Dopa-responsive Rest Tremor Preceding Tachyphemia in Progressive Supranuclear Palsy

Abstract

Progressive supranuclear palsy (PSP) is characterized by progressive postural instability, falls, and supranuclear vertical gaze abnormalities. In this report, we present the case of a 71-year-old woman with dopa-responsive rest tremor followed by tachyphemia and postural instability. She initially presented with dopa-responsive slowness and tremor in the right hand. Two years later, she developed speech difficulties (tachyphemia) and a propensity for falls. Based on the diagnostic criteria for PSP, the patient was diagnosed with probable PSP-RS. The clinical manifestations observed in our patient are unique and are considered important for illustrating a broad spectrum of PSP syndrome.

Introduction

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of 4-repeat tau in neurons, with the phenotype determined by the development and spread of tau pathology. PSP phenotypes now extend beyond the classic PSP with Richardson's syndrome (PSP-RS), which includes an insidious onset and progressive symptoms such as postural instability, falls, gait disturbance, supranuclear vertical gaze abnormalities, pseudobulbar palsy, rigidity in extension, and dysexecutive syndrome (1). After several revisions, the diagnostic criteria for PSP have been greatly expanded to include the phenotypes associated with the disease. The scoring system prioritizes the occurrence of easy falls within 3 years of symptom onset, thus allowing for the diagnosis of PSP even in cases with clear dopa-responsive parkinsonism (2).

Tachyphemia, also known as speech festination, is characterized by an abnormally rapid speech rate and is well documented in patients with a specific subtype of PSP. Pure akinesia with gait freezing (PAGF) emerged as a distinct clinical form in 2007 and it was isolated from PSP-RS and PSP-Parkinsonism. PAGF is characterized by a frozen gait and speech, pronounced postural instability, a lack of limb rigidity, and unresponsiveness to levodopa (3). Till 2017, when PAGF was incorporated into the revised PSP classification as PSP with progressive gait freezing (PSP-PGF), tachyphemia was considered to be a significant symptom of PAGF (1,2). Although the current diagnostic criteria do not address tachyphemia, this symptom remains present and represents one end of the diverse spectrum of PSP syndromes (4).

In this report, we describe a case of dopa-responsive rest tremors, followed by postural instability and dopa-refractory tachyphemia. This unique clinical manifestation is significant because it illustrates the variety of phenotypes that PSP can present with.

Case Report

A 71-year-old, right-handed woman with a history of hypertension and chronic constipation was admitted to our hospital. There was no family history of neurological diseases. Three years prior to presentation, she had experienced tremors in her right hand and sought an investigation at the neurology department. A dopamine transporter scan revealed dot-like features with predominantly left-sided decreases (Figure). Dopamine replacement therapy alleviated her clinical symptoms, including slowness, and zonisamide was added to further improve her tremor with a continued good response to levodopa. A year before this visit, her family noticed that her speech had become unnatural, and she experienced difficulty speaking. In addition, initiating walking had become challenging and occasionally the patient began to experience falls. These newly emerging symptoms were unresponsive to levodopa, thus prompting a referral to our hospital.

Figure.

Radiological images of our patient. T1-weighted magnetic resonance imaging (MRI) showing mild cortical atrophy without midbrain involvement (A). Dopamine transporter scintigraphy showing a bilateral decreased dopamine transporter reuptake (B). ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy demonstrated an early heart-to-mediastinum ratio of 2.37, a delayed heart-to-mediastinum ratio of 2.60 (cutoff>2.2), and a washout ratio of 5.6% (C).

Her speech was unusually fast, which made it difficult to understand what she was trying to say. When she became aware of the acceleration of speech, she spoke at a normal rate for a limited period of time. She tested positive for snout and palmomental reflexes and negative for forced grasping, applause signs, and apparent behavioral or personality changes. The smoothness of extraocular movements was disrupted during pursuit in both horizontal and vertical directions. A rounds-the-house sign was also observed. A series of classic parkinsonian features were present: mild bradykinesia, mild masked face, right-side dominant rest tremor accompanied by re-emergence after raising the hands, mild cog-wheel rigidity in the wrists and knees, and marked postural instability. Increased tendon reflexes were also documented.

After a complete washout of levodopa, a levodopa challenge test was conducted. The intravenous infusion of 50 mg levodopa resulted in a significant improvement in the tremor and gait freezing (Unified Parkinson's Disease Rating Scale, part III score decreased from 36 to 20 points) (Supplementary material 1). However, there was no change in the speech rate, as measured by the time taken to read short fairy tales (from 54 s to 56 s) (Supplementary material 2).

The patient's olfactory function was presumed to be normal, as the Odor Stick Identification Test for the Japanese scored 10 out of 12 (OSIT-J; Daiichi Yakuhin Sangyo, Tokyo, Japan; cutoff ＜8 points). The blood and cerebrospinal fluid test results were normal. Brain magnetic resonance imaging (MRI) showed modest atrophy of the cerebral cortex but no midbrain atrophy or enlargement of the third ventricle (Figure). Spinal cord MRI revealed no atrophy or lesions. ¹²³I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy showed no reduction in cardiac accumulation (Figure).

Discussion

Rest tremors, especially those showing dopamine reactivity, are often observed as one of the major symptoms of Parkinson's disease (PD) (5), and this symptom might be seen in disorders other than PD. PSP is relatively common among these disorders. Indeed, in a retrospective autopsy-confirmed PSP case series, 42% of the patients presented with tremor, and 12.5% of the remaining tremor responded well to levodopa (6). At the onset, our patient showed a clear response to levodopa and the presence of rest tremors of a limb meeting the criteria for PD; however, impaired balance appeared within 3 years of onset, leading to the red flag (7). Tremor-dominant PD patients often follow a more benign disease course, which may be due to a significantly lower load of cortical Lewy bodies, particularly in neocortical areas, compared with other PD phenotypes (8). Accordingly, the unfavorable course of the disease, with the early falls observed in our patient, is atypical for tremor-dominant PD.

Regarding the diagnostic criteria for PSP, the scores of each domain were O2: slow velocity of vertical saccades; P1: repeated unprovoked falls within 3 years of onset; A1: progressive gait freezing within 3 years of onset; A3: Parkinsonism, with tremors and asymmetric and levodopa responsiveness. Furthermore, if the Multiple Allocations eXtinction rule is applied, A3 is ignored owing to the presence of A1; our patient was classified as probable PSP-RS (9). A preserved cardiac accumulation of MIBG, the absence of hyposmia, and the rounds-the-houses sign were supported to rule out the diagnosis of PD (10-12).

Speech disorders in PSP typically involve a slow rate of speech, as observed in other Parkinsonian syndromes (13). However, patients with PSP-PAGF or PSP-PGF exhibit rapid speech despite being variants of PSP. This type of speech is referred to as tachyphemia, which is also known as speech festination (3,4). The pathological hallmark of PSP is the accumulation of tau in the subthalamic nucleus, substantia nigra, and globus pallidus, and the degree of tau accumulation is believed to contribute to subtype differences (1). Currently, the concept of PSP has expanded to include subtypes with cortical manifestations, such as non-fluent aphasia or limb apraxia, thus indicating the diverse distribution and development of the condition (2). Although the specific brain area associated with tachyphemia remains unknown, the fact that the patient could speak at a normal rate when she focused her attention her speaking speed suggests that this dysfunction involves higher-order systems rather than direct language output. Interestingly, it has been reported that more than half of the patients who underwent bilateral ultrasonographic pallidothalamic tractotomy had a deterioration of speech, including tachyphemia (14). In this context, tachyphemia observed in PSP could be interpreted as a result of neuronal degeneration in the output from the globus pallidus to the thalamus. Additionally, γ-aminobutyric acid has been identified as the neurotransmitter involved in the pallidothalamic tract, consistent with the dopamine refractoriness observed in our patient (15). However, one limitation associated with this report is the fact that it remains unclear whether the tachyphemia observed in this case was truly dopa-refractory because we could not rule out the possibility that the dose of the levodopa challenge test had been insufficient to improve tachyphemia (16).

Conclusion

PSP is a neurodegenerative disease characterized by the neuronal accumulation of 4-repeat tau, and recent research has expanded its clinical manifestations far beyond the classic PSP-RS. Depending on the distribution of degenerative sites, dopa-responsive rest tremor may precede PSP-RS and later present with tachyphemia, as observed in our patient. The current diagnostic criteria allow for the diagnosis of PSP, even in the presence of dopa-responsive parkinsonism, if the patient has experienced a fall within the past 3 years. Therefore, it is expected that more cases previously thought to be PD will be reclassified as PSP accompanied by previously unseen phenotypes.

All procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the patient for publication of details of their medical case and any accompanying images.

The authors state that they have no Conflict of Interest (COI).

Financial Support

This work was supported in part by a Grant-in-Aid for Scientific Research (C) [grant numbers 20K07862 and 24K10614 (to N.S.)] and a Grant-in-Aid for Research Activity Start-up) [grant number 23K19557 (to S.I.)]. The authors declare no conflicts of interest relevant to this study.

Supplementary Material

Video 1: Motor symptoms of our patient

Before levodopa infusion, the patient showed a right-sided rest tremor (4-5 Hz), a re-emergent postural tremor, and a freezing gait when turning. These symptoms resolved after the levodopa infusion.

Video 2: Speech of our patient

The characteristic feature of our patient, fast speech, remained unchanged after levodopa infusion.