April, 2002

Acknowledgment
With consultation by: Drs. Alexander ("Sandy") De Lahunta and Brian Summers
New York State Veterinary College, Cornell University, Ithaca, NY

The authors are grateful for the skilled assistance of members of the radiology and pathology departments of the College of Veterinary Medicine University of Georgia in the care of this case.

Signalment, History, Physical Examination   Neurological Examination   Tests Performed   Case Summary/Final Diagnosis

Signalment, History and Physical Examination

Rottweiler, 8 years old, female spayed with apparent blindness, pacing, and circling to her right.

 Signalment: Dog, 8 year-old ovariohysterectomized Rottweiler.

 History: History of apparent blindness, pacing and circling to her right.

 Medications: None at the time of referral.

 Physical Examination: (NAF= no abnormal findings)

 General: NAF

 Integument: NAF

 EENT: NAF

 Cardiopulmonary: NAF

 Abdominal Cavity: NAF

 Musculoskeletal: NAF

 Lymph Nodes: NAF

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Neurological Examination

Note: There are some large video clips, so please be patient while they load.

Some information about the examination is not stated in the text; you are expected to derive it from the video clips.

Several partial seizures occurred during the examination.

 Posture: N

 State of Consciousness: Slightly obtunded?

 Gait: See video  

Sensory Systems Examination (note depressed, absent, asymmetric or misdirected responses)

 Somatosensory System: See video  

 Visual System (Pupillary Light Reflexes and Menace Reflexes): See video  

 Olfaction: See video  

 Auditory: Turned head to right in response to auditory stimulation from either side, including calling her name

 Gustatory: Not examined

Placing and Postural Reactions

 Proprioceptive Placing Reactions: See video  

 Thoracic limb: Left: N - Right: N

 Pelvic limb: Left: N - Right: N

 Hopping/Wheelbarrow: See video  

 Extensor Postural Thrust: Not examined

 Visual & Tactile Placing Reactions: Not examined

 Segmental (Spinal) Reflexes: (Left/Right) (N=Normal, D=Decreased, I=Increased, A=Absent)

Thoracic Limb

 Tendon Reflexes: Biceps N/N; Triceps N/N

 Flexor Reflex (and response to deep pain)
Crossed Extensor Reflex N/N

Pelvic Limb

 Tendon Reflexes: Patellar N/N; Gastrocnemius N/N

 Flexion Reflex: See video  

 Crossed-extensor Reflex: A/A

 Perineal Reflex: N

 Cutaneous Trunci: N
If abnormal, indicate level where the reflex is first identified when testing begins in sacral region and proceeds rostrally

Cranial Nerves

 I. Olfaction:

 II: Menace and Pupillary Light Reflexes:

 III, IV, VI: Normal physiological nystagmus present without positional nystagmus or strabismus.

 V: Facial Sensation and Palpebral Reflexes: See video  

 VII: Normal facial symmetry and normal movement of the muscles of facial expression.

 VIII: Turned head to right to auditory stimulation applied from either side, including calling her name; No head tilt was noted and normal conjugate eye movements were noted. No positional nystagmus or strabismus was noted.

 IX, X, XI: Normal swallowing action with stimulation.

 XII: The tongue musculature was symmetrical and tongue movements were normal.

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Tests Performed

Clinical Chemistry Laboratory Results

Hemogram Results

Cerebrospinal Fluid

Total and Differential Cell Counts; Total Protein

 Fluid from: Cerebello-medullary cistern

 Gross appearance: Clear

 Refractive index: -

 Total Protein: 81.7 mg/dl

 Total erythrocytes: 1 /microliter

 Total nucleated cells: 1 /microliter

Differential Nucleated Cell Counts:

 Smear type:

 Neutrophils: 0%

 Lymphocytes: 12%

 Macrophages: 88%

 Eosinophils: 0%

 Microscopic evaluation: Macrophages look slightly old

Imaging

Radiographs

Thorax (click on an image to see a larger view)

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Case Summary and Final Diagnosis

Summary: An 8 year old ovariohysterectomized Rottweiler was referred for apparent blindness and walking in circles. On neurological examination, the dog was found to be obtunded, head turned slightly to the right and tending to pace and circle to the right. Several partial seizures occurred during the neurological examination. When the skin on the right side of the body was stimulated, she turned directly toward the source of the stimulation; when stimulated on the left side she showed discomfort but did not turn toward the stimulation. There was absence of the menace reflex in the left eye and decreased response to skin stimulation on the left side of the face (Vision CN-V). Responses to auditory stimulation on the left were decreased. Food offered to her from the left side was ignored; if offered from the right side it was readily eaten. Responses to food stimulation were the same when vision was blocked (Food). Her postural reactions were decreased in the left thoracic limb and both pelvic limbs, although the left pelvic limb was more deficient than the right (Proprioceptive placing; Hopping).

Laboratory examinations, including CSF were not diagnostic (Tests). Radiographs of the thorax revealed an 8 cm-diameter soft tissue mass in the caudodorsal aspect of the right cranial lung lobe and an additional 1 cm nodule in the same lobe, with other suspicious soft tissue nodules within the cranial subsegment of the left cranial lung lobe (Rads).

After discussion with the clinicians, the owners elected to have the dog euthanatized and granted permission for necropsy. At necropsy neoplasms were found in the lungs, heart and brain. These were identified as metastatic bronchogenic carcinoma or possibly, ependymoma.

Clinical Syndrome: With the exception of the seizures: the clinical signs of this dog were typical of unilateral neglect syndrome (also referred to as hemi-inattention, unilateral neglect or hemineglect). This subject is discussed below.

Pathology Results and Diagnosis

Gross: The right cranial lung lobe contained a 10 cm incompletely circumscribed pale mass. Both the right and left caudal lung lobes contained 0.5 cm, circumcised, pale nodules. In the heart, a 4 mm pale focus was present in the left ventricular wall near the apex. There were two masses in the right cerebral hemisphere: a 1.5 cm mass within the white matter of the caudal cerebrum; the second was a dorsoventrally flattened, 4-5 cm mass located adjacent to the right lateral ventricle; it contained a central, open, core.

Histopathology: The large mass in the left cranial lung lobe consisted of extensive multifocal and confluent areas of necrotic tissue, islands of neoplastic cells, mineralized tissue and an encompassing ring of disorderly and highly pleomorphic neoplastic cells. The mass was circumscribed but nonencapsulated and compressed the adjacent parenchyma. The neoplastic cells were poorly arranged into irregular fronds consisting of minimal fibrovascular stroma lined by cuboidal to columnar neoplastic cells. There was pronounced cellular atypia and pleomorphism within the population of neoplastic cells. Their nuclei were round to oval and stippled or open and often contained one or two eosinophilic nucleoli. The cytoplasm varied from moderate to abundant and, typically, was faintly basophilic. Mitoses, the majority of which were atypical, were common. The mitotic index was 1.3 (i. e., 13 mitoses/10 microscopic fields at 40X magnification). Clusters of neoplastic cells were often observed within the lumina of lymphatic and vascular channels. One neoplastic aggregate was associated with the presence of a coagulum of fibrin within a vessel lumen. The remaining pulmonary parenchyma had moderate serous exudation into the alveoli. Lymphoplasmacytic infiltrates were observed, although infrequently.

Click on the image to see larger view.

In the brain, there were two large, distinct, circumscribed but not encapsulated masses that histologically resembled the mass observed in the left cranial lung lobe. These masses displaced and partially compressed the surrounding neural tissue. There was extensive central necrosis with sporadic mineralization in both masses. Neoplastic cells were disorderly, forming irregular fronds that surrounded and extended into the central necrotic core. Neoplastic cells were positive on selective histochemical staining for cytokeratin, S-100, and vimentin, but were negative for glial fibrillary acidic protein. (GFAP).

The heart contained a focal encapsulated neoplastic mass that, histologically, resembled those in the lung and brain.

Additional findings: minimal to mild chronic lymphocytoplasmic tubulointerstitial nephritis with periglomerular fibrosis, and mild hepatocellular atrophy.

Diagnosis: Bronchogenic adenocarcinoma or ependymoma with metastasis to heart, lung and brain.

Comment by Drs. Alexander (Sandy) De LaHunta and Brian Summers (after viewing sample histopathology slides):

The mass is a carcinoma, very well demarcated, with no extension into the parenchyma. The mass (as best determined from the slides) was in the lateral thalamus, possibly centered in the thalamocortical fibers and extending into the internal capsule, semiovale region of the cerebrum. Since a pulmonary mass of the same cell type was found, the lung mass is probably the source of the mass in the brain.

Unilateral Neglect (Hemi-inattention) Syndrome in Dogs Revisited

T. A. Holliday, DVM, PhD, Diplomate, ACVIM, (Neurol)

Neurological examination of animals permits "locating" lesions primarily in the postural and locomotor systems but yields little or no insight into the higher functions of the nervous system, those functions that are readily explored in human patients who can cooperate, often even verbally, in the examination. Conversely, the syndrome discussed here, unilateral neglect/hemi-inattention syndrome, is of little value in "locating the lesion" in animals but it does give us at least a tiny glimpse into the higher functions. It is important to note that to recognize this disorder in animals, it is essential to look for global malfunctions, as exemplified in the neurological examination reported by Kube et al. Importantly, hemi-inattention can be overlooked if one performs the neurological examination simply by beginning with the cranial nerves and plodding methodically caudally, The following description of thee syndrome is revised and extended from that published earlier by this author. ¹⁹

Dogs with this syndrome appear to be slightly to moderately obtunded and, if released, tend to walk in circles. Circling can be interrupted readily by stimulation. The direction sometimes can be reversed transiently by urging the dog to move in the opposite direction. Other neurological signs appear on the side opposite the direction of circling. Stimulation of the skin on the "normal" side of the body or head (somatosensory stimulation) elicits normal responses consisting of heightened arousal (e.g., alerting movements of the ears and eyes), and movements of the head, body or limbs appropriately directed at the source of the stimulus. Appropriate behavioral responses occur if the stimulus is painful. Stimulation on the other side elicits responses also; however, movements that occur in response to such stimulation usually are not appropriately directed (toward the stimulated side). Instead they are directed either toward the unstimulated side of the body or straight ahead. (Somatosensory) Sometimes, occasional responses directed toward the stimulated side occur but these are inaccurate and irregular, occurring seemingly in a random fashion. Some stimuli on the affected side of the animal do not elicit observable responses.

Auditory stimulation elicits analogous responses, i.e., there is alerting and turning of the head and eyes toward the sound source in a normal fashion if the sound is directed primarily to the ear on the normal side. If applied to the other ear, alerting may occur, and movements may occur, but are directed toward the inappropriate side or straight ahead, not toward the side of the stimulus. Binaural stimuli (e.g., sounds applied from a direction where binaural stimulation is expected), elicit arousal with movements directed toward the same side where unilateral stimulation elicited normally directed responses.

Visual stimulation in one field elicits appropriately directed responses and alerting; stimulation in the opposite field frequently elicits no responses or simply alerting (Vision and PLR). Throwing an object such as a cotton ball from behind the animal's head and directed to its right or left front is helpful. If responses occur, they are inappropriately lateralized or are directed straight ahead. Attempting to stimulate both fields simultaneously elicits only responses directed toward the animal's "normal" side. (The case presented here by Kube et al. showed asymmetric menace responses with absence of responses sometimes and responses at other times. Perhaps highly important protective reflexes may be more resistant to the problem but this was not evident in the flexion reflexes.)

Importantly, the case of Kube et al. showed highly asymmetric olfactory responses. Previously, we have not made observations on responses to olfactory or gustatory stimuli thus their case provides additional new information.

Any form of stimulation on the affected side of the animal will sometimes cause it to turn to the "normal" side and if not restrained or blocked, continue to turn so that it brings the stimulus source into view on its "normal" side. In some of the videos clips of the case of Kube, et al., the dog seemed to respond to stimulation on its left (neglected) side by turning to its right although movement in that direction was impeded by the restraint needed to hold the dog in the camera's field. (Olfactory Somatosensory)

Affected dogs usually eat with vigor if food is available and they will drink water readily if it is placed before them. Abnormal feeding and drinking behaviors occur regularly in such animals. If food is on the "normal" side of a dish placed before the dog, or if the dog is led to the dish, the food is eaten without difficulty. If the food is placed on the opposite side of the dish, the dog will find the dish and make eating movements, but these are inappropriately directed; thus, it licks or grasps at the bottom of the dish, often vigorously, on the side where there is no food. If the food-laden dish is brought into the dog's visual field from one side, it will begin to eat when the dish enters the lateral regions of the visual field. If the dish is brought into the dog's view from the opposite side, it will not respond until the dish reaches the contralateral side of the field; it then directs eating movements at the inappropriate side of the dish. Similar misdirected responses to food held in the handler's hand were evident in the case of Kube at al. Some affected dogs seem to "find" the food by searching within the container in a circling fashion, turning in the same direction as the spontaneous circling behavior. Analogous events occur in drinking behavior: if two pans are placed adjacent to one another before the dog, one with water and the other empty, it will drink readily if the pan with water in it is placed on its "normal" side. If the empty pan is placed on the "normal" side, the dog will attempt to drink from it, even though it is empty and immediately adjacent to a pan with water in it. These clinical signs do not appear to result from deficits in afferent systems: The dogs do, in fact, respond to stimulation on the affected body side and the thresholds to all stimulus modalities seem symmetrical. Efferent deficits are not present. The asymmetrical nature of the responses sometimes varies greatly, from no responses to responses directed toward the inappropriate side with others merely directed straight ahead rather than to one side. The problem seems to be better described as a global deficit in giving appropriate direction to any stimulation on the "affected" side of the body, with afferent and efferent systems themselves relatively unaffected. It is a disorder of the higher functions that provide direction to responses to stimulation.

Associated Lesions: Various types and locations of lesions have been found in animals that have unilateral neglect. This author's experience has included, mass lesions, infarction of the caudate nucleus, computed tomographic evidence of multifocal ischemia (7 months later the dog was reported to be well), multifocal malacia secondary to disseminated tumor embolism. The variety of lesions associated with hemi-inattention/unilateral neglect does not seem to allow identification of the nature or site of a lesion based solely on presence of the syndrome.

Discussion. Naturally occurring unilateral neglect has been reported in cats20 and experimental lesions in a variety of animals produce equivalent signs. Unilateral absence of responses to visual, olfactory and tactile stimuli was produced in rats, contralateral to lesions of the lateral hypothalamus.4 Also, in rats, lesions of the nigrostriatal system caused by 6-hydroxydopamine hydrobromide produced neglect of contralateral olfactory, visual and tactile stimuli.^5,6In cats, lesions of the lateral midbrain, produced neglect of contralateral olfactory, tactile, proprioceptive, auditory, gustatory and nociceptive stimuli.^7-9 Lesions of the subthalamic region produced contralateral neglect in cats, including neglect of food rewards, even when the cats could observe the food being placed before them.¹⁰ Frontal cortex lesions and midbrain reticular formation lesions also produced the syndrome in cats.¹¹ In dogs, lesions of prefrontal cortex areas were reported to have caused a similar syndrome by Bianchi,¹² who observed that the seemingly paretic limb was used by the animal if the contralateral limb was immobilized. In monkeys, lesions of the midbrain reticular formation produced unilateral neglect.¹³ In the monkey cerebrum, lesions of the frontal lobe,¹⁴ prefrontal region,¹² cingulate gyrus,¹⁵ inferior parietal lobe^16,17 and posterior part of the superior limb of the arcuate sulcus¹⁸ were reported to produce the syndrome. The wide variety of species in which it has occurred or been induced suggests we should be alert for its occurrence in any mammal coming into veterinary care. O'Brien has noted that lesions in the medial forebrain bundle can produce the syndrome²⁰; however as noted above, cerebral cortex lesions produced the syndrome also so it appears possible there may be multiple sites where lesions can lead to the same syndrome.

Human patients with unilateral neglect syndrome may have a rich variety of signs and symptoms. They are described briefly here because it seems possible that analogous events occur in animal patients. In people, there may be loss of responsiveness to touch and vibration in one entire side of the body, deficits in olfaction in one nostril and in taste on one side of the tongue. Asked to raise both arms, patients may raise only the arm on the "good" side of the body; asked to grasp both ears, the ear on the unaffected side is accurately grasped while the affected hand gropes in space or grasps face or cheek.² Visual aberrations are common: patients may deviate their head and eyes to the "good" side or fail to look to the affected side. They may not notice objects, people or events on one side. When reading, they notice only one side of a book, or leave out words on one side of a line or letters on one side of a word. Unilateral neglect of auditory stimulation occurs also.¹ Affected patients may eat from only one side of a tray or plate.¹ Hemi-inattentive patients often appear unaware of their deficits and may deny the existence of any such problem.¹ The visual disturbances are not attributable to simple hemianopsia. Objective testing reveals neglect or inattention of one side of objects or words that are clearly in the intact visual field.³ Conversely, patients with dense homonymous hemianopsia or bitemporal hemianopia may exhibit no evidence of visual hemineglect.¹ Pathological lesions associated with unilateral neglect syndrome in human patients include lesions of the parietal regions of cerebral cortex, and of the cingulate gyrus and frontal lobes. It tends to occur more often in infiltrating, rapidly-developing tumors than in benign masses and it is particularly likely to occur after vascular lesions, especially when there is subarachnoid bleeding.² Signs of unilateral neglect tend to be transient, though the causative lesions are not necessarily so.^1,3(at least one transient case has occurred in dogs¹⁹). Notably, it does not occur in people after hemispherectomy.²

The mechanism underlying unilateral neglect has been characterized as a unilateral defect in the orienting response. Bias in spontaneous exploration of peripersonal space and disordered preparation for response to stimulation have been suggested also.^1,3 These are useful descriptive terms but they do not lead to understanding of the pathophysiology. Likewise, the anatomical basis for the neglect was hypothesized to be located in a "corticolimbic-reticular loop", an hypothesis that helps to explain the association of the syndrome with lesions at widely separated locations but is otherwise of little help.^1-3 Similarly, "biased exploration of peripersonal space" accurately describes circling, a common accompaniment of the syndrome in dogs and experimental animals. Some of the emotional and behavioral components that accompany the syndrome in man, e.g., denial of disturbed function and conceptualizing the affected side of the body as missing rather than as functioning abnormally, cannot be recognized in animals, at least in naive clinical cases.²Nevertheless, similarities of other clinical signs in animals to those seen in human unilateral neglect suggest some of these phenomena may occur in animals.

The neurological examination of animals deals largely with the postural and locomotor systems and often permits accurately "locating" lesions therein; however it gives little or no insight into the higher functions of the nervous system. The latter is much easier to explore in human patients who can cooperate, even verbally, in the examination. While it is of little value in "locating the lesion" in animals, unilateral neglect/hemi-inattention syndrome does serve to give us at least a glimpse into the higher functions in animals. At this time, it seems best described simply as lack of direction given to responses to all forms of stimulation. It is a distortion of responses produced by normal consciousness.

References

1.  Heilman KM, Watson RT. Mechanisms underlying the neglect syndrome. In: Weinstein EA, Friedland RP. ed. Hemi-Inattention and Hemisphere Specialization. Advances in Neurology Vol. 18. 1977; New York: Raven Press;93-106.

2.  Friedland RP Weinstein EA. Hemi-inattention and hemisphere specialization: introduction and historical review. In: Weinstein EA, Friedland RP. ed. Hemi-Inattention and Hemisphere Specialization. Advances in Neurology Vol. 18. 1977; New York: Raven Press; 1-32.

3.  Kinsbourne M. Hemi-neglect and hemisphere rivalry. In: Weinstein EA, Friedland RP. ed. Hemi-Inattention and Hemisphere Specialization. Advances in Neurology Vol. 18. 1977; New York: Raven Press; 41-50.

4.  Marshal JF, Turner BF, Teitlebaum P. Sensory neglect produced by lateral hypothalamic damage. Science 1971; 174:523-525.

5.  Ungerstedt U. Selective lesions of central catecholamine pathways: application in functional studies. In: Ehrenpreis S, Kopin I, ed. Neurosciences Research. New York: Academic Press 1973.

6.  Ungerstedt U. Brain dopamine neurons and behavior. In: Schmitt FO, Worden FG. ed. The Neurosciences. Third Study Program. Cambridge: MIT Press 1974.

7.  Sprague JM. Interaction of cortex and superior colliculus in mediation of visually guided behavior in the cat. Science 1966;153:1544-1547.

8.  Sprague JM, Meikle TH. The role of the superior colliculus in visually guided behavior. Exp Neurol 1965;11:115-146.

9.  Sprague JM, Chambers WW, Stellar E. Attentive, affective and adaptive behavior in the cat. Science 1961;133:165-173.

10. Adey WR, Walter DO, Lindlsey DF. Subthalamic lesions. Arch Neurol 1962;6: 194-207.

11. Reeves AJ, Hagamen WD. Behavioral and EEG asymmetry following unilateral lesions of the forebrain and midbrain of cats. Electroenceph Clin Neurophysiol 1971;30:83-86.

12. Bianchi L. The functions of the frontal lobes. Brain 1895;18:497-522.

13. Watson RT, Heilman KM, Miller BD, et al. Neglect after mesencephalic reticular formation lesions. Neurology (Minneap) 1974;24:294-298.

14. Kennard MA. Alterations in response to visual stimuli following lesions of frontal lobe in monkeys. Arch Neurol Psychiat 1939;41:1153-1165.

15. Watson RT, Heilman KM, Cauthen JC, et al. Neglect after cingulectomy. Neurology (Minneap) 1973;23:1003-1007.

16. Heilman KM, Pandya DN, Geschwind N. Trimodal inattention following parietal lobe ablations. Trans Am Neurol Assoc 1970;95:259-261.

17. Heilman KM, Pandya DN, Karol EA, Geschwind N. Auditory inattention. Arch Neurol 1971;24:323-325.

18. Welch KM, Stuteville P. Experimental production of unilateral neglect in monkeys. Brain 1958;81:341-347.

19. Holliday, T. A. Unilateral neglect (hemi-inattention) syndrome in dogs. Proceedings, Amer Coll Vet Internal Medicine, 1991

20. O'Brien DP. Brain damage and behavior. Proc. 11th Amer Coll Vet. Internal Medicine, 542-546 1993

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