Overcoming the neurologic disease severity-prognosis mismatch

A representative for English springer spaniel Bella, the focus of this article's case study. Part 2 will showcase two additional cases. Photo: Bigstock/Nikki Yancey As practitioners, we often correlate the severity of presentation with prognosis. This, however, is a cognitive bias called premature closure. Premature closure is one of the most common cognitive errors in clinical medicine, in which clinicians rely on pattern recognition to make a rapid diagnosis while failing to consider other possible diagnoses. Although the prognosis of many neurologic diseases is correlated with the severity of signs, there are many important exceptions. These are referred to in this article as “severity-prognosis mismatch” conditions. This article provides summaries of one of three severely neurologically affected patients. (Part two will showcase two more.) All three of these patients ultimately were diagnosed with conditions that carry a good-to-excellent prognosis. The purpose of this article is to demonstrate the important aspects of each of the represented neuroanatomic localizations described in these cases that led to the prioritization of a good prognosis disease. Knowledge of severity-prognosis mismatch conditions is critical to prevent falling trap to premature closure and potentially leading to severe case mismanagement and client misguidance. Case 1: Bella Case summary: Bella is an 11-year-old spayed female English Springer spaniel that was presented to an emergency clinic for a peracute inability to walk. According to her owner, she was sunbathing in the yard earlier in the day. The owner called for the dog to come into the house. Normally responsive, Bella did not return to the house. Her owner found her laterally recumbent and unable to stand. She has been an otherwise healthy dog that receives yearly vaccines and preventatives. She free roams in the yard. On general physical examination, Bella had normal vitals, light pink mucous membranes, and a capillary refill time of two seconds. Thoracic auscultation and abdominal palpation were normal. Her peripheral lymph nodes were soft, small, and symmetrical. She had a full hair coat with no evidence of dermatopathy. A rectal exam was normal. The musculoskeletal examination was normal. Bella’s neurological exam Mentation Quiet, alert, responsive Gait/posture Nonambulatory. Making no attempts to get up. Extensor rigidity in thoracic limbs. Opisthotonus. When lifted, a right-sided head tilt is observed. Muscle mass/tone Increased tone in thoracic limbs when in lateral recumbency. Postural reactions Absent in left limbs. Difficult to assess in right limbs but seem to be present. Spinal reflexes Normal Cranial nerves Slow, inducible horizontal nystagmus, fast phase to the left Palpation No pain on vertebral column palpation or cervical range of motion To arrive at Bella’s neuroanatomic localization, the practitioner is directed toward several important parts of her examination that could be misinterpreted: In the description of Bella’s gait and posture, she is described as displaying extensor rigidity in her thoracic limbs and opisthotonus. Premature closure would lead to the assumption this posture is associated with a poor prognosis. This limiting association with prognosis is present because extensor rigidity and opisthotonus can be associated with a poor prognosis, but the prognostic feature of these signs is localization dependent. There are two conditions that can result in peracute extensor rigidity and opistotonus: decerebrate rigidity and decerebellate rigidity. Decerebrate rigidity occurs due to a severe lesion in the midbrain, effectively “cutting off” the cerebrum from the brainstem. Decerebrate rigidity is associated with a poor prognosis. Contrastingly, decerebellate rigidity occurs due to a lesion in the cerebellum. Decerebellate rigidity is not associated with prognosis. Decerebrate rigidity Decerebellate rigidity Stuporous or comatose Alert Extensor rigidity x4 Extensor rigidity only in thoracic limbs Often other cranial nerve deficits Opsoclonus or nystagmus Lesion is in brainstem (midbrain) Lesion is in cerebellum Associated with poor prognosis NOT associated with prognosis Taken out of context, a patient’s posture can be critically misinterpreted. The failed pattern of associating peracute extensor rigidity and opisthotonus with a poor prognosis represents a cognitive bias that will lead to premature closure in Bella’s case. The posture should be contextualized within the entire exam to create a more accurate pattern. The correct pattern to observe in Bella is she is displaying extensor rigidity, opisthotonus, and flexed pelvic limbs alongside normal mentation. This collection of signs confirms that Bella has decerebellate rigidity, indicating a lesion that involves the cerebellum rather than the brainstem. Therefore, her posture is not associated with prognosis. Is Bella’s neuroanatomic localization left paradoxical vestibular disease? To arrive at this localization, the first step is to recognize Bella is displaying some of the four hallmark signs of vestibular disease: Head tilt Vestibular ataxia Positional strabismus Spontaneous or inducible nystagmus Bella has a subtle right-sided head tilt and horizontal nystagmus with the fast phase to the left was inducible. Next, the practitioner must evaluate the entire neurologic examination to determine which region of the vestibular system is affected in a given patient. There are three vestibular localizations: the peripheral vestibular system, the central vestibular system located in the medulla oblongata, and the central vestibular system located in the flocculonodular lobe of the cerebellum. For simplicity’s sake, lesions affecting the medulla oblongata are referred to hereafter as “central vestibular disease,” and lesions affecting the cerebellum are referred to as “paradoxical vestibular disease.” Patients with peripheral vestibular disease have a lesion affecting the vestibular branch of the vestibulocochlear nerve (CN VIII) located in the inner ear. Thus, patients with peripheral vestibular disease have a normal mentation and only display the hallmark signs of vestibular dysfunction (other than in cases of structural middle/inner ear disease, such as otitis media-internal, in which patients can display a combination of peripheral vestibular dysfunction, facial paresis, and Horner syndrome). Importantly, patients with peripheral vestibular disease have normal postural reaction deficits. Bella’s absent postural reaction deficits on the left side eliminate peripheral vestibular disease as a possible localization for Bella. Patients with central vestibular disease display some combination of the hallmark signs of vestibular disease. Their nystagmus can be horizontal, rotary, or vertical, with vertical nystagmus only occurring with central vestibular disease. Depending on the size of the lesion, patients with central vestibular disease display a variety of other deficits in addition to their vestibular signs. These can include decreased mentation, gait abnormalities other than vestibular ataxia, such as general proprioceptive ataxia and upper motor neuron quality paresis, and a combination of cranial nerve deficits referable to cranial nerves V-XII. Importantly, patients with central vestibular disease can have postural reaction deficits ipsilateral to the side of their head tilt. This does not occur in all cases of central vestibular disease, but when these postural reaction deficits are present, they confirm central vestibular disease. Bella’s postural reaction deficits are contralateral to her head tilt, thus eliminating central vestibular disease as a possible localization for Bella. Patients with paradoxical vestibular disease display some combination of the hallmark signs of vestibular disease. They also can display unilateral cerebellar ataxia, with the affected side being contralateral to the side of the head tilt. Because the cerebellum plays a role in postural reactions, patients with cerebellar dysfunction can have decreased to absent postural reactions. Again, these will be contralateral to the side of the head tilt. Bella’s left-sided postural reaction deficits in conjunction with her right-sided head tilt are consistent with a lesion affecting the left cerebellum. A lesion in the flocculonodular lobe of her left cerebellum is the cause of her paradoxical vestibular disease. Further, her extensor rigidity in her thoracic limbs and her opisthotonus in the presence of a normal mentation are consistent with a lesion in the cerebellum. Collectively, her exam abnormalities are thus most consistent with a lesion affecting the left cerebellum. Differential diagnosis list Using a scheme such as the DAMNITV differential diagnosis list scheme is a valuable method for organizing differential diagnoses for a given patient. Bella’s differential diagnosis list is summarized below: Category Differential Priority Degenerative Storage disorder Inconsiderable Anomalous Hepatic encephalopathy, hypoglycemia, electrolyte imbalance Very unlikely Neoplastic Primary or metastatic brain tumor Strong differential Nutritional Thiamine deficiency Inconsiderable Infectious Various infectious etiologies Possible Non-infectious inflammatory Meningoencephalitis of unknown etiology Moderately considerable Trauma Head trauma Very unlikely Toxin Various toxins Very unlikely Vascular Stroke Strong differential The most likely differentials for Bella’s peracute onset of neurologic dysfunction are a neoplasm affecting the cerebellum and a stroke affecting the cerebellum. Although neoplasia often leads to a more gradual onset of signs, a sudden onset is possible in cases in which the neuroparenchyma no longer can accommodate the increased tissue content within the fixed confines of the skull or if a tumor experiences a hemorrhagic event. Other differentials, including an infectious disease and meningoencephalitis, are considered possible but are less likely. This is because, in general, infectious encephalopathies are uncommon in dogs and typically do not cause peracute signs. Meningoencephalitis of unknown etiology (MUE) is an immune-mediated disease of dogs and can cause a wide spectrum of severity and acuity of signs. It remains less likely for this dog, though, as most cases occur in dogs younger than seven years old. Ischemic strokes in dogs Despite neoplasia being a considerable differential, it is considered much less likely than the top differential for Bella, which is a stroke to the cerebellum. This is a very important differential to consider for a patient presenting with a peracute onset of paradoxical vestibular disease. In fact, it is likely the most common cause of paradoxical vestibular disease in dogs. The rostral cerebellar artery is the most common canine brain artery involved in ischemic strokes.1 This artery supplies the region of the cerebellum that is part of the vestibular system (the flocculonodular lobe). Thus, when this artery develops an embolism, its territory experiences a peracute loss of blood supply. This results in immediate, often severe unilateral cerebellar and paradoxical vestibular signs. Confirmatory diagnosis of a stroke to the region supplied by the rostral cerebellar artery requires an MRI of the brain. A stroke affecting one side of the cerebellum will appear as a sharply delineated region of brightness on T2-weighted imaging, without the appearance of a mass effect. A special series of sequences, called diffusion-weighted imaging (DWI) can also markedly improve the confidence in this diagnosis.2 DWI tracks the flow of water molecules through tissues. Unlike essentially all other conditions, ischemic stroke creates a very specific pattern when two different subsets of DWI are compared (Figure 1). Ischemic strokes will appear bright (hyperintense) on the first image evaluated, called the Trace. On a second image evaluated, called the ADC map, this same lesion will appear dark (hypointense). This combination only occurs with ischemic stroke (as opposed to neoplastic, infectious, and inflammatory conditions). Bella’s MRI was strongly supportive of an ischemic stroke in the region of her left rostral cerebellar artery. Figure 1. Diffusion-weighed imaging (DWI) of an ischemic stroke to the region supplied by the rostral cerebellar artery. The top image is a Trace. Note the strongly hyperintense, wedge-shaped lesion affecting the left cerebellum. The bottom image is the ADC map. Note that the same lesion is now hypointense on the ADC map. This combination is classic for an ischemic stroke. Courtesy Dr. Susan Arnold An alternative course to pursuing a definitive diagnosis is to use “time as a diagnostic test.” Without any intervention, dogs that have experienced strokes are expected to show gradual improvement, whereas dogs with neoplasia or other causes of their paradoxical vestibular signs would not be expected to improve in the absence of targeted therapy. Thus, in cases in which referral for an MRI is not possible and in cases in which a stroke is considered a strong primary differential, clinicians are encouraged to recommend monitoring rather than premature closure. Strokes in dogs can occur for a variety of reasons. These include hypertension, heart disease, hyperadrenocorticism, renal disease, and rarely, hypothyroidism.3 All dogs diagnosed with or are suspected to have experienced a stroke should undergo systemic evaluation for these precipitating signs. This is an important step to take, because if an underlying cause is found, it should be treated to prevent additional stroke events. A diagnosable underlying cause is found in roughly 50 percent of cases. Strokes that occur with a diagnosable underlying cause technically have a slightly worse prognosis than strokes for which an underlying cause cannot be detected. Therefore, it is important to search for precipitating factors, even if the yield is relatively low. Bella’s outcome Prior to being anesthetized for her MRI, Bella’s blood pressure was confirmed to be normal, and a complete blood count and blood chemistry panel did not disclose any abnormalities that would increase suspicion for a primary cause of her presumed stroke. She underwent a brain MRI, which confirmed a stroke affecting the region supplied by her left rostral cerebellar artery. A cerebrospinal fluid (CSF) tap was not performed. She underwent an abdominal ultrasound to continue the screening for stroke causes, and her ultrasound was normal. She subsequently recovered at home, with frequent assistance from her owner to help her ambulate as she regained function. Two weeks after the onset of her signs, she was ambulatory. Twelve weeks after the onset of her signs, she had returned to normal. 3 key takeaways from Bella’s case Two lesion localizations can cause extensor rigidity and opisthotonus, and they carry very different prognostic information. Decerebellate rigidity is not a prognostic indicator. An ischemic stroke to the rostral cerebellar is a common cause of peracute paradoxical vestibular disease in dogs. A large proportion of dogs (80 percent) with ischemic strokes make either a complete or acceptable degree of recovery. Summary There are many situations in which the severity of neurologic signs is correlated with patient prognosis. However, there are many important exceptions to this general pattern. This article serves to provide three important examples of such a “severity-prognosis mismatch.” Clinicians are encouraged to generate thorough differential diagnoses lists, illness scripts, and consult prognostication flowcharts and tables when determining the prognosis for a given patient. Part two will feature two more case studies, along with additional insights for causes and treatments. Susan A. Arnold, DVM, DACVIM (Neurology) is an assistant professor of neurology and neurosurgery at the University of Minnesota College of Veterinary Medicine. She is boarded by the American College of Veterinary Internal Medicine (Neurology). In her role, Dr. Arnold practices neurology and neurosurgery, trains interns and residents, and teaches veterinary medical students in both didactic and clinical settings. References Thomsen B, Garosi L, Skerritt G, Rusbridge C, Sparrow T, Berendt M, et al. Neurological signs in 23 dogs with suspected rostral cerebellar ischaemic stroke. Acta Vet Scand. 2016 Jun 7;58:40. Boudreau E, Kerwin SC, DuPont EB, Levine JM, Griffin JF. Temporal and sequence-related variability in diffusion-weighted imaging of presumed cerebrovascular accidents in the dog brain. Front Vet Sci. 2022 Nov 7 [cited 2024 Dec 30];9. Available from: https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2022.1008447/full Wessmann A, Chandler K, Garosi L. Ischaemic and haemorrhagic stroke in the dog. The Veterinary Journal. 2009 Jun 1;180(3):290–303.

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Overcoming the neurologic disease severity-prognosis mismatch – part 1

How to avoid the cognitive bias of premature closure in diagnosing neurologically affected patients

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