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Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases
Case report
Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases Marjorie A. Murphy MD , Joseph H. Friedman James W. Tetrud MD , Stewart A. Factor DO
MD ,
From the Department of Ophthalmology, Rhode Island Hospital, Brown Medical School (MAM); Department of Clinical Neurosciences, Memorial Hospital of Rhode Island, Brown Medical School (JHF); The Parkinson’s Institute Research and Treatment Center, Sunnyvale, CA (JWT); Parkinson’s Disease and Movement Disorder Center, Albany Medical Center (SAF)
Summary Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case. ª 2005 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(8), 941–945 0967-5868/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.10.013
Keywords: progressive supranuclear palsy, alzheimer’s disease, gaze palsy, parkinson’s disease, striatonigral degeneration, multiple system atrophy Received 30 April 2004 Accepted 11 October 2004 Correspondence to: Marjorie A. Murphy, M.D., Department of Ophthalmology, Rhode Island Hospital, Ambulatory Patient Center 7th Floor, 593 Eddy Street, Providence, RI 02903, Tel.: +401 444 4669; Fax: +401 444 6187; E-mail: [email protected]
INTRODUCTION Progressive supranuclear palsy (PSP) was first described in detail as a distinct clinicopathological entity by Steele, Richardson, and Olszewski in 1964.1 The clinical diagnosis of this disorder requires a supranuclear vertical gaze palsy plus a variable collection of other features.2 PSP is typically an akinetic rigid syndrome, without tremor, that can mimic Parkinson’s disease (PD), particularly in the early stages. There are a variety of signs that help to distinguish it from PD, including relative symmetry, early balance dysfunction and falls out of proportion to other aspects of gait impairment, lack of response to L-Dopa, neck extensor dystonia and stiffness, facial dystonia with a look of astonishment, and frontotemporal dementia. Although PSP is the most common primary parkinsonian disorder after PD, it is commonly underdiagnosed because the gaze palsy may not occur until late in the course and may be absent.3 Hence, the usual clinical diagnostic problem is the absence of a supranuclear gaze palsy in a patient suspected of having PSP, not the appearance of a gaze palsy in someone thought to have a different disorder. We present three cases that were diagnosed in life with PSP whose pathology re-
vealed no evidence of PSP but rather classic changes diagnostic of other common neurodegenerative disorders. None had autopsy detectable lesions to explain the gaze palsies. Case 1. In 1996, a 74-year-old Caucasian man was first evaluated for a four-year course of progressive bradykinesia and gait freezing. He also complained of blurred vision at a distance despite normal ophthalmological evaluations, and his wife reported a memory decline. Tremors had never been observed. He had recently had a cervical laminectomy for C3 to C6 stenosis. His medical history was positive for testicular cancer which had been irradiated 24 years prior, hypertension, cholecystectomy, arthritis, bladder urgency and frequency, and spinal stenosis. On neurologic examination he had mild hypophonia and moderate, symmetric bradykinesia and rigidity. Strength and deep tendon reflexes were normal. He could stand up only by pushing off the arms of his chair. He had a moderately stooped posture and walked slowly with a normal base, diminished stride and no arm swing. His balance was surprisingly good and he took only three steps backwards when pulled quite hard. On examination of his eye movements a severe limitation of both upgaze and downgaze was noted. Optokinetic nystagmus was mildly impaired horizontally and absent vertically. The doll’s eye maneuver could not be performed due to extreme neck stiffness. A brain MRI revealed atrophy in the parietal regions, but no midbrain or tectum atrophy or any other abnormalities. Carbidopa/levodopa 50/200 three times daily was of no benefit and was discontinued. Fourteen months after the initial evaluation he developed episodic involuntary eyelid closure, frequent falls, and required a walker. Balance was poor. An endocrinologist found no evidence of thyroid dysfunction. At his neuro-ophthalmological examination in 1998 he complained of inability to look down, blurred vision, and occasional diplopia. Examination revealed severe limitation of voluntary gaze in all directions with vertical gaze slightly more involved. The supranuclear component of this problem could not be demonstrated due to extreme neck stiffness. The patient died a year later. At autopsy the brain revealed global atrophy as well as atrophy of the subcortical white matter, basal ganglia, thalamus, hypothalamus, amygdala and hippocampus, moderate, patchy atherosclerotic vascular disease and pale substantia nigra. No focal lesions were seen, and Lewy bodies were present in appropriate locations for the diagnosis of idiopathic Parkinson’s disease to be made. No evidence of other neurodegenerative conditions were found. Case 2. A 76-year-old woman with a history of bipolar disorder began developing a progressive disorder of gait, balance, and tremor. At age 80, she had parkinsonian signs that included bradykinesia, a pill rolling-tremor, and cogwheel rigidity mainly on the left which did not respond to carbidopa/levodopa 25/100 and CR 50/200. She developed anxiety and agitation prompting a trial of olanzapine and valproic acid. She was evaluated by one of the authors (JWT) at the age of 83. She was suffering from progressive deterioration of personality, speech, and swallowing and required assistance to eat, dress, and ambulate. Her examination revealed moderately impaired recent memory, an inability to perform three-step commands, but she was fully oriented. There was no language dysfunction, but her speech was nasal and soft. She had nuchal dystonia and a broad-based gait. She could not walk without assistance and tended to freeze. She had a moderate postural, but no resting tremor. There were no signs of corticospinal tract, cerebellar or peripheral nerve impairment. A comprehensive neuro-ophthalmologic evaluation revealed hypometric saccades in all directions, ocular cogwheeling on pursuit attempts, a 60% restriction of upgaze, and 40% restriction of down gaze, mostly overcome with the doll’s eye maneuver. Eye closure apraxia was also noted. The neuro-ophthalmologist concluded that these 941
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findings were consistent with PSP. Cognition and gait continued to decline and sleep apnea developed. She died of pneumonia at the age of 84. Brain autopsy revealed numerous neuritic plaques in multiple neocortical sites as well as many neurofibrillary tangles, correlating with a Braak and Braak state V/VI. These finding were consistent with the CERAD criteria of Alzheimer’s disease. Lewy bodies were not identified by either H & E or synuclein immunohistochemistry. Globose tangles were not identified in the globus pallidus, subthalamic nucleus, periaqueductal gray, substantia nucleus, substantia nigra, dentate nucleus or locus coeruleus. The substantia nigra failed to show any significant loss of pigmented neurons and there was a lack of significant cerebral vascular disease. Thus, the pathological finding supported a diagnosis of Alzheimer’s disease, but not PSP or Parkinson’s disease. Case 3. A 79-year-old woman was first seen in 1995 with a recent onset of micrographia and diminished dexterity. Her brother had been diagnosed with Parkinson’s disease at age 75. On examination mental status was normal. Eye movements were full with the exception of mildly saccadic pursuit and impaired convergence. Optokinetic nystagmus was normal. She had a mildly masked face, mild tongue tremor, and significant neck rigidity. Motor strength and reflexes were normal. She had no extremity tremor. She had moderate rigidity in all limbs and marked bradykinesia. She had no sensory abnormalities, apraxia, or ataxia. She needed to push off the armrests to stand up from a chair. She had a stooped posture. She took small steps and had a cautious gait. She needed multiple steps to pivot. There was decreased arm swing and mild retropulsion. Her UPDRS motor score was 45 and a diagnosis of Parkinson’s disease was made. Carbidopa/levodopa induced improvement of voice, drooling, walking and rigidity and the UPDRS motor score improved to 30 two months later. Within one month she fractured her hip and required a walker. Her UPDRS increased to 39 despite an increase in levodopa to 750 mg/d. Eight months after the initial visit she developed random freezing and worsened parkinsonism. Pergolide 3 mg/d was added without benefit. Ten months later she started having difficulty with downgaze but optokinetic nystagmus was normal. Four months later vertical OKNs were abnormal. Her eyelids became retracted and her facial expression became more typical of PSP. UPDRS motor score was 67. Two years after the first visit horizontal pursuits were saccadic. There was vertical limitation of movement in both directions but worse looking down. Her speech worsened so that she was difficult to understand. She began drooling copious amounts of saliva and she was unable to walk, becoming wheelchair bound. She now began demonstrating limitation in horizontal eye movements, particularly to the left. One year later she was beginning to develop mild cognitive deficits with short-term memory difficulties. Vertical OKNs were completely absent. The rest of her exam was stable. The patient expired in September 1999 after becoming bedridden. On brain autopsy the basal ganglia showed softening and redbrown discoloration in the lateral putamen that was most marked in the posterior sections and was gradually less with more anterior sections. The substantia nigra had loss of pigment that was most marked in the lateral regions. The locus coeruleus was relatively preserved. There was no atrophy of the olive, pons, or cerebellum. On microscopic evaluation, the neocortex demonstrated few senile plaques and no neurofibrillary tangles with thioflavin-S fluorescent microscopy. The senile plaques were primarily diffuse in nature without amyloid cores. In the visual cortex they were associated with amyloid angiopathy of small vessels in layer IV. The hippocampus was normal with only a few diffuse plaques and a rare isolated neurofibrillary tangle. The same was true for entorhinal cortex, basal nucleus of Meynert and amygdala. The Journal of Clinical Neuroscience (2005) 12(8)
basal ganglia were remarkable for severe neuronal loss and gliosis in the lateral putamen. This was much worse in the posterior putamen. The caudate nucleus and globus pallidus were much less affected. There was mild neuronal loss and gliosis in the globus pallidus. In all areas of the basal ganglia there were many a-synuclein-positive glial cytoplasmic inclusions and some extracellular brown granular pigment, as well as pigment within the glial cells. The blood vessels of the globus pallidus were extensively mineralized. The substantia nigra had neuronal loss with extra neuronal pigment and gliosis which was most marked in the lateral and rostral regions. There were no Lewy bodies or neurofibrillary tangles but glial cytoplasmic inclusions were present. Glial inclusions were also seen in the pontine base as well as synuclein-positive neuritic processes and a few synuclein-positive neuronal cytoplasmic inclusions. There were also glial inclusions in the inferior olive. The cerebellum demonstrated mild patchy Purkinje cell loss and rare axonal torpedoes. The cytoplasmic glial inclusions were seen within oligodendrocytes. The final neuropathological diagnosis was multiple system atrophy (striatonigral degeneration-type). DISCUSSION The diagnosis of PSP can be a difficult one, and both false positive and false negative misdiagnoses may occur.4 Pathologically confirmed cases of cerebrovascular disease, diffuse Lewy body disease, multiple system atrophy (MSA), CBD, subcortical gliosis, motor neuron disease, Pick’s disease, pallidoluysonigral atrophy, Whipple’s disease, neurosyphilis, and prion disease have all been clinically misdiagnosed as PSP.5–19 On the other hand, autopsy confirmed cases of PSP have been misdiagnosed as Parkinson’s disease, CBD, MSA, and Alzheimer’s disease.2,11,20–24 Our patients’ clinical characteristics are summarized in Table 1. Supranuclear vertical gaze paresis is considered the primary clinical hallmark of PSP. Upgaze paresis, however, may be present in normal aging25 and may also be a nonspecific sign in other neurodegenerative conditions including idiopathic PD. Supranuclear downgaze paresis is the most specific sign of PSP, although it occurs in CBD6,26 and uncommonly in other conditions.27 The salient diagnostic features of PSP are summarized in Table 2. Litvan3 notes that several features should make one suspect a diagnosis of PSP, including early instability and falls, particularly during the first year of symptom onset, florid frontal lobe symptomatology, and marked slowing of vertical saccades which usually precedes the development of vertical supranuclear gaze palsy. Likewise, Collins et al.28 noted in their post mortem series that early pronounced gait imbalance and supranuclear downgaze
Table 1 Summary of patient clinical characteristics Patient no.
Gender Age at onset Durations (years) Gradually progressive disorder Vertical gaze palsy Late horizontal gaze palsy Bradykinesia Neck rigidity Postural instability Gait disturbance Falls Cognitive deficits Tremor Transient levodopa response
1
2
3
M 70 7 + + + + + + + + + – –
F 76 8 + + – + + + + + + + –
F 79 4 + + + + + + + + + – +
ª 2005 Elsevier Ltd. All rights reserved.
Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases 943
Table 2 Summary of diagnostic features of PSP Clinical characteristics Onset after age 40 Gradually progressive disorder Vertical supranuclear gaze palsy Postural instability with falls in the first year Subcortical dementia Eye movement recordings Decreased horizontal saccade velocity and accuracy with preserved latency Frequent square wave jerks Errors in antisaccade task MRI findings Midbrain atrophy with AP diameter < 16 mm on axial T2-weighted images
paresis were the two signs that are ‘‘red flags’’ for the diagnosis of PSP. PSP was the first dementing illness to be classified as a ‘‘subcortical’’ dementia29, a designation intended to distinguish the signs and symptoms of this type of dementia from that of Alzheimer’s disease and other ‘‘cortical’’ dementias. The ‘‘cortical’’ dementias are characterized by deficits such as aphasia and apraxia, which were then thought to be localized to cortical structures. Subcortical dementias involve deficiencies in memory and executive function. The memory problems are more likely to be deficits in retrieval than deficits in laying down the memory trace itself, so that cues are much more helpful in subcortical than cortical dementias. Not all patients with PSP become demented, but it is common30, and occasional patients will be referred first to a dementia clinic before the motor signs become prominent. Among the subcortical dementias, such as PSP, Parkinson’s disease and multiple system atrophy, there may also be distinctions. PSP appears to cause greater problems in phonemic and semantic fluency than the other two31. Slowing of either upward or downward vertical saccades, before the range of downward gaze becomes restricted, is an early sign of PSP that may be as specific as an actual limitation of gaze.2 In some PSP patients, limitation of upward gaze may occur before limitation of downward gaze. Other common ocular motor signs of PSP2 are (1) greater involvement of vertical than horizontal eye movements, (2) excessive frequency or amplitude of square wave jerks (3) slowness of eyelid opening or closure, and (4) difficulty performing the antisaccade task (looking in the direction opposite to a novel stimulus). With vestibular and optokinetic stimulation, the initiation of quick phases is impaired, leading to a tonic deviation of the eyes in a lateral position in the orbit. Based on clinical observations and their eye movement recordings, Troost and Daroff32 proposed the following progression of eye movement abnormalities in PSP. The earliest abnormalities of horizontal eye movements in PSP are square-wave jerks during fixation, cogwheel pursuit, and hypometric saccades with prolonged duration saccadic steps. At this time, saccades and pursuit in the vertical plane are almost invariably abnormal; usually they are absent downward and grossly impaired in terms of amplitude and gain in the upward direction. As the horizontal pursuit gain gradually decreases toward zero, the saccadic velocity slows. Then both horizontal pursuit and refixation are accomplished by slow, multi-stepped saccades. As the disease progresses further the amplitude gradually becomes limited. When voluntary eye movements are totally paralyzed, vestibular compensatory eye movements remain. Ultimately, if the patient lives long enough, the ocular motor neurons become involved, with paralysis of all reflex and voluntary eye movements. ª 2005 Elsevier Ltd. All rights reserved.
Eye movement recordings may help to distinguish patients with corticobasal degeneration from those with PSP33 and may therefore be a useful adjunct in the evaluation of patients with suspected PSP. In a longitudinal study of eye movements focused on horizontal saccades in PSP patients, Rivaud-Pechoux et al.33 and found an early decrease in saccade velocity and accuracy, high percentage of errors in the antisaccade task, and frequent presence of square wave jerks but preserved saccade latency. Repeated study of eye movements in the clinically diagnosed probable CBD patients showed an increased latency during the course of the disease. There was an increased percentage of errors in the antisaccade task, but an absence of decreased horizontal saccade velocity and accuracy and infrequent presence of square-wave jerks throughout the course of the disease. For horizontal saccades, latency defects are more prominent in CBD and slow saccades and square-wave jerks more common in PSP. Although vertical saccade impairment is the other major criterion in PSP, some CBD patients might show slow vertical saccades later in the disease but with less severity. In addition to eye movement recordings, MRI has been reported to aid in the clinical diagnosis of PSP. Warmuth-Metz et al.34 reported that patients with PSP had lower midbrain diameters than patients with PD and control subjects without any overlap between these two groups. They concluded that measurement of anteroposterior diameter of the midbrain on axial T2-weighted MRI’s is a reliable means to differentiate patients with PSP from those with PD on an individual basis and should be incorporated into the diagnostic criteria for PSP. Anteroposterior midbrain diameters less than 16 mm strongly argue against the diagnosis of PD, with values less than 14 mm found only in patients with PSP. Bhidayasiri et al.35 developed the following hypothetical scheme to account for clinical disorders of vertical gaze. Each rostral interstitial nucleus of the medial longitutidinal faciculus (riMLF) contains burst neurons for both up and down saccades. Saccadic innervation from the riMLF is unilateral to depressor muscles but bilateral to elevator muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye-head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commisure (PC) is the route by which INC projects to ocular motor neurons. Inactivation of PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Discrete lesions of the riMLF, INC, and mesencephalic reticular formation (MRF) may variably be caused by PSP as well as haemorrhage, infarction, metabolic disorders (e.g. Niemann-Pick type C), and compressive lesions. The etiology of the vertical gaze palsies in our three patients is unknown. Though not specifically noted at autopsy, it is nonetheless possible that focal abnormalities of the ri MLF,PC, INC, or MRF may have contributed to their vertical gaze palsies. Attempts have been made to identify a relationship between degeneration within particular brainstem nuclei and gaze palsy in PSP. In typical PSP cases, degeneration of midbrain cholinergic structures (including the riMLF, INC, and superior colliculus) appears to be crucial for the development of supranuclear vertical gaze palsy.36 Likewise, degenerative lesions of the pontine nuclei may be largely responsible for the horizontal smooth pursuit impairment in PSP. The cholinergic nucleus pontis centralis caudalis is severely affected, with loss of up to 60% of its neurons.37 In addition to cholinergic midbrain and pontine structures, the results of the study by Revesz et al.38 showed that omnipause neurons in the pontine nucleus raphe interpositus are affected in PSP. Journal of Clinical Neuroscience (2005) 12(8)
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These neurons act as a gating mechanism and exert tonic inhibition both on the horizontal and vertical saccadic burst neurons in the PPRF and on the vertical saccadic burst neurons in the riMLF.39,40 The morphological and functional integrity of the omnipause neurons is a prerequisite to normal saccades.39,40 The findings by Revesz et al.38 that omnipause neurons are severely depleted and affected by neurofibrillary tangle formation in cases of PSP with supranuclear gaze palsy and only to a lesser degree in those without supranuclear gaze palsy, suggests that degeneration of the nucleus raphe interpositus contributes to the abnormal eye movements in this condition. A study by Halliday et al.41 found a 40% greater decrease in the number of substantia nigra pars reticulata (SNr) neurons in cases of PSP with gaze palsy compared to those without. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in PSP. This study also suggests that the subthalamic nucleus (STN) may contribute to gaze palsy in PSP. The STN receives significant afferent input from the motor and premotor cortices, including the frontal eye fields and the supplementary eye fields42,43 and in turn provides excitatory regulation of the basal ganglia output nuclei, the GABAergic SNr and internal globus pallidus.44 Degeneration of this pathway could more directly influence gaze palsy by causing a reduction in the excitatory regulation of the GABAergic SNr by the STN. However, most of the PSP cases with gaze palsy had slightly more cell loss in the SNr compared with the STN, suggesting a similar involvement of both regions and the same outcome, that is, a decrease in the inhibitory output of the SNr.41 Lesions in the structures noted above were not found in our three patients, but neuronal loss in these areas could easily have been missed. While the gold standard for the diagnosis of PSP remains neuropathologic examination, the use of ancillary tests such as eye movement recordings and MRI may increase clinical diagnostic accuracy. Unfortunately, none of our cases underwent any of the aforementioned studies. These cases serve as a reminder that one should consider diagnostic entities other than PSP in parkinsonian patients who develop prominent eye movement abnormalities.
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First case report of X linked dystonia parkinsonism (XDP) or ‘lubag’ in Australia 945
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First case report of X linked dystonia parkinsonism (XDP) or ‘lubag’ in Australia C. Plummer1,2 MBBS , J. Bradfield2 FRACP , A.B. Singleton3 BS , D. Hernandez3 BS , A.A. Singleton3 PHD , J. O’Sullivan2 FRACP 1 St Vincent’s Hospital, Melbourne, Victoria, Australia, 2 Royal Brisbane Hospital, Brisbane, Queensland, Australia, 3 Mayo Clinic, Jacksonville, Florida, USA
tary neck movements. Our patient presented with a history of repetitive jaw contractions progressing over six months to a severe generalised dystonia manifested by torticollis, retrocollis, upper and lower limb hyperextension, and mandibular thrusting. Neurological examination revealed saccadic pursuit, hypermetric saccades, mild cogwheel rigidity, bradykinesia of the left upper limb and abbreviated stride length. He had been well up to three years ago when he emigrated to Australia. His dystonia was temporarily abated by distraction techniques such as directed voluntary arm swing during ambulation and by assuming a reversed seating position on a chair using the backrest for support. He was placed on a several medications with modest and generally transient improvement. Fifteen months later his disease had progressed with the development of more violent axial hyperextension, severe torticollis, and further weight loss.
METHODS In order to confirm the patient was a carrier of the XDP haplotype we performed PCR amplification of microsatellite markers in and around the previously reported segregating region on chromosome 13 X (spanning approximately 400 kb) using the technique described elsewhere.1 For comparison, confirmed XDP cases were run in parallel.
RESULTS We confirmed that the subject possesses the segregating haplotype ZFP261 150bp, DXS10017 292bp and DXS10018 140bp.
Summary Purpose. To present the first genetically supported case of X linked dystonia parkinsonism (XDP) or ‘lubag’ reported in an Australian hospital. Methods. We performed PCR amplification of microsatellite markers in and around the previously described segregating region for the XDP haplotype. Results. Linkage was confirmed using markers ZNF261, DXS10017, and DXS10018. Conclusion. We present the first case of XDP or ‘lubag’ reported in an Australian hospital. It highlights the enlarging role of genetic testing in facilitating the diagnosis of dystonia in a clinical environment where a disease like XDP is rare, and where a corroborating family history may be unavailable. ª 2005 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(8), 945–946 0967-5868/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.10.012
Keywords: X linked dystonia parkinsonism, XDP, lubag, DYT3 Received 20 September 2004 Accepted 12 October 2004 Correspondence to: C. Plummer, St Vincents Hospital, 52 Victoria Parade, Fitzroy, Victoria, Australia 3065. Tel.: +0392882211; Fax: +0392883350; E-mail: [email protected]
INTRODUCTION X linked dystonia parkinsonism (XDP) or ‘lubag’ is a rare heredofamilial dystonia (DYT3) described in Filipino males. We describe the first case seen in an Australian hospital supported by DNA linkage analysis and provide a brief overview of the condition.
DISCUSSION XDP, or lubag, is endemic on the island of Panay, its establishment is based on a founder mutation event 2000 years ago carrying high penetrance.2 Around 300 cases have been described. Lubag manifests in the fourth or fifth decade as a focal, multifocal, or generalised dystonia variably admixed with signs of parkinsonism. Phenotypic expression can include chorea, myoclonus, and myorhythmia.3 Predominant, or even isolated, parkinsonism tends to be associated with a more favorable prognosis.4 Its rarity notwithstanding, it is the phenotypic heterogeneity of XDP then that can contribute to misdiagnosis. Genetic testing is therefore indicated when the condition is suspected. Indeed, subsequent to the linkage analysis performed on our subject, the specific mutation on the X chromosome has been identified.5 In light of this, we propose to have the proband retested for further confirmation of the diagnosis and, if possible, we will offer such testing to consenting relatives. There is no long term effective treatment for XDP and the majority of patients become significantly disabled by five years from disease onset.6 The application of diversion strategies such as directed arm swing can offer some element of symptomatic relief to these patients in the face of the characteristically poor response of XDP to drug therapy. Surgical experience is limited in XDP and the role of pallidal stimulation and pallidotomy in managing these difficult cases remains unknown. Two cases treated by pallidotomy in the USA died within 48 hours of surgery.7 Death is typically from aspiration pneumonia.
CASE
CONCLUSION
The patient, a 42 year old male, was born in Negros as were his parents. His paternal great grandparents were from Panay. The patient’s brother has a ten year history of uncharacterised involun-
We present the first case of XDP or ‘lubag’ reported in an Australian hospital. It highlights the enlarging role of genetic testing in facilitating the diagnosis of dystonia in a clinical environment
ª 2005 Elsevier Ltd. All rights reserved.
Journal of Clinical Neuroscience (2005) 12(8)
Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases Marjorie A. Murphy MD , Joseph H. Friedman James W. Tetrud MD , Stewart A. Factor DO
MD ,
From the Department of Ophthalmology, Rhode Island Hospital, Brown Medical School (MAM); Department of Clinical Neurosciences, Memorial Hospital of Rhode Island, Brown Medical School (JHF); The Parkinson’s Institute Research and Treatment Center, Sunnyvale, CA (JWT); Parkinson’s Disease and Movement Disorder Center, Albany Medical Center (SAF)
Summary Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case. ª 2005 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(8), 941–945 0967-5868/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.10.013
Keywords: progressive supranuclear palsy, alzheimer’s disease, gaze palsy, parkinson’s disease, striatonigral degeneration, multiple system atrophy Received 30 April 2004 Accepted 11 October 2004 Correspondence to: Marjorie A. Murphy, M.D., Department of Ophthalmology, Rhode Island Hospital, Ambulatory Patient Center 7th Floor, 593 Eddy Street, Providence, RI 02903, Tel.: +401 444 4669; Fax: +401 444 6187; E-mail: [email protected]
INTRODUCTION Progressive supranuclear palsy (PSP) was first described in detail as a distinct clinicopathological entity by Steele, Richardson, and Olszewski in 1964.1 The clinical diagnosis of this disorder requires a supranuclear vertical gaze palsy plus a variable collection of other features.2 PSP is typically an akinetic rigid syndrome, without tremor, that can mimic Parkinson’s disease (PD), particularly in the early stages. There are a variety of signs that help to distinguish it from PD, including relative symmetry, early balance dysfunction and falls out of proportion to other aspects of gait impairment, lack of response to L-Dopa, neck extensor dystonia and stiffness, facial dystonia with a look of astonishment, and frontotemporal dementia. Although PSP is the most common primary parkinsonian disorder after PD, it is commonly underdiagnosed because the gaze palsy may not occur until late in the course and may be absent.3 Hence, the usual clinical diagnostic problem is the absence of a supranuclear gaze palsy in a patient suspected of having PSP, not the appearance of a gaze palsy in someone thought to have a different disorder. We present three cases that were diagnosed in life with PSP whose pathology re-
vealed no evidence of PSP but rather classic changes diagnostic of other common neurodegenerative disorders. None had autopsy detectable lesions to explain the gaze palsies. Case 1. In 1996, a 74-year-old Caucasian man was first evaluated for a four-year course of progressive bradykinesia and gait freezing. He also complained of blurred vision at a distance despite normal ophthalmological evaluations, and his wife reported a memory decline. Tremors had never been observed. He had recently had a cervical laminectomy for C3 to C6 stenosis. His medical history was positive for testicular cancer which had been irradiated 24 years prior, hypertension, cholecystectomy, arthritis, bladder urgency and frequency, and spinal stenosis. On neurologic examination he had mild hypophonia and moderate, symmetric bradykinesia and rigidity. Strength and deep tendon reflexes were normal. He could stand up only by pushing off the arms of his chair. He had a moderately stooped posture and walked slowly with a normal base, diminished stride and no arm swing. His balance was surprisingly good and he took only three steps backwards when pulled quite hard. On examination of his eye movements a severe limitation of both upgaze and downgaze was noted. Optokinetic nystagmus was mildly impaired horizontally and absent vertically. The doll’s eye maneuver could not be performed due to extreme neck stiffness. A brain MRI revealed atrophy in the parietal regions, but no midbrain or tectum atrophy or any other abnormalities. Carbidopa/levodopa 50/200 three times daily was of no benefit and was discontinued. Fourteen months after the initial evaluation he developed episodic involuntary eyelid closure, frequent falls, and required a walker. Balance was poor. An endocrinologist found no evidence of thyroid dysfunction. At his neuro-ophthalmological examination in 1998 he complained of inability to look down, blurred vision, and occasional diplopia. Examination revealed severe limitation of voluntary gaze in all directions with vertical gaze slightly more involved. The supranuclear component of this problem could not be demonstrated due to extreme neck stiffness. The patient died a year later. At autopsy the brain revealed global atrophy as well as atrophy of the subcortical white matter, basal ganglia, thalamus, hypothalamus, amygdala and hippocampus, moderate, patchy atherosclerotic vascular disease and pale substantia nigra. No focal lesions were seen, and Lewy bodies were present in appropriate locations for the diagnosis of idiopathic Parkinson’s disease to be made. No evidence of other neurodegenerative conditions were found. Case 2. A 76-year-old woman with a history of bipolar disorder began developing a progressive disorder of gait, balance, and tremor. At age 80, she had parkinsonian signs that included bradykinesia, a pill rolling-tremor, and cogwheel rigidity mainly on the left which did not respond to carbidopa/levodopa 25/100 and CR 50/200. She developed anxiety and agitation prompting a trial of olanzapine and valproic acid. She was evaluated by one of the authors (JWT) at the age of 83. She was suffering from progressive deterioration of personality, speech, and swallowing and required assistance to eat, dress, and ambulate. Her examination revealed moderately impaired recent memory, an inability to perform three-step commands, but she was fully oriented. There was no language dysfunction, but her speech was nasal and soft. She had nuchal dystonia and a broad-based gait. She could not walk without assistance and tended to freeze. She had a moderate postural, but no resting tremor. There were no signs of corticospinal tract, cerebellar or peripheral nerve impairment. A comprehensive neuro-ophthalmologic evaluation revealed hypometric saccades in all directions, ocular cogwheeling on pursuit attempts, a 60% restriction of upgaze, and 40% restriction of down gaze, mostly overcome with the doll’s eye maneuver. Eye closure apraxia was also noted. The neuro-ophthalmologist concluded that these 941
942 Murphy et al.
findings were consistent with PSP. Cognition and gait continued to decline and sleep apnea developed. She died of pneumonia at the age of 84. Brain autopsy revealed numerous neuritic plaques in multiple neocortical sites as well as many neurofibrillary tangles, correlating with a Braak and Braak state V/VI. These finding were consistent with the CERAD criteria of Alzheimer’s disease. Lewy bodies were not identified by either H & E or synuclein immunohistochemistry. Globose tangles were not identified in the globus pallidus, subthalamic nucleus, periaqueductal gray, substantia nucleus, substantia nigra, dentate nucleus or locus coeruleus. The substantia nigra failed to show any significant loss of pigmented neurons and there was a lack of significant cerebral vascular disease. Thus, the pathological finding supported a diagnosis of Alzheimer’s disease, but not PSP or Parkinson’s disease. Case 3. A 79-year-old woman was first seen in 1995 with a recent onset of micrographia and diminished dexterity. Her brother had been diagnosed with Parkinson’s disease at age 75. On examination mental status was normal. Eye movements were full with the exception of mildly saccadic pursuit and impaired convergence. Optokinetic nystagmus was normal. She had a mildly masked face, mild tongue tremor, and significant neck rigidity. Motor strength and reflexes were normal. She had no extremity tremor. She had moderate rigidity in all limbs and marked bradykinesia. She had no sensory abnormalities, apraxia, or ataxia. She needed to push off the armrests to stand up from a chair. She had a stooped posture. She took small steps and had a cautious gait. She needed multiple steps to pivot. There was decreased arm swing and mild retropulsion. Her UPDRS motor score was 45 and a diagnosis of Parkinson’s disease was made. Carbidopa/levodopa induced improvement of voice, drooling, walking and rigidity and the UPDRS motor score improved to 30 two months later. Within one month she fractured her hip and required a walker. Her UPDRS increased to 39 despite an increase in levodopa to 750 mg/d. Eight months after the initial visit she developed random freezing and worsened parkinsonism. Pergolide 3 mg/d was added without benefit. Ten months later she started having difficulty with downgaze but optokinetic nystagmus was normal. Four months later vertical OKNs were abnormal. Her eyelids became retracted and her facial expression became more typical of PSP. UPDRS motor score was 67. Two years after the first visit horizontal pursuits were saccadic. There was vertical limitation of movement in both directions but worse looking down. Her speech worsened so that she was difficult to understand. She began drooling copious amounts of saliva and she was unable to walk, becoming wheelchair bound. She now began demonstrating limitation in horizontal eye movements, particularly to the left. One year later she was beginning to develop mild cognitive deficits with short-term memory difficulties. Vertical OKNs were completely absent. The rest of her exam was stable. The patient expired in September 1999 after becoming bedridden. On brain autopsy the basal ganglia showed softening and redbrown discoloration in the lateral putamen that was most marked in the posterior sections and was gradually less with more anterior sections. The substantia nigra had loss of pigment that was most marked in the lateral regions. The locus coeruleus was relatively preserved. There was no atrophy of the olive, pons, or cerebellum. On microscopic evaluation, the neocortex demonstrated few senile plaques and no neurofibrillary tangles with thioflavin-S fluorescent microscopy. The senile plaques were primarily diffuse in nature without amyloid cores. In the visual cortex they were associated with amyloid angiopathy of small vessels in layer IV. The hippocampus was normal with only a few diffuse plaques and a rare isolated neurofibrillary tangle. The same was true for entorhinal cortex, basal nucleus of Meynert and amygdala. The Journal of Clinical Neuroscience (2005) 12(8)
basal ganglia were remarkable for severe neuronal loss and gliosis in the lateral putamen. This was much worse in the posterior putamen. The caudate nucleus and globus pallidus were much less affected. There was mild neuronal loss and gliosis in the globus pallidus. In all areas of the basal ganglia there were many a-synuclein-positive glial cytoplasmic inclusions and some extracellular brown granular pigment, as well as pigment within the glial cells. The blood vessels of the globus pallidus were extensively mineralized. The substantia nigra had neuronal loss with extra neuronal pigment and gliosis which was most marked in the lateral and rostral regions. There were no Lewy bodies or neurofibrillary tangles but glial cytoplasmic inclusions were present. Glial inclusions were also seen in the pontine base as well as synuclein-positive neuritic processes and a few synuclein-positive neuronal cytoplasmic inclusions. There were also glial inclusions in the inferior olive. The cerebellum demonstrated mild patchy Purkinje cell loss and rare axonal torpedoes. The cytoplasmic glial inclusions were seen within oligodendrocytes. The final neuropathological diagnosis was multiple system atrophy (striatonigral degeneration-type). DISCUSSION The diagnosis of PSP can be a difficult one, and both false positive and false negative misdiagnoses may occur.4 Pathologically confirmed cases of cerebrovascular disease, diffuse Lewy body disease, multiple system atrophy (MSA), CBD, subcortical gliosis, motor neuron disease, Pick’s disease, pallidoluysonigral atrophy, Whipple’s disease, neurosyphilis, and prion disease have all been clinically misdiagnosed as PSP.5–19 On the other hand, autopsy confirmed cases of PSP have been misdiagnosed as Parkinson’s disease, CBD, MSA, and Alzheimer’s disease.2,11,20–24 Our patients’ clinical characteristics are summarized in Table 1. Supranuclear vertical gaze paresis is considered the primary clinical hallmark of PSP. Upgaze paresis, however, may be present in normal aging25 and may also be a nonspecific sign in other neurodegenerative conditions including idiopathic PD. Supranuclear downgaze paresis is the most specific sign of PSP, although it occurs in CBD6,26 and uncommonly in other conditions.27 The salient diagnostic features of PSP are summarized in Table 2. Litvan3 notes that several features should make one suspect a diagnosis of PSP, including early instability and falls, particularly during the first year of symptom onset, florid frontal lobe symptomatology, and marked slowing of vertical saccades which usually precedes the development of vertical supranuclear gaze palsy. Likewise, Collins et al.28 noted in their post mortem series that early pronounced gait imbalance and supranuclear downgaze
Table 1 Summary of patient clinical characteristics Patient no.
Gender Age at onset Durations (years) Gradually progressive disorder Vertical gaze palsy Late horizontal gaze palsy Bradykinesia Neck rigidity Postural instability Gait disturbance Falls Cognitive deficits Tremor Transient levodopa response
1
2
3
M 70 7 + + + + + + + + + – –
F 76 8 + + – + + + + + + + –
F 79 4 + + + + + + + + + – +
ª 2005 Elsevier Ltd. All rights reserved.
Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases 943
Table 2 Summary of diagnostic features of PSP Clinical characteristics Onset after age 40 Gradually progressive disorder Vertical supranuclear gaze palsy Postural instability with falls in the first year Subcortical dementia Eye movement recordings Decreased horizontal saccade velocity and accuracy with preserved latency Frequent square wave jerks Errors in antisaccade task MRI findings Midbrain atrophy with AP diameter < 16 mm on axial T2-weighted images
paresis were the two signs that are ‘‘red flags’’ for the diagnosis of PSP. PSP was the first dementing illness to be classified as a ‘‘subcortical’’ dementia29, a designation intended to distinguish the signs and symptoms of this type of dementia from that of Alzheimer’s disease and other ‘‘cortical’’ dementias. The ‘‘cortical’’ dementias are characterized by deficits such as aphasia and apraxia, which were then thought to be localized to cortical structures. Subcortical dementias involve deficiencies in memory and executive function. The memory problems are more likely to be deficits in retrieval than deficits in laying down the memory trace itself, so that cues are much more helpful in subcortical than cortical dementias. Not all patients with PSP become demented, but it is common30, and occasional patients will be referred first to a dementia clinic before the motor signs become prominent. Among the subcortical dementias, such as PSP, Parkinson’s disease and multiple system atrophy, there may also be distinctions. PSP appears to cause greater problems in phonemic and semantic fluency than the other two31. Slowing of either upward or downward vertical saccades, before the range of downward gaze becomes restricted, is an early sign of PSP that may be as specific as an actual limitation of gaze.2 In some PSP patients, limitation of upward gaze may occur before limitation of downward gaze. Other common ocular motor signs of PSP2 are (1) greater involvement of vertical than horizontal eye movements, (2) excessive frequency or amplitude of square wave jerks (3) slowness of eyelid opening or closure, and (4) difficulty performing the antisaccade task (looking in the direction opposite to a novel stimulus). With vestibular and optokinetic stimulation, the initiation of quick phases is impaired, leading to a tonic deviation of the eyes in a lateral position in the orbit. Based on clinical observations and their eye movement recordings, Troost and Daroff32 proposed the following progression of eye movement abnormalities in PSP. The earliest abnormalities of horizontal eye movements in PSP are square-wave jerks during fixation, cogwheel pursuit, and hypometric saccades with prolonged duration saccadic steps. At this time, saccades and pursuit in the vertical plane are almost invariably abnormal; usually they are absent downward and grossly impaired in terms of amplitude and gain in the upward direction. As the horizontal pursuit gain gradually decreases toward zero, the saccadic velocity slows. Then both horizontal pursuit and refixation are accomplished by slow, multi-stepped saccades. As the disease progresses further the amplitude gradually becomes limited. When voluntary eye movements are totally paralyzed, vestibular compensatory eye movements remain. Ultimately, if the patient lives long enough, the ocular motor neurons become involved, with paralysis of all reflex and voluntary eye movements. ª 2005 Elsevier Ltd. All rights reserved.
Eye movement recordings may help to distinguish patients with corticobasal degeneration from those with PSP33 and may therefore be a useful adjunct in the evaluation of patients with suspected PSP. In a longitudinal study of eye movements focused on horizontal saccades in PSP patients, Rivaud-Pechoux et al.33 and found an early decrease in saccade velocity and accuracy, high percentage of errors in the antisaccade task, and frequent presence of square wave jerks but preserved saccade latency. Repeated study of eye movements in the clinically diagnosed probable CBD patients showed an increased latency during the course of the disease. There was an increased percentage of errors in the antisaccade task, but an absence of decreased horizontal saccade velocity and accuracy and infrequent presence of square-wave jerks throughout the course of the disease. For horizontal saccades, latency defects are more prominent in CBD and slow saccades and square-wave jerks more common in PSP. Although vertical saccade impairment is the other major criterion in PSP, some CBD patients might show slow vertical saccades later in the disease but with less severity. In addition to eye movement recordings, MRI has been reported to aid in the clinical diagnosis of PSP. Warmuth-Metz et al.34 reported that patients with PSP had lower midbrain diameters than patients with PD and control subjects without any overlap between these two groups. They concluded that measurement of anteroposterior diameter of the midbrain on axial T2-weighted MRI’s is a reliable means to differentiate patients with PSP from those with PD on an individual basis and should be incorporated into the diagnostic criteria for PSP. Anteroposterior midbrain diameters less than 16 mm strongly argue against the diagnosis of PD, with values less than 14 mm found only in patients with PSP. Bhidayasiri et al.35 developed the following hypothetical scheme to account for clinical disorders of vertical gaze. Each rostral interstitial nucleus of the medial longitutidinal faciculus (riMLF) contains burst neurons for both up and down saccades. Saccadic innervation from the riMLF is unilateral to depressor muscles but bilateral to elevator muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye-head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commisure (PC) is the route by which INC projects to ocular motor neurons. Inactivation of PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Discrete lesions of the riMLF, INC, and mesencephalic reticular formation (MRF) may variably be caused by PSP as well as haemorrhage, infarction, metabolic disorders (e.g. Niemann-Pick type C), and compressive lesions. The etiology of the vertical gaze palsies in our three patients is unknown. Though not specifically noted at autopsy, it is nonetheless possible that focal abnormalities of the ri MLF,PC, INC, or MRF may have contributed to their vertical gaze palsies. Attempts have been made to identify a relationship between degeneration within particular brainstem nuclei and gaze palsy in PSP. In typical PSP cases, degeneration of midbrain cholinergic structures (including the riMLF, INC, and superior colliculus) appears to be crucial for the development of supranuclear vertical gaze palsy.36 Likewise, degenerative lesions of the pontine nuclei may be largely responsible for the horizontal smooth pursuit impairment in PSP. The cholinergic nucleus pontis centralis caudalis is severely affected, with loss of up to 60% of its neurons.37 In addition to cholinergic midbrain and pontine structures, the results of the study by Revesz et al.38 showed that omnipause neurons in the pontine nucleus raphe interpositus are affected in PSP. Journal of Clinical Neuroscience (2005) 12(8)
944 Murphy et al.
These neurons act as a gating mechanism and exert tonic inhibition both on the horizontal and vertical saccadic burst neurons in the PPRF and on the vertical saccadic burst neurons in the riMLF.39,40 The morphological and functional integrity of the omnipause neurons is a prerequisite to normal saccades.39,40 The findings by Revesz et al.38 that omnipause neurons are severely depleted and affected by neurofibrillary tangle formation in cases of PSP with supranuclear gaze palsy and only to a lesser degree in those without supranuclear gaze palsy, suggests that degeneration of the nucleus raphe interpositus contributes to the abnormal eye movements in this condition. A study by Halliday et al.41 found a 40% greater decrease in the number of substantia nigra pars reticulata (SNr) neurons in cases of PSP with gaze palsy compared to those without. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in PSP. This study also suggests that the subthalamic nucleus (STN) may contribute to gaze palsy in PSP. The STN receives significant afferent input from the motor and premotor cortices, including the frontal eye fields and the supplementary eye fields42,43 and in turn provides excitatory regulation of the basal ganglia output nuclei, the GABAergic SNr and internal globus pallidus.44 Degeneration of this pathway could more directly influence gaze palsy by causing a reduction in the excitatory regulation of the GABAergic SNr by the STN. However, most of the PSP cases with gaze palsy had slightly more cell loss in the SNr compared with the STN, suggesting a similar involvement of both regions and the same outcome, that is, a decrease in the inhibitory output of the SNr.41 Lesions in the structures noted above were not found in our three patients, but neuronal loss in these areas could easily have been missed. While the gold standard for the diagnosis of PSP remains neuropathologic examination, the use of ancillary tests such as eye movement recordings and MRI may increase clinical diagnostic accuracy. Unfortunately, none of our cases underwent any of the aforementioned studies. These cases serve as a reminder that one should consider diagnostic entities other than PSP in parkinsonian patients who develop prominent eye movement abnormalities.
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First case report of X linked dystonia parkinsonism (XDP) or ‘lubag’ in Australia 945
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First case report of X linked dystonia parkinsonism (XDP) or ‘lubag’ in Australia C. Plummer1,2 MBBS , J. Bradfield2 FRACP , A.B. Singleton3 BS , D. Hernandez3 BS , A.A. Singleton3 PHD , J. O’Sullivan2 FRACP 1 St Vincent’s Hospital, Melbourne, Victoria, Australia, 2 Royal Brisbane Hospital, Brisbane, Queensland, Australia, 3 Mayo Clinic, Jacksonville, Florida, USA
tary neck movements. Our patient presented with a history of repetitive jaw contractions progressing over six months to a severe generalised dystonia manifested by torticollis, retrocollis, upper and lower limb hyperextension, and mandibular thrusting. Neurological examination revealed saccadic pursuit, hypermetric saccades, mild cogwheel rigidity, bradykinesia of the left upper limb and abbreviated stride length. He had been well up to three years ago when he emigrated to Australia. His dystonia was temporarily abated by distraction techniques such as directed voluntary arm swing during ambulation and by assuming a reversed seating position on a chair using the backrest for support. He was placed on a several medications with modest and generally transient improvement. Fifteen months later his disease had progressed with the development of more violent axial hyperextension, severe torticollis, and further weight loss.
METHODS In order to confirm the patient was a carrier of the XDP haplotype we performed PCR amplification of microsatellite markers in and around the previously reported segregating region on chromosome 13 X (spanning approximately 400 kb) using the technique described elsewhere.1 For comparison, confirmed XDP cases were run in parallel.
RESULTS We confirmed that the subject possesses the segregating haplotype ZFP261 150bp, DXS10017 292bp and DXS10018 140bp.
Summary Purpose. To present the first genetically supported case of X linked dystonia parkinsonism (XDP) or ‘lubag’ reported in an Australian hospital. Methods. We performed PCR amplification of microsatellite markers in and around the previously described segregating region for the XDP haplotype. Results. Linkage was confirmed using markers ZNF261, DXS10017, and DXS10018. Conclusion. We present the first case of XDP or ‘lubag’ reported in an Australian hospital. It highlights the enlarging role of genetic testing in facilitating the diagnosis of dystonia in a clinical environment where a disease like XDP is rare, and where a corroborating family history may be unavailable. ª 2005 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(8), 945–946 0967-5868/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.10.012
Keywords: X linked dystonia parkinsonism, XDP, lubag, DYT3 Received 20 September 2004 Accepted 12 October 2004 Correspondence to: C. Plummer, St Vincents Hospital, 52 Victoria Parade, Fitzroy, Victoria, Australia 3065. Tel.: +0392882211; Fax: +0392883350; E-mail: [email protected]
INTRODUCTION X linked dystonia parkinsonism (XDP) or ‘lubag’ is a rare heredofamilial dystonia (DYT3) described in Filipino males. We describe the first case seen in an Australian hospital supported by DNA linkage analysis and provide a brief overview of the condition.
DISCUSSION XDP, or lubag, is endemic on the island of Panay, its establishment is based on a founder mutation event 2000 years ago carrying high penetrance.2 Around 300 cases have been described. Lubag manifests in the fourth or fifth decade as a focal, multifocal, or generalised dystonia variably admixed with signs of parkinsonism. Phenotypic expression can include chorea, myoclonus, and myorhythmia.3 Predominant, or even isolated, parkinsonism tends to be associated with a more favorable prognosis.4 Its rarity notwithstanding, it is the phenotypic heterogeneity of XDP then that can contribute to misdiagnosis. Genetic testing is therefore indicated when the condition is suspected. Indeed, subsequent to the linkage analysis performed on our subject, the specific mutation on the X chromosome has been identified.5 In light of this, we propose to have the proband retested for further confirmation of the diagnosis and, if possible, we will offer such testing to consenting relatives. There is no long term effective treatment for XDP and the majority of patients become significantly disabled by five years from disease onset.6 The application of diversion strategies such as directed arm swing can offer some element of symptomatic relief to these patients in the face of the characteristically poor response of XDP to drug therapy. Surgical experience is limited in XDP and the role of pallidal stimulation and pallidotomy in managing these difficult cases remains unknown. Two cases treated by pallidotomy in the USA died within 48 hours of surgery.7 Death is typically from aspiration pneumonia.
CASE
CONCLUSION
The patient, a 42 year old male, was born in Negros as were his parents. His paternal great grandparents were from Panay. The patient’s brother has a ten year history of uncharacterised involun-
We present the first case of XDP or ‘lubag’ reported in an Australian hospital. It highlights the enlarging role of genetic testing in facilitating the diagnosis of dystonia in a clinical environment
ª 2005 Elsevier Ltd. All rights reserved.
Journal of Clinical Neuroscience (2005) 12(8)