Clinical reasoning in a 37-year-old man with involuntary movements, gait disturbance, and hyperesthesia

How to diagnose and differentially diagnose patients with pancerebellar syndrome? The latest issue of Neurology's Clinical Reasoning Series reports a middle-aged male patient with involuntary movements, gait disturbance, and hyperesthesia.
Through this case, let's learn the diagnosis of pan-cerebellar syndrome together
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Translation: Reflection without trace This article is published by the author authorized by Yimaitong, please do not reprint without authorization
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The first patient was a 37-year-old right-handed man who presented with "progressive involuntary movements, unsteady gait, and hyperesthesia for 2.
5 years
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"
The patient complained of persistent involuntary movements of the head and trunk, severe speech impairment, dysphagia, blurred vision, and binocular diplopia
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No special medical history, no obvious medication history, no alcohol consumption
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Family history of note is the death of an uncle in his 50s due to unexplained gait impairment
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Physical examination showed normal vital signs; MMSE 28/30; left-directed square wave beats in in situ gaze, saccade tracking, bilateral horizontal gaze-induced nystagmus, restricted upper vision; obvious dysarthria with intermittent speech; residual skull Neurological examination showed no obvious abnormality
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Rhythmic and vibratory tremors with an amplitude of 8 cm and a frequency of 3-4 Hz in the head and trunk in resting and fixed positions; postural and motor tremors with an amplitude of 3 cm and a frequency of 3-4 Hz (up to 5 Hz) in the hands and feet; no spontaneous The startle response of myoclonus
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Muscle volume, tone and strength were normal, no fasciculations; tendon reflexes 2+
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Extensive hyperesthesia of extremities and trunk
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Bilateral extremities (lower extremities heavier than upper extremities) have poor distance discrimination; bilateral dyskinesia and incoordination of fine motor movements of fingers (right side is heavier than left side); severe trunk ataxia when standing upright, aggravated when standing; wide gait
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Problem thinking: 1.
Positioning diagnosis? 2.
What clinical tests should be performed? The second group of patients presented with a slowly progressive pan-cerebellar syndrome involving speech, eye movements, and marked ataxia of the trunk and extremities
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Pancerebellar syndrome is usually due to infectious or parainfectious, immune-mediated, or metabolic etiologies
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In this patient, given the slowly progressive symptoms, genetic, metabolic, or immune-mediated causes were primarily considered, with vascular and infectious etiologies unlikely
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However, diffuse hyperesthesia suggests involvement outside the cerebellum, including any part of the sensory pathway
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Systemic physical examination further revealed diffuse pruritus, poor sleep quality, frequent awakenings, alternating constipation and diarrhea, and dysuria
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Lost 20 pounds, no fever or night sweats
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Regular diet, no history of exposure to toxic substances
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Complete blood count, basic metabolic profile, thyroid-stimulating hormone, vitamin B12, vitamin E, iron metabolism profile, urinary copper, tissue transglutaminase IgA, and rheumatology profile were all unremarkable
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Brain MRI showed isolated diffuse cerebellar atrophy (Figure 1A-B)
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Paraneoplastic profiles (amphiphysin, Ma2/Ta, CV2.
1, Ri, Recoverin, SOX1, Titin, Yo, Hu, GAD65, and Tr/DNER) were negative; serum and cerebrospinal fluid (CSF) bacterial and viral cultures were negative
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CSF examination showed elevated protein and positive oligoclonal bands
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Contrast-enhanced CT of the chest, abdomen, and pelvis and fluorodeoxyglucose positron emission tomography scan revealed no malignancy
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Target gene testing for Friedreich's ataxia and spinocerebellar ataxia types 1, 2, 3, 4, and 6 revealed a heterozygous trinucleotide expansion in the frataxin gene and a point mutation on the other allele
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Questions to consider: 1.
Can the above results explain the patient's symptoms? 2.
What other checks should be considered? Part III The differential diagnosis of diffuse cerebellar atrophy is broad and includes intoxication, neurodegenerative disorders, hereditary cerebellar ataxia, paraneoplastic degeneration, and infectious or inflammatory cerebellar encephalitis
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Friedreich ataxia (FA) is the most common inherited ataxia, usually caused by a homozygous GAA trinucleotide expansion in the frataxin (FXN) gene on chromosome 9q13.
2
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Most patients had onset before the age of 20, and the greater the GAA amplification, the earlier the age of onset
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Although true heterozygotes are asymptomatic, compound heterozygotes (like this patient) and patients with small GAA amplification may develop late-onset Friedreich ataxia (LOFA), usually after age 20 years
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LOFA behaves similarly to FA
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Spinal cord atrophy is usually seen regardless of age at onset, but LOFA may have cerebellar vermis atrophy and fourth ventricle enlargement
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LOFA should be considered for young adults presenting with progressive ataxia
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Cerebellar atrophy may be present in many neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple system atrophy, and progressive supranuclear palsy
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Given the patient's age, cognitive preservation, and lack of other hallmark clinical or imaging features, and no history of exposure to alcohol, drugs, or other toxins, these disorders are unlikely
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Therefore, hereditary cerebellar ataxia, paraneoplastic cerebellar degeneration, and immune-mediated cerebellar encephalitis were primarily considered in this patient
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Hyperesthesia and autonomic dysfunction suggest systemic involvement or other pathologies
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Repeat enhanced MRI of the head and cervical spine 10 months later showed progressive diffuse cerebellar atrophy without significant spinal cord atrophy (Figure 1C-E)
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The inflammatory pattern of CSF with systemic symptoms is not typical for LOFA
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A compound heterozygous mutation is a variant of undetermined significance that may cause but does not fully explain the syndrome in this patient
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Given that FA is an untreatable disease, other potentially treatable causes need to be considered
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 Figure 1 Initial MRI and 10-month follow-up MRI
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Brain MRI T2 axial (A, B), cervical spine T2 sagittal (C), and brain T1 sagittal and coronal (D) showed significant progression within 10 months; no spinal cord atrophy (C)
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There were no enhancement lesions in the skull or cervical spine (not shown)
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Serum autoimmune encephalitis antibody spectrum showed high titers of anti-dipeptidyl peptidase-like protein 6 (DPPX)
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The patient received immunosuppressive therapy such as oral prednisone, IVIg, and rituximab
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After treatment, the startle response was significantly improved, and the involuntary movements and hyperesthesia were also temporarily improved, but the symptoms generally progressed
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The patient underwent five plasma exchange (PLEX) sessions for this, and his involuntary movements, pruritus, and hyperesthesia were further improved, and the ataxia of the trunk and extremities was slightly improved, but he was still unable to stand independently, and there was no improvement in speech
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Symptoms remained stable 6 weeks after PLEX, and the patient was scheduled for maintenance PLEX and rituximab for this purpose
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Discussion In 2012, Boronat et al.
described encephalitis mediated by autoantibodies targeting dipeptidyl peptidase-like protein 6 (DPPX)
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DPPX is a regulatory subunit of the voltage-gated rapidly inactivating potassium channel Kv4.
2.
5, and its autoantibody binding to DPPX leads to a decrease in its expression, resulting in hyperexcitability
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DPPX is highly expressed in the hippocampus, striatum, cerebellum, and myenteric plexus, and patients with anti-DPPX encephalitis experience a range of symptoms including cognitive impairment, motor impairment, cerebellar and brainstem dysfunction, and diarrhea with severe weight loss
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Abnormalities reported in previous case series include Parkinson's disease, buccolingual dyskinesia, tremor, myoclonus, rigidity, and startle, as well as postural hypotension and sleep disturbance
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Seizures, pruritus, and paresthesias have been reported to result from hyperexcitability of the central and peripheral nervous systems
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Patients may occasionally present with presentations resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-man syndrome
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Symptoms of anti-DPPX encephalitis typically progress over months to years
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Diagnosis is often delayed due to nonspecific clinical features and unremarkable neuroimaging
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Anti-DPPX encephalitis is often associated with tumors, particularly B-cell lymphomas
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CSF analysis may show increased cellularity and increased IgG
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Treatment of anti-DPPX encephalitis includes immunotherapy, mainly corticosteroids, and other treatments include tacrolimus, rituximab, IVIG, and PLEX
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In a review of 53 patients, 48% experienced significant improvement after immunotherapy
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Delays in treatment initiation may be associated with poorer outcomes
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Over time, untreated inflammation can lead to irreversible shrinkage
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Index: Dylan Meng, Aseel Alsalem, Christina Zhang, et al.
Clinical Reasoning: A 37-Year-Old Man With Involuntary Movements, Gait Disturbance, and Hyperesthesia.
Neurology published online March 29, 2022.
DOI 10.
1212/WNL.
0000000000200514