There are many types of extraneural diseases that might also affect the nervous system in some way:
- Endocrine disorders
- Non-endocrine nutritional and metabolic diseases
- Cardiovascular disease
- Respiratory disease
- Dysfunction of major organs
- Neoplasia
- Infection
- Multisystemic auto-immune diseases
- Infectious agents
This is obviously a wide range of diseases: an entire book can be written on this topic! For this article, I will limit the discussion to more common diseases, organized by the presenting neurologic signs.
DAMNITV: A Methodical Approach Drop-Down Menu
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- D – Degenerative – Lysosomal storage diseases/ inborn errors of metabolism
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- A – Anomalous/congenital – Most of these will fall into other categories (like congenital portosystemic shunting in “toxic” diseases)
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- M – Metabolic – Hypo/hyperthyroid, hypo/hyperparathyroid, Cushing’s, Addison’s, pheochromocytoma, hyperaldosteronism, diabetes mellitus, insulinoma, various other causes of electrolyte and glucose imbalances
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- N – Nutritional – Vitamin deficiencies (especially thiamine deficiency – dietary or GI related), toxicities (i.e., hypervitaminosis A), calcium/phosphorous imbalances
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- N – Neoplastic – Diffuse neoplasias, such as lymphosarcoma and hemangiosarcoma, or metastatic neoplasias. Also consider direct impairment from spread of the neoplastic disease or secondary inflammatory conditions (e.g., polymyositis triggered by lymphosarcoma)
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- I – Inflammatory – I consider this category to include sterile inflammatory conditions, which most often are auto-immune type in dogs. Occasionally this may be secondary to another disease (like underlying neoplasia or rickettsial infection) or can be part of a systemic inflammatory condition like Systemic Lupus Erythematosus (SLE).
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- I – Infectious – This can be a big list! I simplify this into viral, bacterial, fungal, rickettsial, and parasitic diseases. Neurologic manifestations are dependent on the part of the nervous system affected. Some infectious diseases might have “classic” signs like the reverse “D” shaped pupil in cats with FeLV virus associated lymphosarcoma, a rhythmic myoclonus in dogs with distemper, and hindlimb paralysis with arthrogryposis in puppies with neosporosis.
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- I – Idiopathic – There aren’t specific idiopathic syndromes I can think of that are multisystemic
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- I – Iatrogenic – Consider medication side effects (from common drugs used for extra-neural disease like neurologic signs from metronidazole used for gastrointestinal disease)
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- T – Toxic – Hepatic encephalopathy, uremic encephalopathy, ingested toxins
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- T – Trauma – This can certainly affect multiple organ systems at once
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- V – Vascular – Include hypercoagulable disorders, problems with primary and secondary hemostasis, hypertension, hypotension/hypoxia from lung and cardiac diseases
Encephalopathy and Cranial Nerve Signs
(Confusion, altered mental state, vestibular symptoms, blindness, etc.)
Intracranial signs can come from alterations in neurotransmitter levels and function, electrolyte imbalances, cellular toxic injury, and direct mass effect or injury. As with any new patient, you will perform a thorough physical exam to try to localize the lesion more specifically and to look for signs of disease outside the brain.
A minimum database should also include CBC, chemistry, urinalysis, blood pressure and sometimes thyroid and cortisol hormone testing, and chest and belly imaging (radiographs and ultrasound). Just from these first steps you can often focus suspicion on a pituitary tumor, hepatic or uremic encephalopathy, hypertensive encephalopathy, hypoglycemia, and electrolyte imbalances like very high or low sodium. Evidence for some infections and neoplasias might also be identified. We might also find underlying diseases that can predispose to stroke-like events in animals with appropriate history and clinical signs (i.e., acute onset encephalopathy that is improving without interventions).
Sometimes a good history can also raise a red flag for nutritional deficiencies (such as thiamine deficiency), toxins, and some infections.
Seizures and Seizure-like Episodes
(Tremors, fasciculations, hyperexcitability)
Like alterations in mental state, we can get seizures, tremors, and excitability from alterations in neurotransmitter levels and function, electrolyte imbalances, cellular toxic injury, and direct mass effect or traumatic injury. Your preliminary evaluations can find endocrine imbalances like severe hyperthyroidism. Hypoglycemia, hypocalcemia, hepatic encephalopathy and uremia can also be identified in the bloodwork. Hypertension or signs of cardiac hypotension and arrhythmias might also support cardiovascular causes of seizure-like episodes and syncope. Hyperviscosity from severe polycythemia or lipemia might also contribute to intracranial signs and seizure conditions.
Neuromuscular and Episodes of Weakness
Signs of neuromuscular disease usually include exercise intolerance, weakness, and often a shortened, choppy stride. Polyneuropathy might also include a “floppy” component to the gait with weak limb myotatic reflexes. Nerve and muscle can be very sensitive to toxic injury and metabolic derangement.
Hypothyroidism, chronic diabetes mellitus, insulinoma, and Cushing’s can all lead to progressive weakness from nerve and/or muscle disfunction. Addison’s and hyperaldosteronism can also cause generalized weakness and exercise intolerance. Electrolyte disturbances like hypercalcemia and hypokalemia can also cause general weakness. Cardiac dysfunction might lead to exercise intolerance and episodes of weakness, and myasthenia might also present with gastrointestinal signs.
Animals can also get secondary inflammatory conditions (polyradiculoneuritis, cranial neuritis, polymyositis) associated with infections and neoplastic conditions. Any animal that is a suspect for these inflammatory conditions should be screened for underlying diseases that could have triggered the episode.
Myelopathy and Multifocal Neurologic Signs
Myelopathies (spinal cord disorders) are not often associated with metabolic and toxic insults as much as they can be affected by multifocal structural diseases. Neoplasias like lymphosarcoma and hemangiosarcoma are the most common cancers that also affect the nervous system. Metastasis into the brain and spinal cord can also occur with many types of neoplasia like melanoma and mammary carcinoma.
Infections are other common causes of disease in multiple organ systems and can include (but certainly not limited to) viruses (distemper, FIP), rickettsial diseases (RMSF), bacteria (direct extension from bite wounds and ear infections versus hematogenous transmission), fungal (aspergillosis, cryptococcosis, blastomycosis), protozoa (Toxoplasma, Neospora), parasites (Cuterebra and Angiostrongylus), and rarely organisms like Prototheca in Southern states.
Our neurology specialists are here to help you at any stage of the diagnostic process, whether to consult on strange examination findings or to discuss more advanced testing.
Coagulopathies can cause multifocal neurologic signs (either from hypercoagulopathy-associated infarcts or hypertension/hypocoagulation hemorrhages) in the nervous system as well as signs in other parts of the body, such as the skin, gastrointestinal system, eye, and lung.
Very rarely a young animal might have signs of multifocal neurologic dysfunction (like tremors and LMN weakness) that can also sometimes be associated with craniofacial structural abnormalities, organ dysfunction, and changes in blood cell morphology (and many other neurologic and extraneural problems depending on the specific disease). In these cases, inborn errors of metabolism like lysosomal storage disorders should be considered.
Many animals with extraneural diseases might be treated with medications that can have neurologic side effects. When an animal has new neurologic signs, ask about medications or supplements to rule out simple side effects such as metronidazole-induced vestibular disease or chloramphenicol-induced polyneuropathy.
While there is an exhaustive list of toxins that can affect multiple organ systems, some of the more common local toxins include ethylene glycol, wild mushrooms, plants like sago palm, and pesticides like organophosphates.
Finally, some animals may be systemically ill and have changes that mimic neurologic involvement. Any animal who feels very ill may appear dull and generally weak; these animals might have mildly depressed postural reactions and response testing. This should resolve as the pet’s systemic condition is resolving.
I have also examined many animals with multifocal joint and spinal pain at the peak of pyrexia with resolution as the temperature comes back to normal. Many of you have felt joint and muscle pain during a fever; animals can experience the same thing. Sometimes this is hard to differentiate from direct causes of pain and fever like meningitis. Meningitis pain will often remain as the fever resolves, whereas pyrexia-associated arthralgia should resolve as the fever resolves.
Be Methodical, Ask for Help
Remember that these cases can be confusing when we are dealing with multifocal disease. It is important to always be methodical in working up any patient. You will first do your physical exam and get a detailed history. You will use this information to help make a problem list and a differential list for each problem and then use the list to make a diagnostic plan.
Once you have obtained more information from your tests, you either have an answer or you can further narrow your differential list and then create a treatment plan (or more advanced testing plan) for the more likely diseases.
This article is a reminder that neurologic signs might represent a long list of potential causes. We are not always just dealing with disc herniations and brain tumors! At the University of Illinois, specialists are here to help you at any stage of this process, whether it is early-on to consult on strange examination findings or later in the process when you need more advanced testing to figure things out.
By Rosanne Krupka Peters, DVM, DACVIM (Neurology)
