhibitors are reported to provide smoother and more sustained levels of levodopa to the brain. Of these, entacapone and tolcapone reduce the off time, and allow for decreased dosing of levodopa.¹⁴¹ Liver function must be monitored regularly with the use of tolcapone. Tolcapone must be used with levodopa but can decrease the amount of levodopa needed.

Dopamine agonists act directly on dopamine receptors. Bromocriptine seems to be the best tolerated, and its use in parkinsonism is associated with a lower incidence of response fluctuations. It is often given in combination with levodopa and carbidopa. Pramipexole or ropinirole can be used either to delay starting levodopa or to decrease the amount needed. Transdermal application of dopamine agonists can be provided with rotigotine and lisuride.

Selegiline (Eldepryl) and rasagiline have been used to inhibit monoamine oxydase type B (MAO-B) enzyme in the basal ganglia (MAO-B inactivates dopamine). It was thought that selegiline also may be able to delay the neuronal degeneration, but studies do not support that claim.⁴²

Persons with mild symptoms but no disability may be helped by amantadine. Amantadine is also effective for the dyskinesia that develops later in the course of the disease. Coadministration of levodopa and amantadine controls dyskinesia without disrupting the effect of levodopa.

In the striatum the low level of dopamine is accompanied by increased cholinergic transmission. Accordingly, motor functions in individuals are improved by anticholinergic drugs. The side effects of the anticholinergic medications, including sedation, confusion, and psychosis, limit their usefulness, especially with advancing age. MAO-B inhibitors have replaced the use of anticholinergics in treatment of PD.³⁶

Antioxidants have been studied for neuroprotection, such as coenzyme Q10, which helps stabilize mitochondria and appears to decrease the worsening of symptoms. Trophic factors, antiinflammatories, antiapoptotics, and antioxidants have been identified by the National Institutes of Health for further study for control of neuronal death.

Deep brain stimulation uses a pacemaker-like device surgically implanted with electrodes in the nuclei of choice and a pulse generator implanted in the chest. The generator is controlled externally through a magnetic field. When a tremor begins, the client activates the low-voltage, high-frequency generator by passing a magnet over it. Stimulation through the electrodes can be applied to the internal globus pallidus and the subthalamic nucleus or thalamus. Thalamic stimulation is most effective for tremor, with less effect on dyskinesia and rigidity. Electrode implantation in the globus pallidus appears to have good initial effect; however, there is a chance of psychosis and punding activity over time. Most centers are now stimulating the subthalamic nucleus bilaterally, but the individual’s profile leads the decision. Preoperative response to levodopa predicts better outcome after deep brain stimulation of the subthalamic nucleus. The ability to perform ADLs is improved, and there is typically improved sleep time. Apathy and abulia can occur over time; this may be related to withdrawal of levodopa. There can be an increase in sadness or the opposite response with excessive hilarity that may be related to stimulation of the surrounding area or change in subthalamic limbic activity. Edema around the electrode may contribute to the psychotropic effects. The implant is believed to last approximately 5 years and can be removed if another more effective type of treatment is found.⁸ Bilateral subthalamic stimulation, alone or in combination with levodopa, causes improvement in axial signs for posture and postural stability.

While there is little evidence for drug effect on postural stability and gait disorders, researchers in motor control are making progress in identifying the nature of the abnormal responses both inside and outside of the basal ganglia.¹⁶¹ (See Special Implications for the Therapist: Parkinson’s Disease later in the chapter.) Based on the strong evidence that relates prior exercise and activity status to risk of PD, and the recent knowledge gained about neuroplasticity in the brain, it is likely that changes in postural control may come through interventions that drive neuroplastic changes.

Although orthostatic hypotension affects less than 20% of individuals with parkinsonism, it can limit activity. Use of midodrine, fludrocortisone, and etilefrine can be helpful in maintaining normal blood pressure. Supine hypertension may result and must be monitored. Urinary dysfunction is treated via antimuscarinic agents or αagonists. Anticholinergics or scopolamine patches may be helpful for drooling, and use of intraparotid injection of BTX can help. Constipation is common and may precede the motor symptoms in PD; it is usually managed by fluids, fiber, stool softeners and exercise.

Depression is found in over 40% of individuals with PD. Medication interactions must be looked at carefully. Use of serotonin uptake inhibitors may interact with selegiline. Tricyclics can be useful, but the central effects must be monitored more carefully than in the healthy younger population.

Respiratory complications, which are the leading cause of death, can be prevented to some extent with an early aggressive aerobic exercise program, followed by regular moderate activity as the disease progresses. Control of breathing can be facilitated using verbal and tactile stimuli and should be integrated into any intervention.

Behavioral abnormalities can be associated with high doses of dopaminergic replacement therapy, including the phenomenon of punding, characterized by fascination with technical equipment and excessive sorting of objects, grooming, hoarding, or use of a computer. This may be related to the impaired frontal lobe function and a result of psychomotor stimulation. Other abnormalities in reward-seeking behavior related to dopamine are hypersexuality and excessive gambling. Reducing the level of medication is helpful, and some neuroleptics such as clozapine will lessen symptoms of psychosis.

Experimental therapeutics targeted at improving dopaminergic drugs to increase selectivity for various receptor subtypes and at controlling the uptake of dopamine are currently under study. Improved plasma stability is achieved through transdermal application, which bypasses the fluctuations in gastric release. Studies are aimed at potential substances that evoke antiparkinsonism through neurotransmitter systems outside of dopamine. Pharmacologic manipulation of glutamate and GABA neurotransmission includes the drug istradefylline, which is currently undergoing phase III study.¹³ Opiate, serotonin, and histamine receptors are possible sites for intervention. A more careful look at the cholinergic system may help to manage the issues of dementia and find possibilities for reducing the apparent dysfunction at the level of the brainstem that affects sleep wake cycles and orthostasis.

Cell transplantation of grafted dopaminergic neurons in PD continues to hold promise. The striatum (caudate and putamen) are primary targets for the implants. Individual selection, cell-handling variation in surgical techniques, and immunosuppression currently make it difficult to determine success. Graft-induced dyskinesia much like that associated with long-term levodopa use appears in some recipients. It is not clear which individual will develop the dyskinesia, and at this time there is not any medication to control the abnormal movements. Fetal stem cells remain the most successful; however, alternative types are being studied. There is hope for cells derived from the individual’s own body, but the response has been less than hoped for and the current graft survival is low. Rejection of the graft continues to limit effects, and immunosuppression has to be considered as a possible long-term adjunctive therapy with grafts.¹⁸⁴

PROGNOSIS.

In general, all the clinical manifestations in PD worsen progressively, although not to the same extent. Tremor as a presenting symptom may be used to predict a more benign course and longer therapeutic benefit to levodopa. In individuals with newly diagnosed PD, older age at onset and rigidity/hypokinesia as an initial symptom can be used to predict more rapid rate of motor progression.¹⁷¹

The presence of associated comorbidities, stroke, auditory deficits, and visual impairments as well as male sex may be used to predict faster rate of motor progression. Older age at onset and initial hypokinesia/rigidity may be used to predict earlier development of cognitive decline and dementia. Older age at onset, dementia, and decreased dopamine responsiveness may be used to predict earlier nursing home placement as well as decreased survival. Lack of mobility, loss of balance reactions, and weakness result in more falls than in an age-matched normal population. Osteoporosis can result from prolonged inactivity and may be present secondary to advanced age at onset. Falls more often lead to fractures owing to the prevalence of osteoporosis. Fracture healing may be delayed. Posture and gait abnormalities are the most difficult to control in advanced cases.

PD does not significantly reduce life span in most persons who develop the generalized form between 50 and 60 years of age. However, since there is progressive neuronal loss despite the response to treatment, deterioration continues until death occurs, often from infection or other conditions associated with debilitation.

Since the onset of disease is typically in the fifth or sixth decade of life and is progressive despite medication, the economic cost of the disease can be quite high because of loss of income, cost of drugs, assistive devices, and assisted living. Pain, fatigue, and depression also adversely affect the quality of life compared with that of age-matched normal subjects.¹⁵⁹

Secondary Parkinson’s Syndrome

Parkinsonian syndromes, also called atypical parkinsonism or Parkinson’s plus syndromes, are a family of neurodegenerative disorders that result from neuronal loss in different components of the basal ganglia, the brain system of which the dopaminergic midbrain neurons affected in PD are a part. All of these disorders can be difficult to differentiate from PD early in the course of the illness. These disorders have distinctive clinical features, which may emerge only after the onset of parkinsonism. Important clinical clues that one of these disorders is present are symmetric onset of parkinsonism, absence of typical resting tremor, early autonomic dysfunction, prominent dystonia, significant early cognitive impairment, and prominent early falls.²

Iatrogenic parkinsonism or drug-induced parkinsonism results from the use of pharmacologic agents that block dopamine effects or interfere with dopamine metabolism. The most common causes of drug-induced parkinsonism are dopamine antagonist antipsychotic medications. The risk of drug-induced parkinsonism is reduced significantly with newer atypical antipsychotic agents. Another group of drugs that can cause drug-induced parkinsonism is older (non–serotonin antagonist) dopamine antagonist antiemetics. Agents interfering with dopamine production or synaptic vesicular storage can cause drug-induced parkinsonism. These include methyl-para-tyrosine, methyldopa, and reserpine. Flunarizine and cinnarizine, when they are used as vestibular suppressants or cerebral vasodilators, can cause parkinsonism. Sodium valproate may cause tremor that can progress to parkinsonism. Features of iatrogenic parkinsonism are bilateral onset and predominant bradykinesia with increased involvement in the arm compared to the legs in the younger population, but more consistent with PD in older individuals. If drug-induced parkinsonism is suspected, the suspected offending agent is withdrawn, and the individual should improve. With dopamine antagonists or reserpine, improvements can occur within days to weeks after medication withdrawal, but there is sometimes a prolonged latency of months before marked improvement occurs.

Vascular parkinsonism involves primarily the lower extremities. It is associated with lacunar infarcts (see Chapter 32) and probably represents small infarcts in the basal ganglia or corticobasilar pathways. A stroke in the region of the striatum (caudate and putamen) and hemiparesis of the arm is common. Systemic lupus erythematosus may also cause cerebral vasculitis. Vascular parkinsonism presents typically with start hesitation, a broad-based shuffling gait (rather than the narrow-based gait associated with PD), and frequent falls. Depending on the level of damage and the cause, the response to levodopa will vary.

Infectious causes of parkinsonism are suspected when the symptoms develop during the acute or recovery phase of an illness with fever. Cases of parkinsonism have been reported as a result of West Nile virus infection and have historically been associated with encephalitis. Human immunodeficiency virus (HIV) infection can cause parkinsonism via the viral damage in encephalopathy or opportunistic infections.

Toxicity, often related to manganese accumulation in the substantia nigra, can cause parkinsonism and dystonia, seen in miners, factory workers making dry cell batteries, and those exposed to some fungicides.

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