Keywords
hereditary spastic paraplegia - parkinsonism - DatSCAN - pyramidal syndromes - diagnosis
Key Messages
Parkinsonian signs may be an accompanying feature in patients with hereditary spastic
paraparesis (HSP). Dopaminergic neuron vulnerability in HSP patients raises the possibility
that degeneration of central dopaminergic neurons may contribute to the phenotype
of HSP.
Introduction
A 69-year-old male patient presented with progressive gait disturbance that had emerged
over the last 6 years. The patient stated that he felt stiffness in his feet and suffered
from slowness particularly in his lower extremities. One year after the onset of these
symptoms, the patient had applied to another neurology clinic where the lower extremity
spasticity was noted. However, 2 years later, levodopa was initiated for newly developing
parkinsonian signs that had provided a marked improvement in his gait. At follow-up,
his gait gradually deteriorated, and levodopa-induced dyskinesia had also emerged
the last year. Further interrogation revealed that the patient suffered from constipation
for a long time and symptoms of rapid eye movement sleep behavior disorder for the
last few years. He had no symptoms such as dizziness, erectile dysfunction, or gastroparesis,
related to autonomic dysfunction. At admission to our clinic, the patient was on treatments
of levodopa/benserazide (4 × 125 mg), amantadine 100 mg, ropinirole 0.375 mg, and
levodopa/carbidopa 50/200 mg. He stated a benefit from levodopa lasting for 3 hours;
however, he suffered from severe “off” periods before levodopa dosage. Besides, severe,
disabling dyskinesias were observed during medication “on” period. His parents were
nonconsanguineous and the family history was unremarkable. The patient was orientated
and cooperative. During the interview, the patient's communication and mental status
were evaluated to be within normal limits. His speech was compatible with spastic
dysarthria and palatal reflexes were bilaterally increased. The sensory, cerebellar
tests and motor examinations were within normal limits. However, the deep tendon reflexes
were increased, and severe lower extremity spasticity was observed. Confirming the
pyramidal tract dysfunction, bilateral Babinski sign and clonus reflexes were also
positive. Extrapyramidal examinations showed bilateral bradykinesia, rigidity, and
bradymimi. Besides, postural instability was apparent ([Supplementary Videos 1] and [2]). The results of the laboratory investigations including hemogram, routine serum
biochemistry and serum levels of vitamins B12 and E, homocysteine, ceruloplasmin,
venereal disease research laboratory, human immunodeficiency virus, and human T-lymphotropic
virus were unremarkable. The cranial magnetic resonance imaging (MRI) showed mild
atrophy of the cerebellum. Spinal MRI showed longitudinal spinal cord atrophy that
was prominent in the cervical and thoracic spine ([Fig. 1]). Nerve conduction study and needle electromyography (including various muscles
innervated by distinct symptoms in both upper and lower extremities) revealed normal
findings. Motor evoked potential responses, recorded bilaterally from the abductor
digiti minimi, were found to be delayed. We have excluded the structural, inflammatory,
and infectious causes, in addition to amyotrophic or primary lateral sclerosis, arteriovenous
fistulas that might explain the clinical manifestations. Taken together, the clinical
diagnosis of complicated HSP was established. Due to the atypical presentation of
pyramidal signs, the dopamine transport single-photon emission computed tomography
scan (DatSCAN) was also performed that showed decreased tracer uptake in the bilateral
striatum, more significant in the putamen. However, the next-generation sequencing-based
HSP gene panels and whole-exome sequencing results were unremarkable. The amantadine
dosage was increased to 300 mg daily that provided marked improvement in “on” period
dyskinesia.
Supplementary Video 1 The neurological exam of the patient recorded during off period.
Supplementary Video 2 The neurological exam of the patient recorded during on period showing severe levodopa-induced
dyskinesia.
Fig. 1 The cranial magnetic resonance imaging shows mild cerebellar atrophy and enlargement
of the fourth ventricle (A–B). The spinal cord atrophy is also observed that is prominent in the thoracic spinal
cord (C) (arrows).
HSP is diagnosed after a thorough clinical examination and the identification of typical
symptoms.[1] However, to confirm a molecular diagnosis of HSP, the identification of pathogenic
mutations in a spastic paraplegia (SPG)-designated gene is required. On the other
hand, despite the use of next-generation sequencing-based HSP gene panels or whole-exome
sequencing, a genetic diagnosis cannot be made in 51 to 71% of all suspected cases
of HSP.[1] In our patient, the genetic diagnosis was also lacking that was the main limitation
of the report. However, the clinical presentation and delayed motor evoked potential
responses and the laboratory data excluding the secondary causes led to the clinical
diagnosis of HSP. Recent reports emphasized that patients with complicated HSP display
widespread degenerative pathologies in the cerebellum, cerebral cortex, thalamus,
and brainstem.[2] However, parkinsonism is uncommon in HSP, and the related literature data is limited.[3]
[4]
[5] Therefore, the clinical manifestation of parkinsonism in our patient including severe
on and off periods in the early course of the disease and the DatSCAN results showing
decreased tracer uptake in the bilateral striatum is quite valuable. In a crucial
study, Kim et al investigated nine HSP patient with (99mTc) TRODAT-1 single-photon emission computed tomography and found reduced striatal
ligand uptake in images of four of the patients.[5] In a remarkable study using the Drosophila model of HSP,[6] the DatSCAN with 123I-ioflupane revealed that patients with the SPG11 mutation and parkinsonism exhibited
abnormal DAT binding potential. A study on 35 patients with HSP demonstrated that
21% (n = 7) of the patients had parkinsonian signs.[3] DatSCAN was performed in three of these patients that showed bilateral presynaptic
denervation in one patient, mild unilateral denervation in another subject, and normal
findings in the third patient.[3] In our patient, levodopa-induced dyskinesia had emerged in the early period of the
disease. The occurrence of dyskinesia in the early period suggests severe striatal
dopaminergic neuron damage and possible increased gamma-aminobutyric acid (GABA) (A)
receptors content in the internal globus pallidus that was shown to exist in postmortem
samples from levodopa-treated parkinsonian patients.[7] A comorbid idiopathic Parkinson disease (PD) is a crucial possibility that needs
to be excluded. However, the clinical manifestations of extrapyramidal signs were
bilateral, tremor was not present, and the emergence of the levodopa-induced dyskinesia
was at the very early period of the clinic, which was discordant for idiopathic PD.
Besides, presynaptic dopaminergic denervation was also symmetrical in contrast with
the findings in idiopathic PD.
The observations of dopaminergic neuron vulnerability in HSP patients raise the possibility
that degeneration of central dopaminergic neurons may contribute to the phenotype
of HSP. The documentation of these rare variants will aid to understand the unknown
pathophysiology of the disease course. The results of these reports may also suggest
alternative classification methods, such as parkinsonian-pyramidal syndromes.[4] These study results may also change the clinical evaluation processes of some subgroups
of patients with pyramidal syndromes and atypical scenarios.
