Neurology: Case of the Month

Check Your Diagnosis — Patient 7

Lori Guyton, M.D.

Diagnosis

Progressive Supranuclear Palsy (PSP)

Clinical Summary

This 48 year old female was referred to the Department of Neurology for evaluation of a two year history of weakness, imbalance (primarily postural instability), dysarthria, vision abnormalities, and a slow, slightly stiff gait without festination.

This patient's eye signs were an important clue to her diagnosis. Funduscopic exam revealed completely normal macula, vessels, and periphery in each eye. The cup to disc ratio was 0.2 in each eye, and there was no disk edema or optic atrophy. When asked to look in the various positions of gaze, she had a -3 under action of elevation and a -3.5 under action of depression. Horizontal gaze was normal. Doll's head maneuver was intact vertically. Bell's phenomenon was intact bilaterally. In summary, she had a vertical gaze palsy including down gaze, which was overcome with a doll's head maneuver vertically, indicating that the nuclear and infranuclear mechanisms for upward gaze were intact and that the defect was supranuclear.

The patient also had declined in work performance and exhibited bradykinesia. She had loss of facial expression, a decreased blink reflex, paucity of speech, dysarthria, and dysphagia. The differential diagnosis with this clinical picture of basal ganglia dysfunction included the following:

Parkinson's disease: Parkinson's disease is characterized by an asymmetric resting tremor, bradykinesia, and rigidity followed by postural instability. While this diagnosis was a consideration, it was less likely because of the significant supranuclear palsy.

Another consideration was Corticobasal Ganglionic Degeneration (CBGD). This condition is characterized by unilateral rigidity, cortical sensory symptoms, alien limb, and unilateral apraxia often using one hand to control the other. Contralateral symptoms, along with bulbar symptoms may then occur. Our patient did not fit the typical clinical picture for CBGD; there was no apraxia, alien limb, or cortical involvement.

Postencephalitic Parkinsonism: This diagnosis usually follows a history of fever, stupor, coma, and focal neurologic deficit. Although ophthalmoplegia was present in our patient, there was no history of fever or infection prior to the onset of her symptoms.

Multi-infarct Parkinsonism: This condition is characterized by progressive elements of parkinsonism. While there is difficulty initiating a step, there is no festination. When sitting, these patients can move their legs with great facility. This etiology is usually diagnosed by CT or MRI when multiple strokes are seen in the basal ganglia or brainstem. Our patient's MRI showed no evidence of prior strokes.

One must also consider the spectrum of Multi-System Atrophy, including Olivopontocerebellar Atrophy (OPCA) and Shy Drager Syndrome (SDS). OPCA is often inherited. It can be characterized by parkinsonism, ataxia, diplopia, horizontal gaze palsy, sluggish eye movements, and occasionally optic atrophy. OPCA does not respond well to L-dopa. In comparison, Shy Drager Syndrome results in autonomic dysfunction involving orthostasis, and bowel and bladder dysfunction. Our patient had no family history of similar symptoms, her horizontal eye movements were intact, and she had no evidence of orthostasis.

This brought us to our final consideration and the diagnosis of Progressive Supranuclear Palsy (PSP). This patient was felt to most likely represent the clinical picture of PSP. The gait impairment, postural instability, dysphagia, significant bilateral vertical gaze palsy, and decreased convergence with intact Bell's phenomenon and Doll's eyes maneuver, were all in accord with the diagnosis of PSP.

An EEG, MRI, EMG/NCV, and LP were performed. All were essentially normal other than the MRI which revealed a 6 mm microadenoma of the pituitary gland. The brainstem was completely normal without evidence of atrophy. The patient's clinical history, exam, and studies were consistent with the diagnosis of PSP.

As therapy, the patient was continued on Eldepryl. She will follow-up with her neurologist and may possibly be started on high-dose trihexyphenidyl HCL, depending on her tolerance for the side effects of the medication.

Discussion

Epidemilogy

Progressive supranuclear palsy was first recognized as a new disorder by Richardson, Steele, and Olszewski in 1964. According to Jackson et al. (1983), PSP is the most common degenerative form of parkinsonism after Parkinson's disease. The prevalence of PSP is approximately 1.39 per 100,000, with no gender preference, a mean age of onset of 60 to 63 (standard deviation of 6-7 years), and mean survival of 5.9 years.

Diagnostic Criteria

Essentials for the diagnosis of PSP according to the National Institutes of Neurological Disease and Stroke (July, 1996) are as follows:

  • Onset at or over age 40
  • Progressive course
  • Bilateral supranuclear disorder of ocular motility: hesitancy of down gaze, up gaze, or both; impaired vertical optokinetic nystagmus; poor suppression of vertical vestibuloocular reflex
  • Rigidity with axial predominance, postural instability, frequent falls
  • Bradykinesias
  • No other evidence of disease

Other confirmatory manifestations include poor or absent response to levodopa, axial dystonia with cervical hyperextension, dysarthria and dysphagia, apraxias of eyelid opening, echolalia and palilalia. A patient with PSP usually does not have cerebellar symptoms, polyneuropathy, aphasia, sensory deficits, or seizures.

Ophthalmological Characteristics

PSP is characterized by supranuclear disturbance of eye movement function, particularly with saccades, pursuit, vestibuloocular reflex, vertical, and horizontal movements.

Saccadic disturbances: Neurons in the reticular formation of the midbrain and pons contain burst neurons responsible for generation of all types of saccades. The parapontine reticular formation (PPRF), receives input from the contralateral frontal eye field which is responsible for horizontal saccades. The rostral interstitial nucleus of the medial longitudinal fasciculus is required for vertical saccades. The total number of spikes in each burst activity is proportional to the size of the eye movement. Neuronal loss in PSP produces deficits at all levels of the supranuclear control of saccades; producing long latency hypometric slow saccades, first for vertical and later for horizontal movements.

Pursuit: The pursuit system, tracking or smooth eye pursuit movements, utilize the primary visual cortex, and the middle, superior temporal cortex. Projections descend from the temporal lobe to the dorsolateral pontine nuclei (DLPN) and to the flocculus and the vermis of the cerebellum. Severe neuronal loss in the brainstem areas involved with smooth pursuit, such as the DLPN, and lesions of the cerebellum, can account for the disturbance in smooth pursuit eye movements seen in PSP.

Vestibuloocular reflex: The vestibuloocular reflex (VOR), allowing the eyes to maintain a stable position in place, is dependent on the semicircular canals which respond to rotational acceleration, the utricle and saccule which respond to linear acceleration. Normally, slow rotation of the head to the right, produces a contralateral movement of the eyes to the left. In PSP, the eyes are moving with the head, and there is no contralateral movement. The abnormality of VOR produced by peripheral neuropathy or brainstem dysfunction results in a vertical abnormality, decrease gain, and failure of VOR suppression.

Vertical and horizontal eye movements: The vertical gaze is controlled by the interstitial nucleus of the MLF, medial portion which is involved with up gaze, and lateral portion concerned with down gaze. PSP involves downward gaze and eventually upward gaze. Bilateral lateral MLF lesions produce impaired vertical gaze. When horizontal gaze is affected, there may be loss of excitatory burst neurons in the PPRF. Reflex horizontal movements produced by oculocephalics are preserved until neurons in the vestibular complex are lost.

First, pursuit in the vertical direction, particularly downward is impaired. Next, the vertical saccades downward are lost, but the VOR is intact. Clinically, the horizontal movement would be affected next with square wave jerking. Once saccades and pursuit are totally impaired, vestibular compensation remains. Blinking becomes decreased, and there is suppression of blinking to bright light. Ultimately, reflex eye movements disappear as the ocular motor neurons become involved.

Neuropathology

The pathology of progressive supranuclear palsy is characterized by neurofibrillary tangles and granulovacuolar degeneration. The neurofibrillary degeneration with neuronal loss and gliosis affects the striatum, pallidum, subthalamic nucleus, substantia nigra, locus coeruleus, tectum, tegmentum, basis pontis, and certain cranial nerve nuclei. Pathology in the dentate is distinct with eosinophilic granular degeneration of neurons and atrophy of the superior cerebellar peduncle, with slight loss of purkinje cells. Tau-positive astrocytes or processes help to confirm the diagnosis of PSP. Lewy bodies have only been reported in single cases of PSP.

Radiographical Findings

With computed tomography, there is a reduction in midbrain AP diameter and midbrain atrophy. Also associated is dilatation of the quadrigeminal plate cistern, visualization of the cerebral aqueduct, dilatation of the third and fourth ventricle, and temporal lobe atrophy.

Neurochemistry

The nigrostriatal pathway is dramatically affected in PSP with decreased dopamine in the caudate and putamen. Dopamine deficiency differs in PSP, from that in Parkinson's disease, which may be the reason for a different clinical presentation. In PSP, the dopamine deficiency in the putamen is equal to that in the caudate. In Parkinson's disease, the deficiency in the putamen is greater than that in the caudate. In PSP, the D1 receptors are unchanged, but the D2 receptors are decreased in the caudate and putamen.

Treatment

The treatment of progressive supranuclear palsy is palliative and supportive. Rigidity and bradykinesia may respond to levodopa, but axial dystonia and ophthalmoplegia are not affected. Other medications, such as tricyclic antidepressants, amantadine, and anticholinergics have been only minimally effective. Currently, there is no effective medication to alleviate all the symptomatology. However, it is important to educate the patient and his family and provide physical, occupational, and supportive care.

References

  1. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy: report of NINDS workshop. Neurology. 1996;47:1-9.
  2. Roltach K, Riley D, DiScenna A, Zivotofsky A, Leigh R. Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes. Ann Neurol. 1996;39:368-77.
  3. Daniel SE, Bruin V, Lees A. The clinical and pathological spectrum of Steele-Richardson-Olszewski syndrome. Brain. 1995;118:759-70.
  4. Litvan I, Agid Y. Progressive supranuclear palsy. Oxford University Press, 1992.
  5. Golbe L, Davis P, Schoenberg B, Duvoisin R. Prevalence and natural history of progressive supranuclear palsy. Neurology. 1988;38:1031-4.
  6. Duvoisin R, Golbe L, Lepore F. Progressive supranuclear palsy. Can J Neurol Sci. 1987;14:547-55.
  7. Schonfield S, et al. Computed tomographic findings in progressive supranuclear palsy: correlation with clinical grade. Mov Disord. 1987;2:263-78.

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