LESION LOCALIZATION AND DIFFERENTIAL DIAGNOSIS OF NEUROLOGICAL DISEASE

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1 THE NEUROANATOMIC DIAGNOSIS WHERE S THE LESION? Scott J. Schatzberg, DVM, PhD, DACVIM (Neurology) The Animal Neurology & Imaging Center Albuquerque, NM LESION LOCALIZATION AND DIFFERENTIAL DIAGNOSIS OF NEUROLOGICAL DISEASE The past ten years has been marked by a dramatic increase in the availability of sophisticated neuro-diagnostic tests (electrodiagnostics, computed tomography, magnetic resonance imaging, etc). The advantages of such technology are profound in terms of diagnostic capabilities and have allowed for progress in our understanding of complex neurological disorders. However, despite their relatively high sensitivity, these diagnostic tests often lack specificity in terms of identifying the exact nature of different disease processes. The clinician therefore must still rely upon clinical skills to adequately select and interpret all diagnostic tests. A precise localization of the problem within the nervous system (neuroanatomic diagnosis) and an understanding of the suspected disease processes (differential diagnosis) are critical to the successful management of our patients. FUNCTIONAL NEUROANATOMY AND NEUROANATOMIC DIAGNOSIS Based on the animal s history and neurological examination, the clinician can determine if the animal is affected by a neurological disease. If neurological disease is suspected, an attempt should be made to make a neuroanatomic diagnosis prior to establishing a differential diagnosis list. The major anatomic regions of the nervous system are prosencephalon/forebrain (cerebral hemispheres and thalamus), brainstem (midbrain, pons and medulla oblongata), cerebellum, spinal cord and the neuromuscular system (peripheral nerve, neuromuscular junction and muscle). A basic knowledge of the function of each of these anatomic regions is essential in the interpretation of the neurological examination findings. The examination aims to test the integrity of these various components of the nervous system and, if present, to detect any functional deficit. Normal findings are equally important to the abnormal findings in establishing the neuroanatomic diagnosis. The neurological evaluation includes a list of the abnormal examination and historical findings. Each of these abnormalities should be correlated to a specific region or to specific pathways within the peripheral and/or central nervous system (Table 1). An attempt should be made to explain the abnormal findings with a single lesion within one of the following region of the nervous system: prosencephalon cerebellum brainstem [C1 C5] [C6 T2] [T3 L3] - [L4 L6] [L7 S3], neuromuscular system. Lesions within these regions of the nervous system result in predictable and specific clinical signs listed below. In localizing a lesion, it is not necessary that all the clinical signs listed be present. If a single lesion cannot explain all of the abnormalities, the anatomic diagnosis is considered to be multifocal or diffuse. A correct neuroanatomic localization is essential in the choices and interpretations of all neurodiagnostic tests. Moreover, the neuroanatomic diagnosis is critical to the generation of an appropriate differential diagnosis. Clinical signs Seizure Narcolepsy/cataplexy Hemi-neglect syndrome Abnormal behaviour Visual dysfunction Head pressing Circling With loss of balance Without loss of balance Head tilt, nystagmus, falling, rolling Strabismus Depression, stupor, coma Neurolocalization Diencephalon Eyeball, optic nerve, optic chiasm, forebrain Vestibular apparatus Forebrain Vestibular apparatus Vestibular apparatus CN III, IV, VI Brainstem or Forebrain

2 Difficulty to prehend CN V, XII, caudal brainstem Dysphagia CN IX, X, caudal brainstem Dropped jaw Bilateral CN V Paralysis of eyelid, lip, nostril and/or ear CN VII Megaesophagus CN X Laryngeal paralysis CN X Tongue paralysis CN XII Deafness Auditory apparatus Table 1. Example of clinical signs and associated neuroanatomic localizations Anatomy and function - The prosencephalon/forebrain is the area of the brain located rostral to the tentorium cerebelli (supratentorial region). It includes the cerebral cortex and white matter, basal nuclei, diencephalon (divided in thalamus, subthalamus, metathalamus and hypothalamus). The cerebral cortex is important for behavior, vision, hearing, fine motor activity and conscious perception of touch, pain (nociception), temperature and body position (conscious proprioception). The cerebral white matter mainly conveys ascending and descending sensory and motor activities. The basal nuclei are involved in muscle tone, initiation and control of voluntary motor activity. The diencephalon is the most rostral part of the brainstem. It is responsible for control of autonomic (appetite, thirst, temperature, electrolyte and water balance) and endocrine functions, sleep and consciousness. It also is involved in olfactory function (CN I: olfactory nerve projects to the hypothalamus and other parts of the limbic system), vision and pupillary light reflex (CN II: optic nerve and optic chiasm are located on the ventral surface of the hypothalamus) and acts as a visual (lateral geniculate nucleus), nociceptive and proprioceptive sensory relay system to the cerebral cortex. Finally, the cell bodies of upper motor neurons are located in the motor cortex (pyramidal system), the diencephalon and motor centre of the brainstem (extrapyramidal system). Table 2 lists clinical signs associated with prosencephalic dysfunction. Table 2. Prosencephalon/forebrain neurolocalization Muscle tone Other findings Altered mental status Behavioral changes Abnormal movement and posture: pleurothotonus (usually ipsilateral), head pressing, pacing, wandering aimlessly and/or circling (usually ipsilateral) Normal gait Postural reaction deficits in contralateral limbs to increased in contralateral limb to increased on contralateral limb Blindness and abnormal menace response with normal or abnormal pupillary light reflexes Abnormal response to facial sensation Seizures (Narcolepsy) (Hemi-neglect syndrome) (Movement disorder) Brainstem Anatomy and function - Embryologically, the brainstem consists of all of the brain except the prosencephalon/forebrain and cerebellum. It includes the mesencephalon (midbrain), the pons, the medulla oblongata and the cerebellar peduncles. The brainstem contains the regulatory centers for consciousness (reticular activating system) and breathing (medullary reticular formation). It links the cerebral cortex to the spinal cord through ascending sensory and descending motor pathways. Finally, it has ten pairs of cranial nerves

3 involved in a variety of motor and sensory functions including equilibrium and hearing. Table 3 lists clinical signs associated with brainstem dysfunction. Table 3. Brainstem neurolocalization Muscle tone Other findings Altered Paresis/paralysis of all four limbs (tetraparesis/plegia) or of ipsilateral thoracic and pelvic limbs (hemiparesis/plegia) (Opisthotonus) (Decerberate rigidity) Postural reaction deficit on all four limbs or on ipsilateral thoracic and pelvic limbs Normal to increased spinal reflex on all four limbs or on ipsilateral thoracic and pelvic limbs Normal to increased tone in all four limbs or on ipsilateral thoracic and pelvic limbs Cranial nerve abnormalities (CN III to XII) Intact to slight decreased (Respiratory and cardiac abnormalities) Cerebellum Anatomy and function - The cerebellum controls the rate, range and force of movements without actually initiating motor activity. It coordinates muscle activity and smooths movements induced by the upper motor neurons. Because of its close association with the brainstem vestibular nuclei, it also functions in the maintenance of equilibrium and the regulation of muscle tone when the body is at rest or during motion. Finally, the cerebellum normally has an inhibitory influence on urination. Table 4 lists clinical signs associated with cerebellar dysfunction. Table 4. Cerebellar neurolocalization Muscle tone/mass Other findings Intention tremors of head and eye Hypermetria with preservation of strength Truncal ataxia Broad-based stance (Decerebellate rigidity) Delayed and then exaggerated response to postural reaction testing Ipsilateral menace deficit with normal vision and normal facial motor function (Vestibular signs) (Anisocoria) (Increased frequency of urination) Spinal cord Anatomy and function - The spinal cord is composed of a central core of grey matter containing cell bodies of sensory, interneuron and lower motor neurons. The cell bodies of efferent neurons are present in the ventral (somatic motor neuron responsible for innervation of striated muscles) and lateral grey column (cell bodies of preganglionic sympathetic neurons in the thoracic segments and preganglionic parasympathetic neurons in the sacral segments). The cell bodies of afferent (sensory) neurons are present in the dorsal root ganglion. The outer

4 portion of the spinal cord is composed of white matter divided in three columns or funiculi. The dorsal funiculus consists essentially of ascending tracts mainly involved in proprioception. The lateral funiculus contains both ascending (proprioception, touch, pressure, temperature and pain pathways) and descending (motor pathways) tracts. The ventral funiculus contains only descending motor tracts. A spinal cord segment is defined as a portion of the spinal cord, which gives rise to one pair of spinal nerves. There are eight cervical, thirteen thoracic, seven lumbar, three sacral and at least two caudal spinal cord segments. Some spinal cord segments lie in the vertebra of the same annotation while others do not. Neurological lesion localisation refers to spinal cord segments. Innervation in the body is organized in a segmental pattern. Each cutaneous region of the body (dermatome) and group of muscle fibers (myotome) is innervated by one or more spinal cord segment. Functionally, the spinal cord can be divided in four regions: cranial cervical [C1 to C5] cervico-thoracic [C6 to T2] thoraco-lumbar [T3 to L3] and lumbo-sacral [L4 to S3]. LMN cell bodies are located within the grey matter of the cervico-thoracic intumescence (segments [C6 to T2]) for the thoracic limbs and lumbo-sacral intumescence (segments [L4 to S3]) for the pelvic limbs. Lesions at the level of the intumescences result in LMN signs in the corresponding limb(s). Figure 1 (DeLahunta, 1983) summarizes clinical signs associated with spinal cord dysfunction. Figure 1. Clinical signs associated with spinal cord lesions. From: DeLahunta, Veterinary Neuroanatomy and Clinical Neurology, 2 nd edition, Saunders 1983 Peripheral nerve Anatomy and function The peripheral nervous system consists of 12 pairs of cranial nerves and 36 pairs of spinal nerves that extend from or to the spinal cord and brainstem. Peripheral nerves contain both motor and sensory axons. The motor axons extend from neurons located in the ventral horn of the spinal cord or grey matter of the brainstem. The sensory axons have a cell body in the dorsal root ganglion or in homologous ganglia of cranial nerves. Most spinal nerves leave the vertebral canal through intervertebral foramina formed between the pedicles of adjacent vertebrae. A cutaneous region innervated by afferent nerve fibres from a single spinal nerve is called a dermatome. The musculature innervated by a single spinal nerve is termed a myotome. Individual muscles are innervated by multiple spinal nerves. In the limbs, muscles are supplied by nerves arising from large plexuses consisting of intermingled nerve fibres coming from ventral branches of spinal nerves. The brachial plexus (formed by the ventral branch of the sixth, seventh and eight cervical and the first two thoracic spinal nerves) innervates the thoracic limbs while the lumbosacral plexus (formed by the last five lumbar nerves

5 and the three sacral nerves) innervates the pelvic limb. Table 5 lists clinical signs associated with peripheral nerve dysfunction. Table 5. Peripheral nerve neurolocalization Muscle tone Other findings Flaccid paresis/paralysis on affected limb(s) (motor) Postural reaction deficit on affected limb(s) (sensory) Decreased to absent spinal reflex on affected limb(s) Decreased to absent tone on affected limb(s) (motor) Muscle atrophy on affected limb(s) (motor) Deficits in neuropathy involves cranial nerves Decreased to absent nociception and sensation Paraesthesia Self-mutilation Muscle Anatomy and function Skeletal muscle functions to maintain body posture, produce movement, and provide a reservoir source of energy. It is an integral part of the motor unit composed of the lower motor neuron (cranial nerve nucleus or ventral horn cell body and axon extending along a peripheral nerve), the neuromuscular junction and the muscle innervated. The motor unit is the final common pathway for motor activity and the muscle is the final effector of this motor unit. The functional cellular unit is the muscle fiber, or myofiber. Each muscle fiber is comprised of several hundred myofibrils, which in turn contain several hundred myofilaments. The number of muscle cells innervated by one motor neuron varies according to the muscle group. Table 6 lists clinical signs associated with muscle dysfunction. Table 6. Muscle neurolocalization Muscle tone/mass Stiff and stilted gait - Paresis Exercise induced weakness/stiffness to altered if severe weakness Hypotonia (except for myotonic myopathy) Muscle atrophy or hypertrophy Limited joint movement due to muscle contracture Reflexes may be altered by involvement of innervated muscles

6 DIFFERENTIAL DIAGNOSIS OF NEUROLOGICAL DISEASE Determination of a differential diagnosis list is essential in choosing and interpreting any diagnostic test however sophisticated they may be. The aim of diagnostic testing should only be to confirm or exclude the potential differentials and should not replace the clinical evaluation. The differential diagnosis list is influenced by: - Historical data: questioning of the owner should be aimed at defining the onset and progression of the condition. Furthermore, historical data can give clues as to how widespread or focal the disease process is in the nervous system, whether there was evidence of asymmetry, and how severe the signs have been. - Neurological findings: the aim of the neurological evaluation is to define the lesion localization (prosencephalon/forebrain, brainstem, cerebellum, spinal cord segment, peripheral nerve, neuromuscular junction, muscle) and distribution (focal, multifocal, diffuse) within the nervous system. Disease processes that can affect the nervous system may be classified according to the DAMNIT V (degenerative anomalous metabolic neoplastic nutritional - inflammatory/infectious traumatic toxic vascular) scheme. Each disease process has a typical signalment, onset and progression, as well as a typical distribution within the nervous system (Figure 2, Table 7). Degenerative diseases Degenerative diseases can affect any part of the nervous system. They typically have an insidious onset and slow progression. Many of these diseases, which involve morphologic degeneration of the nervous tissue, are familial or hereditary. Age of onset is variable, as some may affect young animals shortly after birth (eg cerebellar abiotrophy) while others affect adult animals (eg degenerative myelopathy). Degenerative diseases often affect the nervous system in a symmetrical fashion. Anomalous Neurologic signs can result from malformations that directly involve the nervous tissues or that involve the tissue surrounding the neural axis (cranium and vertebral column). In patients with nervous tissue malformations, clinical signs typically are non-progressive or slowly progressive early in life. Cranial or vertebral malformations do not always affect the nervous system and are often incidental findings identified on imaging (eg radiographs). If present, neurological disease typically is recognized early in life and signs tend to be non-progressive or slowly progressive over time. Occasionally, spinal malformations do not cause neurological signs until later in life as a result of stenosis of the vertebral canal, progressive deformity or instability. Metabolic disorders - Metabolic disorders can affect animals of any age. Clinical onset is variable but most often is subacute. Acute onset of signs is rare but may be seen with substrate deficiencies. Diffuse non-specific signs or bilaterally symmetric deficits referable to the prosencephalon/forebrain are the most common localizations. Most of these conditions tend to wax and wane over time. Neoplasia Neoplasia is more common in animals over 5 years of age but may occur at any age. Neurological signs typically are chronic and progressive in nature, although acute deterioration is common (especially if associated with spontaneous hemorrhage, impairment of vascular supply or loss of compensatory mechanisms in normal surrounding tissue). Other determinant factors in clinical expression of neoplasia include: size, histological nature, growth rate, associated inflammatory responses and location within the CNS or PNS. Neurological deficits may be asymmetric or symmetric and often suggest a focal lesion. Nutritional diseases Nutritional diseases affecting the nervous tissue are rare in small animals. As for metabolic diseases, neurological signs are typically bilaterally symmetrical. Their onset is variable (subacute or insidious) and they typically are slowly progressive. Distribution can be diffuse or multifocal as some nutritional disease may affect selective area of the CNS. Inflammatory and infectious diseases Inflammatory or infectious diseases can have an acute, subacute or more insidious onset depending on the specific cause. Sign typically progress without treatment although the signs may wax and wane in some cases early after the onset. Neurological deficits may refer to a focal or multifocal lesion and are asymmetric or symmetric. Idiopathic disorders Idiopathic disorders tend to produce an acute onset of non-progressive or regressive signs. Neurological deficits vary with each syndrome but most often refer to a focal asymmetrical or symmetrical lesion. Trauma Traumatic disorder usually have a peracute or acute onset. Signs typically remain static or improve over time. Neurological deficits can be symmetric or asymmetric and often refer to a focal lesion. Worsening of

7 edema (associated with secondary injury) can result in progression of neurological signs for a short period of hours. Toxic disorder Numerous toxins can affect the nervous system, either primarily or secondarily. Toxicities often produce acute onset and diffuse or bilaterally symmetric signs from the time of the onset referable to a prosencephalic/forebrain lesion. Vascular disorders - Vascular disorder can result from loss of blood supply (ischemia/infarction) or from hemorrhage into the nervous system. They are characterized clinically by a peracute or acute onset of nonprogressive or regressive signs. Deficits typically are focal initially and often asymmetrical. Worsening of edema (associated with secondary injury) can result in progression of neurological signs for a short period of hours. Hemorrhage may produce a more progressive onset over a very short period of time. Clinical signs typically regress after hours; this is attributable to diminution of mass effect associated with hematoma resorption or edema resolution. O N SET A N D PR O G R ESSIO N Severity Inflam m atory N eoplastic D egenerative M etabolic D A M N I T V V ascular T raum a T im e

8 Figure 2. Disease processes categorized by onset and progression Acute progressive with asymmetrical signs: 1. Inflammatory/infectious disease 2. Neoplastic Acute progressive with symmetrical signs: 1. Metabolic disorder 2. Nutritional disorder 3. Neoplastic 4. Inflammatory/infectious disease 5. Toxicity Acute non-progressive: 1. Vascular disorder 2. Trauma 3. Idiopathic Chronic progressive with symmetrical signs: 1. Degenerative disorder 2. Anomalous 3. Metabolic 4. Neoplastic 5. Nutritional 6. Inflammatory/infectious disease 7. Toxicity Chronic progressive with asymmetrical signs: 1. Neoplastic 2. Inflammatory/infectious disease Table 7. Expected disease categories categorized by onset, progression and symmetry of the neurological signs.

examination in Companion Animals

Peer reviewed The Neurologic examination in Companion Animals Part 2: Interpreting Abnormal Findings Helena Rylander, DVM, Diplomate ACVIM (Neurology) In the January/February issue of Today s Veterinary