Correspondence *Movement Disorders Program, Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA

Email ksethi@mcg.edu

The case

A 48-year-old left-handed man who had been diagnosed with Parkinson's disease (PD) 9 years earlier was referred to a movement disorders program for management of motor fluctuations. Before his diagnosis, the patient had noticed progressive slowing of movement in his left side and eventual loss of shoulder motion when raising his arm over his head. He was treated for presumed arthritis with a course of NSAID therapy, but derived no benefit. Approximately a year after his PD diagnosis, he had developed similar slowing of movement on his right side. Over the following year, his handwriting became smaller and less legible, and his wife commented that his speech was softer and slurred at times. To date he has not developed resting tremor or postural instability.

The patient responded well to carbidopa–levodopa (CD–LD) in the first year of treatment following his PD diagnosis. He subsequently required steadily higher doses of CD–LD, however, and ropinirole was added to provide additional motor benefit. During the 2 years leading up to his presentation to the movement disorders program, disabling motor fluctuations with painful left-foot dystonia began to emerge during 'wearing-off' periods between CD–LD doses. His gait became characterized by frequent freezing episodes and marked forward bending of the trunk (camptocormia). The camptocormia commonly emerged within the 30 min before his next scheduled CD–LD dose and was described as uncomfortable but not painful. He also developed peak-dose dyskinesias involving his legs and trunk.

At the time of presentation, the patient was on sustained-release CD–LD 50 mg/200 mg with entacapone 200 mg four times a day, supplemented with regular CD–LD 10 mg/100 mg four times a day as needed. He was also taking ropinirole 3 mg three times daily. A gadolinium-enhanced MRI scan of the brain was performed 1 week before his initial visit and the results were unremarkable.

On neurological examination in the 'off' state, the patient scored 30 out of 30 on the Folstein Mini-Mental State Examination. No frontal release signs were present, and extraocular movements were normal. The patient had considerable hypomimia and marked bilateral bradykinesia, with more involvement of his left side than his right in finger tapping, fist opening, rapid pronation–supination and foot tapping. He could not abduct his left shoulder past 45° but otherwise his strength was normal. No resting or postural tremor was evident. The patient had marked axial rigidity and bilateral cogwheel rigidity in all extremities but more evident on his left side. His gait was notable for slow shuffling steps, en bloc turning, freezing, and marked camptocormia of nearly 45°. When standing, he was able to correct his camptocormia slightly, to roughly 30°. No paraspinal muscle wasting or scoliosis was noted. The patient's arm swing was diminished bilaterally and his pull test was normal. When he was supine, the camptocormia was not present.

The patient was re-examined after being given a dose of regular CD–LD 37.5 mg/150 mg with entacapone 200 mg, and within 30 min his bradykinesia had considerably improved and he had regained the complete range of motion in his left shoulder. When walking he had a normal stride with residual diminished arm swing on his left side, but complete resolution of his camptocormia (see Supplementary Video 1 online).

The patient's medication was adjusted to CD–LD–entacapone 37.5 mg/150 mg/200 mg five times daily. He declined evaluation for deep brain stimulation (DBS) therapy. The switch to CD–LD–entacapone provided more reliable onset of 'on' time to within 30 min of taking each dose, and full resolution of the camptocormia. Two months later, however, the patient was still experiencing notable 'off' periods, which were associated with recurrence of his camptocormia. On his own initiative, he supplemented his CD–LD–entacapone therapy with additional sustained-release CD–LD 50 mg/200 mg, which resulted in worsening dyskinesias. The patient's dose of CD–LD–entacapone was subsequently lowered to 25 mg/100 mg/200 mg six times a day and he was discouraged from taking additional levodopa. He still complained of 'wearing-off' periods between CD–LD–entacapone doses, which occurred especially on awakening in the morning. To treat his 'off' symptoms he was started on rescue treatment with apomorphine 0.4 mg injections up to five times daily as needed. The patient is currently reconsidering DBS. He declined further evaluation of his camptocormia with electromyography (EMG) testing.

Discussion of diagnosis

PD is a hypokinetic movement disorder associated with degeneration in multiple neuronal systems caused by progressive loss of dopaminergic neurons in the substantia nigra. The clinical diagnosis of PD requires bradykinesia with at least one of the other following cardinal features: resting tremor, cogwheel rigidity, or postural instability (UK PD Society Brain Bank criteria).¹ Resting tremor is very common in patients with PD and is present at the time of diagnosis in roughly 75% of cases,² but is not a required feature.

The unusual feature in this patient was camptocormia that was present only during the 'off' state and that responded dramatically to levodopa (Figure 1). Camptocormia can have many causes, including flexion dystonia of the trunk and extensor myopathy.³ Camptocormia was first described in 1818 and was thought to be primarily a psychogenic phenomenon particularly associated with wartime stress in soldiers,⁴ although subsequent case reports clearly establish it as a nonspecific component of extrapyramidal dysfunction and of other neuromuscular diseases.^{1, 2, 3} Camptocormia is a rare but well-described clinical feature of PD and other parkinsonian syndromes; however, the mechanism of pathogenesis remains unclear. It has been proposed that camptocormia is an extreme form of the characteristic stooped posture that is associated with PD.⁶ In this case, the camptocormia was probably an 'off'-state flexion dystonia and was unlikely to have resulted from an extensor myopathy, as his gait and posture nearly normalized following treatment with levodopa (see Supplementary Video 1 online). Such a robust response to levodopa is uncommon in PD-associated camptocormia; like other axial symptoms of PD, this feature of the disease tends to show little or no response to dopaminergic therapy. The usual lack of response suggests that non-dopaminergic mechanisms controlling gait and posture have a prominent pathogenic role in the majority of camptocormia cases, although this role remains poorly understood.⁶

Figure 1 Camptocormia in Parkinson's disease

(A) The patient in the 'off' state, demonstrating marked forward flexion of the trunk. (B) Resolution of the patient's camptocormia in the 'on' state, following administration of regular carbidopa–levodopa with entacapone. For further examples, see Supplementary Video 1 online.

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Differential diagnosis

The first step in the differential diagnosis of PD is to identify parkinsonism, as described above (UK PD Society Brain Bank criteria).¹ The next step is to determine whether the parkinsonism is caused by PD, an atypical parkinsonian syndrome (APS), or a pharmacological agent. A comprehensive medication history should be obtained to facilitate the identification of agents that might cause drug-induced parkinsonism. Certain 'red flags' in a patient's history could point towards APS (Box 1); specifically, early postural instability, autonomic dysfunction, and cognitive decline early in the clinical course of disease suggest a diagnosis other than PD. A distinguishing feature of PD is that patients almost always have a robust response to levodopa, compared with the modest or absent response in patients with APS.⁷ In the present case, the gradual progression of the clinical course (over 9 years), asymmetric onset of bradykinesia and rigidity, preserved postural reflexes and cognition, and excellent response to levodopa, supported the diagnosis of PD.

The differential diagnosis of camptocormia alone is broad. As mentioned above, a variety of neuromuscular disorders can cause camptocormia, including motor neuron disease, myopathies, and muscular dystrophies.^{4, 8} Camptocormia can also be a component of primary or secondary dystonia, as well as of tardive dystonia related to chronic use of neuroleptics.³ In addition to PD, forms of APS such as multiple system atrophy, corticobasal degeneration and progressive supranuclear palsy could include camptocormia as part of the clinical picture. Other reported causes of camptocormia include psychogenic disorders, spinal deformities, paraneoplastic syndrome associated with Hodgkin's lymphoma, and sodium valproate use.^{9, 10} Spine imaging with CT or MRI can help to rule out primary orthopedic etiologies. EMG can be useful for distinguishing between an extensor myopathy and a flexor dystonia as the root cause of camptocormia. In the context of an abnormal EMG result, biopsy of the affected muscles can help to identify the underlying myopathy.¹¹

Treatment and management

Treatment of PD involves enhancement of dopaminergic transmission through various pharmacotherapeutic strategies. All patients with PD eventually require dopaminergic therapy, either with levodopa or with a dopamine agonist; combination therapy of levodopa and a dopamine agonist is also often used. Dopaminergic therapy is optimized to provide maximal resolution of PD symptoms while minimizing motor fluctuations. In our experience, the timing of symptom relief with continuous-release CD–LD can be unpredictable, leading to delayed or no 'on-time' compared with regular CD–LD. We have found that most patients prefer a combination of regular CD–LD and entacapone, which provides a more reliable onset of action and a longer 'on-time' compared with continuous-release CD–LD, as is evident in the patient in this Case Study. Selective monoamine oxidase B (MAO-B) inhibitors such as selegiline or rasagiline are other treatment options. MAO-B inhibitors prolong the effect of endogenous dopamine by blocking its metabolism, and have a modest but important benefit in reducing 'off-time'. Research is ongoing to investigate whether MAO-B inhibitors might also have neuroprotective properties, which, if proven, would advocate their use in early PD.¹² Apomorphine, a short-acting dopamine agonist that is administered subcutaneously, can help alleviate symptoms of PD by providing a short-lived rescue therapy to address the disabling 'off' periods before other dopaminergic medications take effect.

Dyskinesias can be more difficult to treat. A simple approach is to administer frequent small doses of levodopa. Medications that have a direct antidyskinetic effect, such as amantadine or clozapine, could be useful as adjunctive therapy.¹² Research currently underway is comparing CD–LD–entacapone with standard CD–LD to see if the former could reduce the risk of patients with PD developing motor complications over time. Continuous-release formulations of dopamine agonists (e.g. rotigotine) and of levodopa have recently become available in Europe and are awaiting approval in the US. Rotigotine can be delivered via a transdermal patch, while levodopa can be delivered in gel form directly to the gastrointestinal tract via a duodenal pump. Continuous-release formulations have the advantage of maintaining a level plasma concentration of the drug, rather than the peaks and valleys inherent in oral administration.¹³ Continuous release could be especially beneficial in levodopa administration, as this method of delivery might alleviate motor complications associated with the pulsatile nature of oral therapy.

DBS is a therapy option that can markedly improve PD symptoms in properly selected patients while reducing motor complications and improving quality of life.¹⁴ Typically, the subthalamic nucleus or globus pallidus internus is targeted for stimulator electrode placement. The patient in this Case Study is considered a good candidate for this procedure on the basis of his normal cognition, relatively young age, his excellent response to levodopa, and the presence of significant motor fluctuations and dyskinesias.

The management of PD-associated camptocormia can be particularly challenging. Camptocormia is associated with a wide variety of neuromuscular disorders including motor neuron disease, myopathies and muscular dystrophies; EMG testing should be performed to rule out these diagnoses. Adjustments to dopaminergic therapy can resolve camptocormia in some patients, as demonstrated in the present case, but such a robust response to antiparkinsonian medications alone is generally rare and, in some cases, levodopa can worsen PD-related camptocormia.^{5, 6} Botulinum toxin can help some patients, especially if the camptocormia is caused by activity of the rectus abdominis muscles rather than by paraspinal muscle atrophy.^{3, 11} Generally, antispasmodic drugs such as baclofen or cyclobenzaprine are ineffective at reducing camptocormia. In individual case reports, subthalamic and pallidal DBS have been shown to be effective in treating camptocormia.^{15, 16, 17} The overall efficacy of DBS in relieving PD-related camptocormia, however, has not been determined.

Conclusions

This case highlights many classic features of PD, including prominent asymmetric bradykinesia, rigidity and gait difficulties later in the course of the disease, and response to levodopa. In addition, PD can involve a wide variety of other nonspecific symptoms, such as the present patient's camptocormia. The exact etiology of camptocormia in PD is unknown, but in this case it probably reflects a rare form of 'off' dystonia that is responsive to dopaminergic therapy. Such a dramatic response is rare, however, which suggests the involvement of non-dopaminergic pathways in the pathogenesis of most cases of PD-related camptocormia. Camptocormia can be caused by a variety of neuromuscular disorders that involve the paraspinal muscles; these disorders can be identified with appropriate imaging, electrophysiological testing, and muscle biopsy.

In cases of non-dopaminergic PD-associated camptocormia response to medical therapy is modest at best, but botulinum toxin is the optimum treatment if flexion dystonia is the main cause of the camptocormia. DBS has shown promise in the treatment of non-dopaminergic PD-associated camptocormia and could emerge as the most reliable treatment for these difficult cases.

Acknowledgments

The patient is thanked for allowing publication of the photographs and supplementary online material, for which the patient's written consent was obtained.

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Subject areas under which this article appears: Neurodegenerative disease | Movement disorders