Video Representation of Dopamine-Responsive Multiple System Atrophy Cerebellar Type

Background

Multiple system atrophy cerebellar type (MSA-C) is a subset of MSA that presents with predominant ataxia along with lesser signs of parkinsonism and autonomic dysfunction [1]. Per established consensus criteria developed in 2008, an MSA diagnosis is categorized as definite, probable, or possible [1,2]. The consensus criteria utilize neuropathological findings, clinical signs (autonomic instability, Parkinson traits, cerebellar syndromes), and poor levodopa response as rated per the Movement Disorder Society Unified Parkinson’s Disease Rating Scale or the Unified Multiple System Atrophy Rating Scale [1–5]. MSA is further classified by subtype based on the predominance of symptoms at presentation, either parkinsonian or cerebellar (although autonomic symptom predominance is another possibility, it is not officially recognized as a subtype) [1,2]. The predominance can change with serial examinations, and the classification of the MSA subtype may consequently change as well [1,2]. Previous studies have shown benefits from carbidopa/levodopa therapy for the MSA parkinsonian subtype (MSA-P), but few studies have focused on MSA-C. Martin et al [6] conducted a retrospective review of patient clinical history through electronic medical records and found a response rate to carbidopa/levodopa of up to 50%; however, they included data before the differentiation of MSA-P vs MSA-C via the first consensus criteria. Ishida et al [7] conducted a small clinical trial with 9 patients with either MSA-P or MSA-C who were treated with levodopa. Clinical improvement was seen in 4 MSA-P patients and 1 MSA-C patient in this trial. Lin et al [3] reviewed previous studies of MSA, including MSA-C, and found that up to 40% of MSA patients were responsive to carbidopa/levodopa. The apparent benefit seen in MSA-P patients treated with carbidopa/ levodopa therapy has been theorized to be due to parkinsonism symptoms being the target of carbidopa/levodopa; these symptoms are more prominent in MSA-P than in MSA-C [1,2]. With the predominance of MSA-P in North America and Europe, more studies have been conducted on MSA-P than MSA-C [3]. The MSA-C subtype is predominant in Japan, but the existing literature of MSA-C therapy with carbidopa/levodopa in that population is limited [6–8]. We present a video case of MSA-C that demonstrated significant improvement with carbidopa/ levodopa therapy.

Case Report

A right-handed 61-year-old man presented to the hospital with progressive gait changes that had been slowly worsening over the past several months and had rapidly deteriorated several days preceding his hospitalization. He had been able to use a walker prior to this exacerbation but was forced to transition to a wheelchair. He also noted stiffness and pain bilaterally in his lower extremities along with an inability to perform actions at work. He had previously consulted outpatient neurology at other institutions for his gait instability. Prior electro-myography and nerve conduction study revealed mild sensory neuropathy in his lower extremities. Additional prior brain and cervical and lumbar spinal magnetic resonance imaging (MRI) revealed no significant pathologic processes aside from chronic microvascular ischemia and past lumbar and cervical decompression surgeries in 2016 and 2019, respectively.

The patient was evaluated and admitted to the hospital for further workup. His neurologic examination was positive for bilateral cogwheeling rigidity that was more pronounced in the lower extremities, difficulty initiating movement, difficulty standing up from a seated position, slow saccadic eye movements, masked facies (hypomimia), dysarthria, bilateral upper and left lower extremity ataxia, and reflexes 3/4 in the upper extremities bilaterally and left lower extremity, as well as right ankle clonus (Video 1). Cervical and lumbar spine MRI was consistent with prior imaging and no neurosurgical intervention was recommended.

Brain MRI showed diminished volume of the cerebellar hemispheres, middle cerebellar peduncles, and inferior pons with the presence of a “hot cross bun sign” (Figure 1). Lumbar puncture was performed and was negative for any infectious or paraneo-plastic process. Laboratory serum testing was done for copper, angiotensin-converting enzyme, HIV, human T-lymphotropic virus, heavy metals, vitamin B1, and tissue transglutaminase, in addition to the Venereal Disease Research Laboratory test and measurement of Lyme antibody and gliadin antibody. Serum test results were unremarkable.

The patient was presumptively diagnosed with probable MSA-C and started on carbidopa/levodopa-controlled release (CR) 25–100 mg (Sinemet CR), 1 tablet 3 times daily with meals. On the first day of the trial regimen, he reported significant improvement. His gait substantially improved, and he was able to stand from a seated position with minimal assistance and ambulate with a walker prior to discharge (Video 2). This improvement was confirmed by the neurology team along with physical and occupational therapy and physical medicine rehabilitation. The patient was discharged to inpatient rehabilitation on the same carbidopa/levodopa CR regimen, with the addition of carbidopa/levodopa immediate release (IR) 25–100 mg, 0.5 tablet, 2 times daily. The follow-up outpatient visits at 1, 5, and 9 months demonstrated minimally improved bilateral upper extremity and left lower extremity ataxia, but significantly decreased rigidity and bradykinesia. The patient continued use of his walker, and he reported no significant adverse effects from his medication. Carbidopa/levodopa IR 25–100 mg was increased from 0.5 tablet 2 times daily to 1 tablet 3 times daily at the 9-month visit due to decreased efficacy.

Discussion

With this case report we highlight the clinical presentation of MSA-C in video format and illustrate the robust response that treatment with carbidopa/levodopa CR and IR can have in patients with this disorder. Our patient had been undiagnosed for 4 years prior to his presentation, thus confirming the complex diagnostic and clinical suspicion for the disease. Identifying the type of ataxia in an adult commonly poses a unique diagnostic challenge, and there is often a delay in diagnosis, as was the case for our patient. Concurrently, he had a misdiagnosis of alcohol-induced ataxia, even in the absence of consumption. The differential diagnosis considered is shown in Table 1.

The consensus criteria for MSA have been used to further characterize patients with suspected MSA as having either definite, probable, or possible MSA depending on the clinical presentation and associated pathological findings [1]. Additional features supporting a diagnosis of MSA were also seen in our patient, including orofacial dystonia, dysarthria, and atrophy of the middle cerebellar peduncle and pontine region along with the “hot cross bun” sign. With a presumptive diagnosis of probable MSA, a trial of carbidopa/levodopa 25–100 mg CR 1 tablet 3 times daily and carbidopa/levodopa 25–100 mg IR 0.5 tablet 2 time daily was done, and it led to improvement in his cogwheeling, dysarthria, gait, and station.

The treatment of MSA is similar to that of sporadic parkinsonism with the use of levodopa, which can control bradykinesia and rigidity in MSA patients [2]. MSA is often clinically differentiated from Parkinson’s disease owing to poor and decreased responsiveness to levodopa as determined through evaluation techniques such as clinical motor examinations, the Movement Disorder Society Unified Parkinson’s Disease Rating Scale, or the Unified Multiple System Atrophy Rating Scale [4,5]. However, few trials have examined the effectiveness of levodopa therapy in MSA-C patients [6–8]. While bradykinesia and rigidity improved in our patient, he experienced minimal improvement in his ataxia. Although his movements were notably smoother, he was still considered as being ataxic. Several other studies have also demonstrated levodopa responsiveness in MSA patients that exceeds what is normally expected according to diagnostic criteria [2]. Based on the results of prior studies of MSA treatment response, the treatment methods used for patients with Parkinson’s disease and those with MSA have diverged without a clear consensus of the benefits/risks of each treatment [2].

Conclusions

The variability in treatment efficacy and adverse effects along with other autonomic complications seen in MSA patients warrants additional studies to determine the most effective treatment modalities for MSA-P and MSA-C patients [2]. Further randomized controlled studies are needed to assess the efficacy of carbidopa/levodopa CR and IR in the treatment of MSA-C patients.