Atypical Parkinsonism

Fig. 3.1

Brain MRI with the “hot cross bun” sign in a patient with multiple system atrophy (cerebellar type)

Levodopa may have benefits in the early stage of the disease; however, its effectiveness wanes as the disease progresses [2]. Minocycline, a tetracycline with potential neuroprotective effect, did not change the disease course after 24 and 48 weeks of treatment in a randomized double-blind study (Minocycline European MSA Trial) [11]. Recent clinical trials (2013–2015) showed no benefits of treatment with lithium, rifampicin, riluzole, and rasagiline in patients with MSA [12].

Postural hypotension can be addressed with simple practical measures including a high-salt diet, increased fluid intake, use of thigh-high compression stockings and head-of-bed elevation during sleep. If these measures are not sufficiently effective, pharmacological measures include fludrocortisone (0.1–0.3 mg daily), midodrine (2.5–10 mg 3 times daily), and droxidopa (100–600 mg 3 times daily). Urinary incontinence is usually treated with oxybutynin (5–10 mg at bedtime), although its use may be associated with the magnification of any cognitive dysfunction. Constipation may be alleviated using laxatives and high-fiber foods. There are positive reports on the use of sildenafil for erectile dysfunction in patients with MSA [2, 6].

Progressive Supranuclear Palsy

Progressive supranuclear palsy, also called Steele–Richardson–Olszewski syndrome in honor of the three pioneers who identified this nosological entity, is a distinctive and probably underdiagnosed neurodegenerative syndrome. It is the second most common cause of degenerative parkinsonism after PD in most series [13, 14]. The “classic” PSP syndrome, also referred to as Richardson syndrome, is characterized by a higher level (frontal) gait impairment, ophthalmoparesis (predominantly downward gaze palsy without correction with oculocephalic maneuvers [supranuclear vertical gaze palsy]), frontal cognitive dysfunction, and (often tremorless) symmetrical, axial-predominant, posturally impaired parkinsonism with falls occurring within a year of symptom onset [2]. Retrocollis and apraxia of eyelid opening are focal/segmental dystonic manifestations that may be documented in PSP . A subset of patients develops bulbar as well as pseudobulbar manifestations, particularly pseudobulbar affect (emotional incontinence). The prevalence of PSP is age-dependent and estimated to be 6–10 % of the incidence of PD, or 6–7 cases per 100,000 people [15, 16]. PSP has a peak onset at the age of 63 years with no cases reported under the age of 40. The clinically probable diagnosis, which is the highest antemortem category of diagnostic certainty (definitive diagnosis can only be made at autopsy), is usually made 3.6–4.9 years after the onset of clinical signs [15].

There have been increasing clinical, neuroimaging, molecular pathology, and genetic insights into PSP in recent years. It is a tauopathy characterized by deposits of neurofibrillary tangles in the brain that are made of hyperphosphorylated microtubule-associated protein tau. The abnormal tau protein and neuropil threads accumulate in the subthalamic nucleus, globus pallidum, red nucleus, substantia nigra, striatum, pontine tegmentum, oculomotor nucleus, medulla, and dentate nucleus. Although a few familial cases with MAPT gene mutations have been reported, this disorder remains largely sporadic. A genome-wide association study has confirmed that the most common risk allele for PSP is the H1 haplotype of the MAPT gene [15–17].

In the adult human brain, tau protein has six isoforms formed by alternative splicing that are derived from a single gene. Disordered regulation of exon 10 splicing may therefore explain tau aggregation into neurofibrillary tangles in PSP and other tauopathies. The microtubule-binding domain contains either three 31 amino acid repeats (3R) or four 31 amino acid repeats (4R). In the normal adult brain, the ratio of 3R and 4R tau isoforms is similar. In PSP , it is at least 3:1 in favor of 4R tau [2, 15–17].

Similar histopathological findings can be seen in other forms of tauopathies (e.g., Guadeloupian parkinsonism), which complicates the pathological diagnosis of PSP . The most specific features are star-shaped astrocytic tufts and neurofibrillary tangles that are seen under light microscopy and strongly immunostain with tau antibodies [16, 17].

Progressive supranuclear palsy is frequently misdiagnosed as PD, and less than half of patients with pathologically proven PSP are diagnosed correctly as having PSP at presentation. The National Institute of Neurological Disorders and Stroke/Society for PSP (NINDS/SPSP) criteria detect disease in only 50–70 % of patients in the first 3 years after disease onset [18]. These diagnostic shortcomings may at least in part be due to the phenotypic diversity, grouped into six well-documented clinical PSP phenotypes, recognized through neuropathological studies [15, 16]

1.

Richardson’s syndrome ( RS ): As described above, this is the “classic” clinical presentation of PSP .
2.

PSP parkinsonism ( PSP – P ): The PSP -P phenotype occurs in about one-third of cases and is a more indolent form with a PD-like levodopa-responsive presentation. This is the type most likely to be diagnosed as PD for the first 5 years, as falls and oculomotor abnormalities do not occur until at least that many years have passed.
3.

PSP pure akinesia with gait freezing ( PSP – PAGF ): This PSP phenotype is highly predictive of PSP -tau pathology. It occurs as a syndrome that includes progressive gait disturbance with start hesitation and subsequent freezing of gait, speech or writing in the absence of tremor, rigidity, dementia or eye movement abnormalities during the first 5 years of the disease.
4.

PSP progressive non-fluent aphasia ( PSP – PNFA ): It is characterized by nonfluent spontaneous speech with hesitancy, phonemic errors, and agrammatism. This language-based PSP presentation also includes the more recently identified syndrome “progressive apraxia of speech.”
5.

PSP cerebellar : Kanazawa et al. [19] described cerebellar involvement in PSP . They studied 22 consecutive Japanese patients with pathologically proven PSP and 3 patients developed cerebellar ataxia as the first major symptom.
6.

PSP corticobasal syndrome ( PSP – CBS ): It is characterized by progressive, asymmetrical, levodopa-unresponsive parkinsonism with ideomotor apraxia, cortical sensory loss, alien limb phenomenology, dystonia, and myoclonus of the most severely affected limb.

The most important MRI abnormalities in PSP patients are midbrain atrophy and superior peduncle atrophy (Fig. 3.2) [20]. The “humming bird” and “morning glory” signs have high specificity but rather low sensitivity [16, 17]. [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) studies in PSP patients show characteristic brain glucose hypometabolism in the mesial frontal and insular regions and in the midbrain [2].

Fig. 3.2

Brain MRI (midsagittal T1-weighted image) showing atrophy of the midbrain in a patient with progressive supranuclear palsy

There are no effective symptomatic or curative treatments for PSP . Poor or absent response to levodopa is one of the diagnostic criteria for PSP with marked or prolonged levodopa benefit being an exclusion criterion [2, 15, 16]. Serotoninergic drugs such as selective serotonin reuptake inhibitors, 5-hydroxytryptophan, and methysergide have no confirmed benefit in PSP , in addition to cholinergic drugs, such as acetylcholinesterase (AChE) inhibitors, and muscarinic agonists. Botulinum toxin may be helpful in PSP for treating dystonia such as retrocollis and apraxia of eyelid opening, reducing disability provoked by these symptoms [15]. A dextromethorphan/quinidine combination may be helpful among those who develop troublesome pseudobulbar affect. Recent clinical trials with tideglusib (an inhibitor of glycogen synthase kinase-3), davunetide intranasal spray (shown to promote microtubule stability and reduce tau phosphorylation), and high-dose coenzyme Q10 and rasagiline (1 mg/day) have failed to support clinical benefits [12].

Corticobasal Degeneration

Corticobasal degeneration (CBD ) was first described in 1968 as a “corticodentatonigral degeneration with neuronal achromasia” [21] and is the leading cause of the so-called corticobasal syndrome (CBS ). Given the heterogeneity of the clinical syndrome (CBS can be due to many etiologies, including CBD , but also Alzheimer’s disease, frontotemporal lobar degeneration, and PSP ) and the pathological syndrome (CBD can be associated with CBS , PSP syndrome, PNFA, and posterior cortical atrophy syndrome), the diagnosis of CBD /CBS may remain elusive during life [2]. Only 25–56 % of suspected CBS cases have been given pathological confirmation of CBD [22]. CBS typically presents in the sixth decade of life with markedly asymmetrical symptoms in the upper limbs, less commonly in the lower limbs. It is evenly distributed between the sexes and, owing to its rare occurrence, the exact prevalence of this syndrome is not known but is believed to be around 2 in 1,000,000 people [2, 23, 24]. It is a progressive disease with a survival span of about 7 years. The most common clinical signs and symptoms are asymmetrical levodopa-resistant parkinsonism with dystonia, myoclonus, and cortical signs, including cortical sensory loss, apraxia, and alien limb phenomenon in the most severely affected limb. Cognitive impairment tends to be less overt than in PSP but greater than in MSA . Other less common symptoms are abnormal eye movements (increased latency of saccades), postural instability, falls, abnormal gait, axial rigidity, and a high-amplitude tremor that is greater posturally when resting [2, 22, 23].

Corticobasal degeneration is characterized by the widespread deposition of hyperphosphorylated 4-repeat tau in neurons and glia, and neuronal degeneration in the frontotemporal cortex and substantia nigra. The hallmark feature is the astrocytic plaques that differentiate CBD from other 4R tauopathies, particularly PSP . Similar to PSP , CBD is associated with the H1 haplotype of the MAPT gene [24].

Neuropathological studies have shown that CBS may be due to Alzheimer’s disease, PSP , and forms of frontotemporal dementia. Conversely, pathologically confirmed CBD cases may exhibit a range of phenotypes including CBS but also frontotemporal dementia, primary progressive aphasia (PNFA, in particular), and posterior cortical atrophy [2, 25].

Neuroimaging studies of CBS patients, including brain MRI and FDG-PET or SPECT, show asymmetrical frontoparietal atrophy and hypometabolism respectively [26]. Cerebrospinal fluid biomarkers have not yet been adequately studied in patients with CBS /CBD [22–24].

As with other forms of APD, there is a low yield in the symptomatic treatment available for CBS . There is generally no response to dopaminergic drugs, including levodopa at doses as high as 2 g/day. Myoclonus can be alleviated with clonazepam and/or valproate or levetiracetam. Focal arm dystonia may be alleviated with anticholinergic drugs or botulinum toxin [2]. Dementia can be treated with cholinesterase inhibitors, but the effectiveness of this approach remains unproven.

Physical Therapy in Parkinsonian Syndromes

There is scarce evidence on specific physical therapies in parkinsonian syndromes, such as PSP , MSA , and CBD . In most cases, long-term efficacy has not been reported. Patients with APD reviewed above can exhibit faster progression, less or no response to antiparkinsonian medications, and shorter survival compared with PD, all of which limit response to physiotherapy. Further controlled studies to provide guidance to physical therapists in the management of these diseases are lacking.

Below is a summary of the (largely anecdotal [case reports or case series]) studies investigating the effect of physical therapy to improve motor control in patients with PSP , MSA and CBD .

Physical Therapy in Progressive Supranuclear Palsy

Patients with PSP are usually referred for physical therapy (PT) to treat balance and gait problems with frequent falls. Gait training and movement strategies that are useful in PD may also be applicable in PSP and other APDs. Behaviorally, balance impairment in the mediolateral plane (i.e., sideways) is often seen in patients with APDs, but not in patients with PD [27]. This is reflected by the distance between the feet during gait, which is typically normal (or even narrow) in PD, but widened in PSP and MSA . Estimating this stance width is difficult in clinical practice, without objective measures. Nevertheless, this mediolateral balance impairment can be revealed using two simple tests: (1) inability to perform tandem gait (one or more side steps being abnormal) [28]; and (2) self-report by patients who have lost the ability to ride a bicycle [29]. Both tests are useful for distinguishing PD from atypical parkinsonism, even in the early course of the disease [27].

Suteerawattananon et al. [30] described the rehabilitation of one patient (a 62-year-old man) diagnosed with PSP . His major problems were impaired balance and frequent, abrupt falls. His PT program included walking training, balance perturbation, and step training using body weight support with a treadmill. Training sessions lasted 1.5 h and took place 3 days a week for 8 weeks. Fall incidence, balance, and gait were assessed before, during, and after the program. The patient reported fewer falls during and after training. Balance and gait improved after training [30].

Steffen et al. [31] evaluated a 72-year-old man diagnosed with mixed PSP and CBS features after 6 years of disease. He had asymmetric limb apraxia, markedly impaired balance, and frequent falls during transitional movements. PT intervention included routine participation in a PD group exercise program (mat exercises and treadmill training) and intermittent participation in individual locomotor training on a treadmill. The exercise group met for 1 h, twice weekly. The individual treadmill sessions lasted 1 h, once weekly, for two 14-week periods during the follow-up period. Over a 2.5-year follow-up period, fall frequency decreased, and tests of functional balance showed improved stability (functional reach tests) and maintained balance function (Berg Balance Scale). Tests of walking performance showed only a slight decline. A four-wheeled walker was introduced and accepted by the patient early in the intervention period. With supervision, he remained ambulatory in the community with this wheeled walker. The authors concluded that PT, relying on locomotor training using a treadmill and a long-term exercise program of stretching and strengthening, may improve some dimensions of balance, slow the rate of gait decline, prevent progression to wheelchair dependence, and decrease the number of falls. Contrary to the expected decline in function, this patient maintained independent mobility beyond 2 years [31].

Steffen et al. [32] subsequently published a longer-term (10 years) follow-up in the same PSP /CBS patient. The falls (reported weekly over the study period by the patient and his wife) decreased from 1.9 falls per month in year 1 to 0.3 falls per month in year 10. Taken together, the functional data described in these reports with regard to mobility, balance, walking speed, falls, and endurance strongly suggest the importance of a regular and aggressive exercise program to prolong longevity, decrease the number of falls, and promote stability of function (including balance and ambulation) for a patient with suspected CBS /PSP syndrome [32].

It is known that people with PSP have difficulty suppressing the vestibulo-ocular reflex (VOR) [18]. The inability to generate saccades can compromise safe ambulation. Anticipatory saccades normally occur in situations that involve changing the direction of walking [33] or before obstacle avoidance [34]. When saccades are not generated quickly, there is an increased risk for falling [35].

Rehabilitation strategies for PSP are likely to differ from those for PD because vertical gaze palsy is unique to PSP and has the potential to create additional balance and mobility problems. Therefore, the rehabilitation for PSP should involve “eye-movement training” in addition to balance and gait training.

Lindemann et al. [36], using dual-tasking paradigms to assess differences between patients with PSP who fell frequently and those who fell less often, found more ocular movement difficulties, decreased postural stability, and decreased cognition in the former than in the latter group. The frequent fallers demonstrated a significant increase in cadence and a decrease in step length compared with the infrequent fallers, but the groups did not differ significantly under dual tasking for maximal gait speed. These findings may reflect a first adaptation with dual tasking to produce safer walking by decreasing step length. A decrease in cadence was found to be the next adaptation, when needed. These findings also suggest that falls might result from cognitive and ocular dysfunction in addition to the parkinsonian features [36].

Zampieri et al. [37] investigated 19 adults with possible or probable PSP and postural instability. Balance training accompanied by eye movement and visual awareness exercises was compared with balance training alone. The gaze control was assessed using a vertical gaze fixation score and a gaze error index. Gaze control after the balance plus eye exercise significantly improved, whereas no significant improvement was observed for the group that received balance training alone [37].

Recently, Seamon et al. [38] described an intervention using a virtual gaming system to improve gait, postural control, and cognitive awareness to reduce falls and improve the quality of life for a patient with PSP . A 65-year-old woman with a 5-year disease duration and frequent falls, poor ability to visually track objects, axial rigidity, retropulsion, poor postural control, with reaching and cognitive decline was assessed. She was provided with the Xbox Kinect for 12 one-hour sessions over 6 weeks in an outpatient setting. The games were selected to challenge functional motor and cognitive tasks based on patient enjoyment. After the intervention with virtual reality the patient showed decreased falls and maintenance of scores on the Berg Balance Scale, Timed Up and Go (TUG), and 10-Meter Walk Tests above fall risk values. A decline in quality of life measures, PDQ-39 and Fear of Falling Avoidance Behavior Questionnaire, may be attributed to an increase in cognitive awareness of deficits promoted by the intervention structure. According to the authors, the implementation of a gaming intervention using a virtual gaming system is feasible for reducing fall risk and maintaining function and mobility when used in an outpatient setting [38].

In conclusion, these studies have suggested that a combination of balance/walk interventions [30–32, 37, 38] and eye movement training [37] may improve the functional performance of patients with PSP .

Physical Therapy in Multiple System Atrophy

Patients with MSA present not only a functional incapacity, but also a greater severity of motor symptoms compared with patients with PD [39]. They also exhibit muscle weakness [40] with subsequent impaired muscle performance [41] and loss of balance [39]. These factors contribute to an increased risk for falls. Clinical practice suggests that most patients might be poorly responsive to antiparkinsonian drugs. In this context, rehabilitation strategies may be helpful.

The beneficial effects of Tai Chi in the improvement of gait and posture in PD patients are well established in the literature [42–44]. Venglar [45] described the effects of an 8-week Tai Chi class on two patients: one with PD, the other MSA . Both patients demonstrated improved scores on the Activities-specific Balance Confidence Scale and the Functional Reach Test. One subject also demonstrated improved scores for the Timed Up and Go test. Both subjects reported subjective improvements in balance and balance awareness. This study indicated that Tai Chi might be a viable option for improving balance in patients with MSA [45].

Wedge [41] showed that a low to moderate intensity conventional resistance training program was able to improve the functional ability, balance, and muscle performance in a 68-year-old woman with a 2-year history of MSA . Examination included range of motion, muscle strength, motor control ambulation with and without assistive device, and determination of orthostatic hypotension. Functional Reach, TUG, timed single limb stance, and the Performance Oriented Mobility Assessment tests were used to assess safety, balance, and fall risk. Hypokinesia and festinating gait were observed during ambulation. Transfers from sitting to standing were functional, but compromised safety. Impairments of muscle performance were found at the ankle, knee, and hip. Low to moderate intensity, lower extremity resistance training was added (twice weekly) to an existing program of balance and flexibility exercises. Clinically meaningful gains were achieved in all functional measures, and the patient performed SLS for 10 s when previously unable. More importantly, she achieved her goal of remaining at home. The addition of resistance training to an existing program of balance and flexibility exercises did not cause any adverse effects and appears to have led to improvements in balance and functional ability [41].

Batista et al. [46] assessed quality of life, activities of daily living, motor symptoms, functional ability, and neuromuscular parameters in a patient with MSA . The program of resistance training with instability was performed twice a week during 24 weeks for a total of 48 sessions performed. The patient was tested and trained in the clinically “on” state (fully medicated) during the morning time within 1.5 h of taking his last dose of the dopaminergic drug. Each training session lasted between 40 and 50 min, and started with a 10-min warm-up on a bicycle ergometer (20–40 rpm). The resistance training with instability devices consisted of conventional external load lower-limb resistance training machines (i.e., leg press and plantar flexion) and free exercise (i.e., half-squat) with unstable devices (i.e., balance pad, dyna discs, balance discs, BOSU ball, and Swiss ball). The unstable devices were placed between the patient’s base of support (i.e., the body area responsible for sustaining most of his body weight and/or on the point of force application) and the resistance training machines for each individual exercise. Progression with the unstable device was included in the training program from less unstable to more unstable. After the 6-month training, the patient’s left and right quadriceps muscle cross-sectional areas and leg press one-repetition maximum increased by 6.4 %, 6.8 %, and 40 % respectively; the TUG, sitting to standing transfer, dynamic balance, and activities of daily living improved by 33.3 %, 28.6 %, 42.3 %, and 40.1 % respectively; and the severity of motor symptoms and risk of falls decreased by 32 % and 128.1 % respectively. Most of the subscales of quality of life demonstrated improvements as well, varying from 13.0 to 100.0 %. This study showed that resistance training may decrease the severity of motor symptoms and risk of falls, and improve functional ability, neuromuscular parameters, and quality of the life in patients with MSA [46].

Current treatment strategies for MSA focus on the control of neurogenic orthostatic hypotension (nOH ) [47]. Patients with severe nOH suffer from debilitating symptoms that substantially impair their ability to complete activities of daily living and reduce their quality of life. A high incidence of fall-related fractures and trauma occurs in patients with severe nOH [48]. Classic nO H symptoms, such as orthostatic dizziness and syncope, and less appreciated symptoms, such as coat-hanger pain and cognitive impairment, can force patients to curtail activities that involve standing or walking [49]. In addition to pharmacological strategies (see above) [50] patients may be treated with physiotherapy[51]. Exercises, especially activities that are performed recumbent or in water, are encouraged to prevent deconditioning, which can exacerbate nOH [52]. However, patients should avoid exercising in the morning, when orthostatic symptoms are typically worse. Is also recommended that when changing position they should do so slowly to allow time for autonomic adaption. For instance, when going from a supine position to walking, patients should sit before standing and stand for several minutes before walking [53].

Physical Therapy in Corticobasal Syndrome

Early in the disease course, PT may help to improve or maintain mobility and help with assessing the need for assistive devices (e.g., walkers) to improve gait and decrease the risk for falls. Later in the disease course, involvement of physiotherapists is critical for home safety assessments and appropriate wheelchair provision (e.g., to prevent pressure ulcers) and to instruct caregivers on range of motion exercises.

To our knowledge, there are only two studies describing the effects of PT [54] and PT plus repetitive transcranial magnetic stimulation (rTMS) [55] in patients with CBS .

Kawahira et al. [54] studied the effect of repetitive facilitation exercise in a patient with CBS . This exercise included movements of each isolated finger using the stretch reflex and skin–muscle reflex and repetitive movements demanded in activities of daily living and manipulation of objects. To evaluate improvements in hand functions by repetitive facilitation exercise, 1-week repetitive facilitation exercise sessions for the hand were administered alternatively to the left or right hand. The number of finger taps by the hand increased during each 1-week repetitive facilitation exercise session for the hand, but did not increase during 1-week sessions without repetitive facilitation exercise. After 1 month of treatment, there was an improvement in activities of daily living, including wearing clothes, manipulating objects, and cooking. These results suggest that facilitation exercises and repetition movements in activities of daily living might aid recovery in patients with CBS [54].

Shehata et al. [55] investigated low-frequency repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool in CBS . Twenty-six patients with clinically probable CBS were followed for 12–18 months while receiving low-frequency rTMS combined with rehabilitation treatment and botulinum toxin injection in the affected dystonic limb. There was improvement in the UPDRS (measure of motor severity) and quality of life after 3 months of therapeutic interventions (P < 0.001 and <0.05 respectively). No significant deterioration in cognitive function was detected over the study period. There was a reduction in the caregiver burden after 3 months of interventions (P < 0.01); this improvement was maintained for up to 18 months. The authors concluded that the combined treatment approach was effective in improving quality of life and reducing the caregiver burden [55].

Demand for rehabilitation in this and other parkinsonian populations will increase, but more research is necessary to answer basic questions regarding the type and dosage of the above rehabilitation strategies.

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