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Show Journal of Neuro- Ophthalmology 15( 4): 230- 235, 1995. i 1995 Lippincott- Raven Publishers, Philadelphia Vertical Gaze Paralysis and Intermittent Unresponsiveness in a Patient with a Thalamomesencephalic Stroke David Q. Beversdorf, M. D., Lawrence R. Jenkyn, M. D., John T. Petrowski III, O. D., Laurence D. Cromwell, M. D., and Richard E. Nordgren, M. D. A patient with paralysis of upward gaze and downward gaze, absent oculocephalic reflexes, and absent vertical saccades also demonstrated intermittent stupor over the first 9 days of presentation. Magnetic resonance imaging ( MRI) demonstrated an infarct in the tegmentum of the mesencephalon including the right red nucleus and the periaqueductal area, superior to the oculomotor nucleus, and contiguous through the left thalamus. The infarct included the area around the rostral interstitial nucleus of the medial longitudinal fasciculus ( riMLF), as well as the midbrain reticular formation. Mechanisms are proposed for the unusual concurrent sign of intermittent unresponsiveness in this case. Key Words: Vertical gaze palsy- Stroke- Rostral interstitial nucleus of the medial longitudinal fasciculus- Parinaud's syndrome- Unresponsiveness. Vertical gaze paralysis is often associated with a variety of other neurological signs, such as those of Parinaud's syndrome ( 1- 3) ( pupillary light- near dissociation, lid retraction, ocular skew deviation, retraction nystagmus, or downward gaze; however, the definitions in the literature are variable). The combination of paralysis of downward and upward gaze has been localized to unilateral lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus ( riMLF), located in the tegmentum of the midbrain within the midbrain reticular formation ( 4,5). We report a case in which intermittent unresponsiveness is a prominent feature of vertical gaze paralysis. CASE REPORT Manuscript received February 17, 1995. From the Section of Neurology ( D. Q. B., L. R. J.), Departments of Ophthalmology ( J. T. P.), Radiology ( L. D. C.), and Pediatrics ( R. E. N.), Dartmouth- Hitchcock Medical Center, Lebanon, New Hampshire, U. S. A. Address correspondence and reprint requests to Dr. D. Beversdorf, Section of Neurology, Dartmouth- Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, U. S. A. A 76- year- old woman with a past medical history significant for non- insulin dependent diabetes mellitus, hypertension, asthma, and a remote history of tobacco smoking, was seen in an area hospital after awakening in the morning with slurred speech, sluggishness, and dizziness. On evaluation, the patient's arousal level had deteriorated to semipurposeful responses only to painful stimuli. The right pupil at that time was reported as fixed and midposition, whereas the left responded fully. The patient's arousal improved to the point of appropriately discussing politics several minutes later. Over the next 24 h, the patient had two further episodes of similar loss of arousal with rapid recovery. Over that same period, the patient had noticed some right- sided weakness and had once mentioned difficulty with her vision. The patient was then transferred to Dartmouth- 230 PARINAUD VARIANT AND INTERMITTENT STUPOR 231 Hitchcock Medical Center ( DHMC). On arrival, the patient was arousable to painful stimuli and would quickly drift back to sleep. The patient would say only " yes," " no," or " leave me alone." The patient's right pupil was minimally reactive and 4 mm, whereas her left pupil was 1.5 mm and sluggishly reactive. Extraocular muscles were reported as normal at that time, and her extremities appeared to move symmetrically. Reflexes and response to pinprick were also symmetric. Two days after admission, the patient remained confused, believing the year to be 1939, but was fully alert. The patient complained of inability to see below midline. Her visual fields were found to be intact, but there was complete bilateral paralysis of upgaze and downgaze, including absent vertical oculocephalic reflexes. Horizontal gaze was intact to voluntary and reflex ( oculocephalic) testing. Once on her third day of hospitalization and twice on her fourth day, the patient again had episodes of decreased arousal. Her blood pressure was found to be elevated during these episodes ( to 212/ 122 on one occasion), and the patient was again only minimally arousable at these times, demonstrating semipurposeful movement to noxious stimuli. At no point was the patient given the benzodiazepine antagonist flumazenil. Each episode lasted - 30 min, and there were no abnormalities in her heart rate, heart rhythm, temperature, respirations, or oxygen saturation. The patient's pupils would constrict to pinpoint diameter during these episodes. The patient had no further episodes after the fourth hospital day, and her baseline confusion cleared over the next several days. She had no recall of her events. The patient was discharged home 9 days after admission with complete bilateral loss of upward and downward gaze, including oculocephalics. The patient also continued to have small pupils, 2 mm and reactive bilaterally. These ocular findings persisted at her 2- month follow- up visit, although minimal recovery of downgaze occurred. At the follow- up examination, vertical saccades could not be induced using an optokinetic nystagmus ( OKN) stripe drum. Bell's reflex ( eyes deviating upward with lid closure) was absent bilaterally. The patient demonstrated a mild exophoria at distance on cover testing. At near, the patient was unable to converge and manifested a small- angle exotropia. The angle of the tropia was the same in all directions of lateral gaze, ruling out a muscle or cranial nerve paresis. Formal visual fields were normal for the patient's age. Studies while in hospital included an electrocardiogram, demonstrating normal sinus rhythm and a right bundle branch block. Prothrombin time was 11.8 s with an international normalized ratio of 1.06. Partial thromboplastin time was 21 s. Hemoglobin was 12.7 g/ dl; hematocrit, 38%; white blood cell count, 9,000; and platelet count, 393,000. Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, magnesium, and phosphorus were within normal range. Erythrocyte sedimentation rate was 44 mm/ h. None of A- C FIG. 1. T- 2 weighted magnetic resonance image ( MRI) of the lesion ( white arrows) in our case. A: Infarct on the left side of the superior thalamus. B: Bilateral infarct of the inferior thalamus, left more extensive than right. C: Infarct on the right side of the midbrain involving the red nucleus, the area around the rostral interstitial nucleus of the medial longitudinal fasciculus ( riMLF) and a portion of the reticular activating system ( left- right orientation is opposite of that of the schematic representation in Fig. 2). / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 232 D. Q. BEVERSDORF ET AL. TABLE 1. Summary of related cases In the literature Cases Lesion Upgaze Downgaze Moriyasu et al. ( 7) Yamamoto ( 8) Ranalli et al. ( 9) Segarra, case 2 ( 10) Pierrot- Deseilligny et al., case 5 ( 11) Pierrot- Deseilligny et al., case 6 ( 11) Mills and Swanson ( 12) Wall et al. ( 13) Jenkyn et al. ( 14) Buttner- Ennever et al. ( 15) Bogousslavsky et al. ( 4) This case Unilateral infarct riMLF Bilateral infarct thalamomesencephalic junction riMLF, nD, rostral pole inC Midbrain infarct superior to oculomotor nerve Upper MLF, superior red nucleus, thalamus, mesencephalic reticular formation and periaqueductal grey Small bilateral thalamic infarcts, left > right Dorsomedial nuclei of thalamus lesions Rostral midbrain and lower diencephalon infarcts Left MLF and underlying tegmentum Bilateral destruction of riMLF ( nD and inC preserved) Right riMLF Bilateral infarct thalamomesencephalic junction Paralyzed Paralyzed Limited saccades and pursuit Paralyzed Paralyzed saccades and pursuit Paralyzed saccades and pursuit Pursuit slowed, saccades absent Paralyzed Normal Paralyzed saccades and pursuit Paralyzed Paralyzed Partially retained Paralyzed Limited saccades and pursuit Paralyzed Paralyzed saccades and pursuit Paralyzed saccades and pursuit Pursuit slowed, saccades absent Paralyzed Normal Paralyzed saccades and pursuit Paralyzed Paralyzed Cases Reflexes Level of consciousness Other Moriyasu et al. ( 7) Yamamoto ( 8) Ranalli et al. ( 9) Segarra, case 2 ( 10) Pierrot- Deseilligny et al., case 5 ( 11) Pierrot- Deseilligny et al., case 6 ( 11) Mills and Swanson ( 12) Wall et al. ( 13) Jenkyn et al. ( 14) Buttner- Ennever et al. ( 15) Bogousslavsky et al. ( 4) This case Oculocephalics retained Oculocephalics limited Oculocephalics retained Oculocephalics: vert OK, horizontal absent; vertical OKN: absent fast phase; horizontal OKN: intact; calorics OK Absent to nearly absent oculocephalics Vertical oculocephalics absent, bilateral simultaneous calorics impaired Oculocephalics retained, OKN absent Vertical oculocephalics retained, OKN lost Vertical oculocephalics and OKN lost No change No change Only initially impaired ( with cardiac event) Coma, then lethargic and " akinetic mutism of mesencephalic origin" Coma, then memory loss Coma, then memory loss Coma, then lethargy, apathy, memory loss Initially impaired Initially impaired Waxing and waning Apparently no change Waxing and waning Convergence nystagmus Pupillary responses normal, eyes down with eye closure Dilated pupils Pupillary responses normal Pupillary responses normal Vertical saccades seen on ENG, pupillary responses normal, eyes up with eye closure Ataxia, poorly responsive pupils Incomplete bilateral internuclear ophthalmoplegia Pupillary responses normal Locked- in Recovery except for eyes ENG, electronystagmogram. these laboratory values varied significantly throughout her stay, and her blood sugar remained in the 100s or 200s ( mg/ dl), including testing during her episodes. The patient's arterial blood gas panel revealed a pH of 7.37, a partial C02 pressure of 49 mm Hg, and a partial 0 2 pressure of 64 mm Hg, which are within normal range. The patient's liver function tests and thyroid function tests were within normal limits. Her urinalysis was remarkable only for protein, and her urine culture was negative. Cerebrospinal fluid ( CSF) pressure, protein, and glucose were normal, and there was no xanthochromia. One white blood cell was observed on CSF smear, and all other stains and cultures ( routine, fungal, and acid- fast bacillus) were negative. CSF cryptococcal antigen and VDRL were also negative. Echocardiography showed left ventricular hypertrophy consistent with her history of hypertension, and continuous electrocardiographic monitoring did not reveal any dysrhythmias ( including during an episode). An EEG demonstrated intermittent frontal delta rhythm activity. Metanephrines, vanillylmandellic acid, and urine catecholamines were negative. Computed tomography ( CT) and magnetic resonance imaging ( MRI) ( Fig. 1) demonstrated an infarct in the left thalamus and in the right midbrain superior to the oculomotor nucleus, including the red nucleus ( as well as the area around the riMLF). This infarct was contiguous through the thalamomesencephalic periaqueductal area. Carotid Dop-plers revealed 16- 49% stenosis of both common carotid arteries as well as the left internal carotid. The right internal carotid artery was 50- 79% ste-nosed. Vertebrals had anterograde flow. The patient declined cerebrovascular angiography. / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 PARINAUD VARIANT AND INTERMITTENT STUPOR 233 Bogousslavsky et al Moriyasu et al B Yamamoto Ranalli et al Segarra, case 2 Mills and Swanson Wall et al Jenkyn et al Buttner- Ennever et al current case FIG. 2. Approximate schematic representation of lesions ( black arrows) from selected cited cases ( left side of drawing represents left side of patient). Row A, from left: Bogousslavsky et al. ( 4), Moriyasu et al. ( 7), Yamamoto ( 8), Ranalli et al. ( 9), Segarra, case 2 ( 10). Row B, from left: Mills and Swanson ( 12), Wall et al. ( all cases similar; 13), Jenkyn et al. ( 14), Buttner- Ennever et al. ( 15), this case ( in box). The drawings are modified from Segarra ( 10). Left- right orientation of these drawings are opposite that of the MRI in Fig. 1. DISCUSSION Complete bilateral paralysis of upgaze and downgaze [ considered by some a variant of the Parinaud syndrome, or the pretectal syndrome ( 6)] has been localized by Bogousslavsky et al. ( 4) to a unilateral lesion of the riMLF, not involving the nucleus of Darkschewitsch ( nD) or interstitial nucleus of Cajal ( inC). In that report, however, the pupillary reflexes could not be defined because of trauma from cataract surgeries. Therefore, full correlation with our case with small and reactive pupils cannot be made, although our MRI findings do help with correlation. Several important distinctions should be made between the case of Bogousslavsky et al. ( 4) and our case. Our case had intermittent impairment of arousal, whereas their case did not describe any alteration in consciousness. Furthermore, the lesion in our case was significantly more widespread. In the case of Bogousslavsky et al. ( 4), vertical optokinetic testing with a drum failed to elicit a response, but oculocephalic maneuvers led to a full response bilaterally, whereas both tests failed in our case. Finally, in their case, the patient developed tetraplegia with a near locked- in state and eventually died, whereas our patient was left with only the eye- movement abnormalities. Several other cases in the literature have some features similar to those of our case. Those cases with similar oculomotor findings or prominent alterations in consciousness are summarized in Table 1. Approximate locations of many of the cited lesions are diagrammed in Fig. 2. A diagram of the locations of relevant structures is in Fig. 3. As would be expected, the lesions with the greatest involvement of the reticular activation system correlate with the greatest alterations in consciousness. The only report in the literature featuring waxing and waning consciousness, as in our case, was that of Buttner- Ennever et al. ( 15). Although the course and duration of the episodes were longer than those in our case, this patient also lacked vertical pursuit and saccades. Optokinetic testing elicited no response, but oculocephalic re- / Neuro- Ophthalmol, Vol. IS, No. 4, 1995 234 D. Q. BEVERSDORF ET AL. FIG. 3. Locations of the relevant structures within schematic representations of the thalamus, midbrain, and pons. RN, red nucleus; CNIII, oculomotor nucleus; MLF, medial longitudinal fasciculus; riMLF, rostral interstitial nucleus of the MLF. The drawing is modified from Segarra ( 10). sponses were full. Pupillary responses were normal. Autopsy revealed bilateral destruction of the riMLF with preservation of the nD and inC ( 15). The phenomenon of intermittent unresponsiveness has received attention in the recent literature ( 16- 19). These reports, however, pertain to intermittent stupor of idiopathic origin. In our case, the proximity of the lesion to the mesencephalic reticular formation may clearly be implicated. It is well established that mesencephalic lesions can cause hypersomnia ( 20). Certainly, our case demonstrated many other signs of midbrain ischemia at varying times, such as transient right- sided weakness and pupillary abnormalities. Therefore, we propose that our patient's intermittent stupor was related to intermittent ischemia more widespread than the observed fixed lesion and involving more of the thalamomesencephalic reticular formation. This could be a result of a steal phenomenon occurring because of the hypertensive episodes, thus drawing blood away from the midbrain. In our case, the infarct involved a portion of the territory of the posterior thalamosubthalamic paramedian artery ( 10,21). Perhaps a proximal stenosis of this particular vessel was a cause of this possible steal phenomenon. Alternatively, it is possible that a pressor effect of the reticular formation ( 20) is induced by the ischemia and that the hypertensive episodes are a result of rather than a cause of the ischemia. Regardless of which mechanism is in operation in this case, it is worthy of report that intermittent stupor may be a logical neuroanatomical accompaniment to focal thalamomesencephalic lesions, including the area of the riMLF, and consequently can be seen in cases of Parinaud's syndrome. This particular lesion resulted in a complete vertical gaze paralysis and intermittent stupor in the case we observed. Finally, cases such as these need not have the poor outcomes frequently reported elsewhere ( 4,10- 12,15). 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