Neurological Diagnosis & Localization

Allyson R. Zazulia, M.D

Localization means “where,” is the lesion responsible for a patient’s symptoms and signs. Localization requires an understanding of the anatomy and physiology of the nervous system, its blood supply, and the disease processes that affect it. The process of localization begins during history taking, is refined during the general and neurological examinations, and is re-assessed after any relevant diagnostic studies are completed.

Despite sophisticated neuroimaging and laboratory studies, technology cannot replace the clinician’s anatomical localization based on history and examination. Lesions may go undetected on standard imaging studies unless the studies are specifically focused on the anatomical region hypothesized to be involved. Similarly, neuroimaging or laboratory studies may disclose incidental abnormalities that have no bearing on the patient’s symptoms and the further pursuit of which can lead to unnecessary time, expense, and potentially patient harm. Take the case of a patient with back pain and difficulty walking. In the absence of a thorough H & P and lesion localization, an MRI of the lumbar spine is obtained, showing a left L5 disc herniation. The patient is sent to an orthopedist and undergoes discectomy. At best, his symptoms do not improve with surgery or continue to progress. At worst, he develops a serious post-operative complication. Here’s the way it should have worked: Further history reveals that the pain was not radicular (as would occur with a disc); walking was difficult because his legs felt stiff and he couldn’t feel the ground with his feet, and he had been having urinary urgency and incontinence as well as impotence for the past 6 months. Based on these symptoms, your hypothesis at this point is that he has a spinal cord lesion. Since you know that the spinal cord ends at L2, you know that there is no role for imaging of the lumbar spine. Examination reveals tenderness over the lower thoracic spine, full strength, bilateral lower extremity spasticity and hyperreflexia with extensor plantar responses (upgoing toes), and sensory loss below T9. You can now further refine your localization to the thoracic spinal cord and order the appropriate imaging study, which shows an extradural mass at T7 compressing the spinal cord.

Localization involves two separate steps:(1)type localization and(2)topographical localization.Type localizationidentifies the type of dysfunction present within the nervous system. There are five possibilities: focal, multifocal, diffuse, specific system, and combination.

1. Afocallesion is one in which a single, discrete neuroanatomical locus can account for all the patient’s symptoms and signs. Examples include(a)a left cerebral hemispheric infarction in a patient with sudden onset right hemiplegia and aphasia;(b)a pituitary tumor in a patient with papilledema and subacute onset amenhorrhea and bitemporal hemianopia; and(c)a right median neuropathy in a patient with weakness of the right abductor pollicis brevis and numbness of the first 3½ digits on the right hand.

2. Amultifocalprocess involves more than one locus, but the loci remain discrete. Modification of the previous examples that would indicate multifocal localization include(a)multiple cardiac-origin emboli in a patient with a new systolic heart murmur and sudden onset right hemiplegia and aphasia (left cerebral hemisphere) and left superior quadrant visual field cut (right posterior temporal hemisphere);(b)metastases in a smoker with chronic cough, papilledema, and subacute onset left arm and leg dysmetria (left cerebellar hemisphere) and left homonymous hemianopia (right optic tract); and(c)mononeuritis multiplex (neuropathy involving multiple discrete nerves) in a patient with weakness of the right abductor pollicis brevis and numbness of the first 3 ½ digits on the right hand (right median nerve), tingling in the fifth digit and the ulnar half of the fourth digit on the left hand and weakness of the left first dorsal interosseus (left ulnar nerve), and numbness of the left lateral leg and dorsal foot and weakness of left ankle dorsiflexion and eversion (left superficial peroneal nerve).

3. Diffuselocalization indicates widespread dysfunction of a part of the nervous system. Examples include(a)encephalopathy due to a variety of metabolic or toxic causes;(b)dementia; and(c)numbness and pain in a stocking and glove distribution due to diabetic small fiber peripheral neuropathy.

Note that in both a multifocal and a diffuse process, there is involvement of more than one discrete physical location. But in multifocal, the lesions remain discrete, whereas in diffuse, the dysfunction is generalized. In the case of neuropathy, for example, a multifocal process will be evident by signs and symptoms in the distribution of multiple specific nerves (e.g., median, ulnar, and femoral), as discussed in the example of mononeuritis multiplex above. Some nerves are involved and some aren’t. In axonal neuropathy (a form of diffuse nerve disease), on the other hand, the distal-most portions of all axons are involved, resulting in stocking and glove distribution sensory and motor loss.

4. Specific systemlocalization is a subset of diffuse localization. In specific system processes, there is diffuse dysfunction of a particular pathway or neurotransmitter system. The progressive diffuse weakness, atrophy, fasciculation, and spasticity in amyotrophic lateral sclerosis (Lou Gehrig’s disease) occur because of loss of the anterior horn cells and degeneration of the corticospinal tracts. The progressive loss of vibration and proprioception in vitamin B12 deficiency is a manifestation of posterior column dysfunction. The delirium, mydriasis, hypertension, dry mouth, urinary retention, and constipation of atropine overdose reflect blockade of muscarinic cholinergic receptors.

5. Topographical localizationinvolves determining the anatomical level within the nervous system that accounts for all the patient’s findings. Often, it is best to start from the periphery and work centrally, considering each of the possible sites listed in the table below. The middle column lists the terms commonly used to describe the disease processes affecting these areas and the right column lists the symptoms and signs typical of lesions at these sites.

Site Dysfunction Typical symptoms/signs
Muscle Myopathy Proximal weakness (motor only)
Neuromuscular junction Fatigable weakness (motor only)
Peripheral nerve Neuropathy Pain; motor, sensory, and reflex loss in specific nerve distribution, OR distal symmetric sensory loss and/or weakness
Plexus (brachial or lumbosacral) Plexopathy Mixed nerve and root distribution
Spinal nerve root Radiculopathy Radicular pain; motor, sensory and reflex loss in specific root distribution
Nerve cell body
Anterior horn cell “LMN disease” LMN weakness and reflex loss
Dorsal root ganglion Sensory neuronopathy Sensory loss and reflex loss
Spinal cord
Myelopathy LMN weakness at level of lesion; UMN below level of lesion; sensory level; dissociated sensory loss; neurogenic bladder
Posterior fossa
Brainstem Cranial nerve deficits; impaired LOC; crossed or bilateral motor or sensory deficits
Cerebellum Ataxia; tremor; nystagmus
Thalamus LOC or memory disturbance; hemisensory loss and/or pain; hemiataxia; neglect or aphasia
Basal ganglia Chorea; athetosis; dystonia; tremor; rigidity
Cerebral cortex Encephalopathy Hemiplegia (UMN) and/or hemisensory loss; aphasia; neglect; hemianopia; dementia; seizure
Subarachnoid space/meninges Headache, altered LOC, cranial nerve deficits

LMN=lower motor neuron: weakness, atrophy, reflex loss, fasciculations.

UMN=upper motor neuron: weakness, spasticity, hyperreflexia, extensor plantar response.

LOC=level of consciousness.
This is where your knowledge of neuroanatomical pathways and the signs and symptoms that go along with damage to these pathways comes in. Since the nervous system is a continuum, a particular symptom may represent a lesion at multiple levels. Thus, a complaint of weakness may represent dysfunction at the level of the muscle, neuromuscular junction, peripheral nerve, plexus, spinal nerve root, lateral column of the spinal cord, pyramidal tract in the brainstem, internal capsule, or cerebral motor cortex. It is thepatternof weakness (e.g., proximal vs. distal, unilateral vs. bilateral, face vs. limbs),associated symptoms(e.g., numbness, visual disturbance, language dysfunction), andexamination findings(e.g., atrophy, fasciculations, and hyporeflexia or spasticity and hyperreflexia) that allow you to narrow down the possibilities. So, for example, weakness, numbness, and reflex loss within the distribution of a particular spinal nerve root implies a radiculopathy, whereas weakness of the face, arm, and leg all on the same side of the body implies a lesion within the motor pathways above the level of the facial nucleus in the mid-pons.

During the process of localization, ask yourself three questions:

1. What is the necessary minimal amount of neuroanatomy thatmust bedamaged in order to produce the patient’s symptoms/signs? A patient with monocular blindnessmust havea lesion on the same side somewhere between the cornea and optic chiasm. A patient with an absent tendon reflexmust havea lesion within the afferent-efferent arc serving that reflex. A patient with aphasiamust havea lesion of the dominant (95% left) cerebral hemisphere.

2. If the lesion is here, does it explainallthe findings? If the answer is no, you should carefully re-examine the data and your conclusions. Either the localization is wrong or the disease process is multi-focal or diffuse.

3. If the lesion is here, whatelseshould be present? That’s another way of saying, does the patient have the expectedneighborhood signsto go along with your proposed localization?

Let’s take the complaint of unilateral facial weakness. With this small amount of information (face and unilateral), we can already narrow down the possible sites of involvement to peripheral nerve (cranial nerve VII) within subarachnoid space or temporal bone, brainstem (pontine lesion affecting the VII nerve nucleus or fascicles), or supranuclear motor pathways supplying the face (e.g., genu of internal capsule or lateral motor cortex). But we obviously need to do better than this before beginning to address what the patient has. The first question should be what is the pattern of weakness? If the patient has lower facial weakness (drooping at the corner of the mouth or inability to raise the corner of the mouth when smiling) with relative sparing of the upper face, this is consistent with an upper motor neuron lesion (a.k.a. supranuclear or above the level of the facial nucleus in the pons). If instead the patient has weakness that involves the entire half of the face equally (facial droop as well as inability to close the eye), this is consistent with a lower motor neuron lesion (at the level of the VII nerve or the VII nerve nucleus in the pons). Our patient complains of both facial droop and inability to close the eye. So now we need to differentiate between a pontine lesion and a peripheral nerve lesion. What neighborhood signs would you expect with a lesion of the facial nucleus or intrapontine nerve fibers? If you remember your brainstem anatomy (or pull out a diagram of the pons, seeFigure 1), you’ll recall that the facial nerve fibers course around the abducens nucleus and that the abducens nerve fibers course just medial to the facial nucleus as they exit the pons. The parapontine reticular formation lies just ventromedial to the abducens nucleus. So an associated ipsilateral lateral rectus palsy or conjugate gaze palsy would localize the lesion to the pons. Since the facial nerve fibers pass between bundles of corticospinal tract fibers, an associated contralateral hemiparesis would also localize the lesion to the pons. What if instead of associated diplopia or contralateral arm and leg weakness, the patient complains of hearing loss and tinnitus? This suggests involvement of the auditory nerve. The two places that the facial nerve is in close proximity to the auditory nerve are within the cerebellopontine angle (Figure 2) and within the temporal bone. If we wanted to, we could localize a VII nerve lesion even more precisely in terms of where the lesion is in relation to the departure of the nerve to the stapedius muscle, the chorda tympani, and the greater superficial petrosal nerve (based on the presence or absence of hypersensitivity to sound, loss of taste, and impaired lacrimation, respectively). Why bother doing this? It is not a simple exercise in mental masturbation; rather it is an exercise that allows us to begin to address etiology. The pathophysiological processes underlying an intrinsic pontine lesion (e.g., vascular or demyelinating disease) differ from those underlying a cerebellopontine angle lesion (e.g., tumor), which differ from those underlying a peripheral facial nerve lesion (e.g., trauma, infection, or idiopathic).

Figure 1. Axial section through pons at level of facial nucleus.

Figure 1. Axial section through pons at level of facial nucleus.

Figure 2. CN VII and CN VIII at cerebellopontine angle.

Figure 2. CN VII and CN VIII at cerebellopontine angle.


In neurology, a patient’s dysfunction is not only the expression of where the disease occurs, i.e., a consideration of which cross-section of circuits is down, but also a reflection of the particular disease process causing the disability. A neoplasm, an infarct, and demyelination in the right frontal lobe will all cause left-sided weakness, but at different rates (time-intensity profile) and with different individual features (headache, seizures, papilledema, episodic waxing and waning, aggravation by heat, etc.).

Time-intensity Profile

So the next step in neurological diagnosis is to interpret temporal features of the patient’s symptoms in terms of pathophysiological principles. You need to know what the very first symptom was. Patients often pick the most dramatic events and play down earlier subtle details. Don’t let them. Ask for earlier, perhaps less obvious symptoms of the same thing. Warning signs. Ask if they were absolutely 100% normal before this started. “Oh yeah, come to think of it, I did have an episode of dizziness and vomiting a month ago. It must have been something I ate.” Maybe, but perhaps more likely is that it was the first episode of a recurring pathophysiological process at the same anatomical site. This piece of history is crucial. You must dig for it. On the other hand, don’t be fooled when patients draw connections that aren’t true, e.g., “It all happened after I slipped in the Wal-Mart parking lot . . .” Just take all the information in and draw your own conclusions at the end.

Over what period of time did the symptoms develop? Seconds, minutes, hours, days? What happened next? Many clues about etiology become clear from constructing a time-intensity profile because this teaches us about disease processes through anatomy.

1. Acute: minutes to hours. This implies acute metabolic dysfunction as occurs with ischemia, seizure, trauma, etc.

2. Subacute: days to weeks. May be smooth, stair-step, or crescendo. This suggests an expanding lesion, as occurs with tumors, abscess, etc.

3. Recurrent-remittent: episodic attacks of symptoms with rapid recovery to normal health. This implies repeating episodes of a single process as occurs with transient ischemic attacks (TIA), seizures, migraine, and multiple sclerosis. In the case of seizures, migraine, and often TIAs, the symptoms are highly stereotypical. In the case of multiple sclerosis, symptoms vary depending on the lesion site, and the process may evolve to a secondarily progressive one in which there is only partial recovery from each attack.

4. Chronic-progressive: months to years. This implies gradual deterioration as occurs with degenerative diseases like Alzheimer’s dementia, Huntington’s chorea, etc.

Symptom typescan also provide a clue as to pathophysiology:

1. Negative symptoms. Reduction (weakness, numbness) or complete loss (paralysis, analgesia) of function. Implies at least partial or complete failure of impulse conduction in a functional system. This can be reversible (e.g., TIA) or irreversible (e.g., infarction).

2. Positive symptoms. Exaggeration of a physiological phenomenon. These can be brief and very intenseparoxysmal (as in epileptic seizures) or episodic and recurrent (as in hemifacial spasm or trigeminal neuralgia). These examples imply abnormal excessive discharges in gray matter or ephaptic excitation in a fiber pathway and are considered “irritative.” Positive symptoms can also be slow and continuous: chorea, dystonia, nystagmus, tremor. Here positive symptoms imply chronic imbalance in complex integrated motor pathways, perhaps reflecting the effect of degeneration or removal of onecomponent part.

3. Secondary symptoms.Symptoms referable to “mass effect.” A lesion(e.g., tumor, infarct) causes primary symptoms by local destruction and secondary symptoms as the lesion “grows” through development of edema, pressure on adjacent brain (new, more severe symptoms), herniation (stupor, coma, midbrain signs), blockage of CSF pathways (papilledema, stupor), and stretching of vessels and meninges (headache, stiff neck).

4. Behavioral symptoms.Complex changes in personality and behavior. Occasionally these can be described as dementia, depression, or temporal lobe seizures. Although complex, disorders of perception (neglect and denial), motor behavior (apraxia), language (mutism, aphasia) or mood can usually be approached by the same stepwise method used for any neurological dysfunction. In these cases, however, it is imperative to interview relatives, neighbors, or other independent observers to obtain the historical data. But the process is the same: symptom analysis, anatomy, pathophysiology.


Determination of etiology is the last step in neurological diagnosis, occurring after lesion localization and consideration of pathophysiology. Once the patient’s symptoms, illness time course, demographic factors (age, sex, occasionally ethnicity), risk factors, and other medical conditions are put together with the exam findings and predicted anatomical localization, you will discover that the etiological possibilities are reduced to just a few. If this step-by-step diagnostic method is not followed, on the other hand, you will be left with a long list of remote etiologies. Categories of etiology in neurological disease are similar to those of non-neurological disease genetic, congenital, infectious, immune, endocrine, metabolic, toxic, traumatic, vascular, mechanical, neoplastic, degenerative, psychological except for the addition of demyelination, epilepsy, and migraine in neurological disease.

Presentation of the Patient with Neurological Disease

Going through the above process of localization will be essential to you as a third year student on Neurology and as a physician who encounters any patient with neurological complaints. The neurological H&P is structured to reflect this by expanding on the Assessment section that is common to all other areas of medicine. Whenever you present or write up an H&P on a patient with neurological disease, your history and exam should always be followed by a paragraph consisting of(1)a brief summary of the patient’s history and exam findings,(2)a statement about anatomical localization,(3)the diagnosis, and finally(4)the management plan.

Thebrief summary of history and examserves two purposes: to distill all the information you have collected on the patient into the essential facts and to review the highlights of your presentation for any listener whose mind may have been wandering. It should include the patient’s age, gender, any relevant past medical history, symptoms (including a time course for them), and exam findings. This is the time you should use words such as “rapidly progressive” or “in a stepwise fashion over the past 6 months” to describe the time-intensity profile and the time you can use medical terminology to interpret the patient’s symptoms and exam findings. An example: You report that your 64-year-old female patient with a history of asthma, hypertension, diabetes, renal insufficiency, and tubal ligation complains of waking up this morning with blurred vision and seeing two of everything except when she looks to the left. You report on the exam that the patient has limitation of abduction of the right eye, an increase in the separation of the two images when looking to the right, vibratory loss at the great toe bilaterally, and retinopathy. Your summary statement would be something like,”This 64-year-old woman with a history of hypertension and diabetes had the acute onset of horizontal diplopia upon awakening this morning and on exam has a right sixth nerve palsy.”I include hypertension and diabetes because these are causes of sixth nerve palsies and are thus relevant to the problem. I leave out the medical conditions (asthma, renal insufficiency, tubal ligation) and exam findings (mild vibratory loss in the toes and retinopathy) that likely have no direct link to the problem.

Theanatomic localizationis a single sentence defining the structures and pathways involved and where the lesion must be to explain them. In our example, you might say,”This localizes to the right sixth nerve anywhere along its course[including the subarachnoid space, cavernous sinus, superior orbital fissure, and orbit]or to the right sixth nerve nucleus in the pons.” If there are multiple findings, your localization would be theunifyinglocalization for all of them.

Thediagnosisstatement should clearly indicate the diagnosis you believe to be most likely and include a short list of other important possible diagnoses and a short explanation for why you believe them to be less likely.”The most likely diagnosis in this hypertensive and diabetic patient is vasculopathic sixth nerve palsy. A small right pontine ischemic stroke could also be responsible, but this is less likely given the lack of associated neighborhood signs.”Note that while you shouldconsiderevery condition in the differential diagnosis (and may be questioned on them in rounds), you do not need to list them all in your H&P. But if you feel compelled to discuss more, you could add a sentence like,”Based on the patient’s age, symptom time course, lack of preceding trauma, and lack of associated neurological or systemic abnormalities, other causes of sixth nerve palsy such as trauma, intracranial tumor, multiple sclerosis, meningitis, and giant cell arteritis would be exceedingly unlikely.”

Themanagement planthen discusses how you intend to rule out or rule in potential diagnoses and the treatment you will offer.”Since the vast majority of sixth nerve palsies due to vasculopathy[i.e., damage to the microscopic blood vessels supplying the nerve]or unknown causes resolve spontaneously without treatment in 3-6 months, the plan is to monitor the patient on a monthly basis until resolution, looking for new signs or symptoms that would suggest an alternative diagnosis. In the absence of additional signs or symptoms, no further work-up is needed. If diplopia persists beyond 6 months, she will be referred to an ophthalmologist for Fresnel prisms. In the meantime, she will be given an eye patch for symptomatic relief. Finally, since the possibility of a small pontine infarct cannot be entirely excluded, even if no lesion were seen on MRI, she will be started on an aspirin a day and should see her internist for better management of hypertension and diabetes.”

So, I like to think of the presentation as “building a case for the verdict” (verdict=diagnosis you believe the patient has). First you present the raw facts (history and exam findings), then you summarize and interpret the facts in a logical fashion (summary and anatomical localization), next you state what you believe to be the correct conclusion and discount all other conclusions (diagnosis), and finally you say what you’re going to do about it (management plan).