Generalized Tremors in Dogs: 198 Cases (2003–2023)

3.1 Final Diagnoses

Eighteen different causes were found in dogs with generalized tremors (Table 1). The most common disease categories associated with generalized tremors in dogs were toxic (95/198; 48%), inflammatory (59/198; 29.8%) and metabolic (33/198; 16.7%), with degenerative (5/198; 2.5%), idiopathic (4/198; 2%) and neoplastic (2/198; 1%) being uncommon. The most common final diagnoses included intoxication (91/198; 46%), IGTS (49/198; 24.7%), hypocalcemia (13/198; 6.6%), meningoencephalitis of unknown origin (MUO; 9/198; 4.5%), hypoglycemia (6/198; 3%), hypercalcemia (5/198; 2.5%) and degenerative encephalopathies (5/198; 2.5%). Causes of metabolic diseases were variable (Supporting Information S1).

3.2 Epidemiology

Most dogs with generalized tremors were purebreds (145/198; 73.2%). One hundred three dogs (52%) were females, and 95/198 (48%) were males, of which a total of 133/198 (67.2%) were neutered. Median age at onset of the tremors was 3.2 years (range, 3 months–14.3 years; interquartile range [IQR], 1.3–7.6 years), with 94/198 (47.5%) of dogs being young, 71/198 (35.9%) middle-aged, and 33/198 (16.7%) old. Median body weight was 10.9 kg (range, 1.29–53 kg; IQR, 7.4–20 kg). The most commonly represented breeds were crossbreeds (49/198; 24.7%), Labrador retrievers (22/198; 11.1%), Jack Russell terriers (19/198; 9.6%) and West Highland White terriers (14/198; 7.1%; Supporting Information S2). Onset of neurological signs was hyperacute (97/198; 49%), acute (61/198; 30.8%) or chronic (40/198; 20.2%); no dog presented with subacute onset. Neurological signs were progressive (153/198; 77.3%) or nonprogressive (45/198; 22.7%), and symmetric (174/198; 87.9%) or lateralized (24/198; 12.1%). Generalized tremors were the main reason for referral in 84/198 (42.4%) dogs.

Signalment, presentation, clinical and neurological findings, diagnostic findings, treatment, and outcome for the most common diagnoses (n > 4) in dogs with generalized tremors are presented in Table 2.

3.3 Tremor Phenotype

Generalized tremors were present in all dogs (Video 1). They were usually continuous (173/198; 87.4%) rather than episodic (25/198; 12.6%). In a few dogs, additional intention head tremor (8/198; 4%), palpebral tremor (7/198; 3.5%) or mandibular tremor (5/198; 2.5%) was found. Dancing sign was present in 5/198 (2.5%) dogs. Postural tremors were reported in 10/198 (5.1%) dogs. Worsening of tremors with excitement or noise was reported in 19/198 (9.6%) dogs. Ceasing of tremors while walking was reported in 7/198 (3.5%) dogs. Assessment of tremor presence during general anesthesia was reported in 9/198 (4.5%) dogs; in 6/9, tremors were absent, and in 3/9, tremors were present during general anesthesia. Assessment of tremor presence during sleep was performed in 17/198 (8.6%) dogs; in 13/17, tremors were absent, and in 4/17, tremors were present during sleep. Weight-bearing lifting limb test (WEBLT) was performed in 6/198 (3%) dogs; this evaluation showed no change in tremor intensity in 3/6 dogs, decreased tremors in 2/6, and cessation of tremors in 1/6 dog. Tremor phenotypes for the most common diagnoses (n > 4) in dogs with generalized tremors are presented in Table 3.

3.4 Statistical Analysis

In the univariable analysis, clinical variables of dogs with intoxication were compared to dogs with IGTS. Dogs with IGTS were female (p = 0.002), younger (p = 0.002) and had an acute progressive often lateralizing presentation (p < 0.001 for all three features). Dogs with intoxication were male (p = 0.002), young and middle-aged (p = 0.002) and had a hyperacute nonprogressive symmetric presentation (p < 0.001 for all three features). Behavioral changes (p = 0.02) and hypersalivation (p = 0.04) were more common presenting complaints in dogs with intoxication compared with dogs with IGTS, where hyporexia was more common in IGTS (p < 0.001). Dogs diagnosed with intoxication had only tremors (45%) as a neurological finding compared with dogs diagnosed with IGTS (22%; p = 0.01). Dogs with intoxication were more likely to manifest abnormal mentation (p = 0.01), bilateral mydriasis (p = 0.02) or generalized hyperesthesia (p = 0.002) compared with dogs with IGTS. Dogs with IGTS were more likely to manifest titubation (p < 0.001), head tilt (p < 0.001), ataxia of all limbs (p < 0.001) or cranial nerve deficits (p < 0.001) such as menace response deficits (p < 0.001), nystagmus (p = 0.003) or opsoclonus (p < 0.001) compared with dogs diagnosed with intoxication. Neuroanatomical localization was more likely to be multifocal in intoxication (p < 0.001) and vestibulocerebellar in IGTS (p < 0.001). Tremors were likely to have additional intentional features in IGTS (p < 0.001), whereas additional mandibular (p = 0.04) or palpebral (p = 0.01) tremor or dancing sign (p = 0.04) were more likely to be manifested in IGTS. Improvement within 48 h from the onset of signs without corticosteroid administration occurred exclusively in dogs with intoxication (p < 0.001). These dogs received supportive treatment, including IV fluid treatment, activated charcoal, intralipid emulsion, or a combination of them. Multivariable analysis was performed on all variables that reached significance in univariable analysis, but no variables reached statistical significance.

4.1 Comparison of Intoxications and IGTS

Dogs with intoxication were usually young or middle-aged and had a hyperacute nonprogressive symmetric presentation, whereas dogs with IGTS were young with an acute progressive often lateralizing presentation. Intoxication traditionally is hyperacute, with clinical signs usually occurring within 24 h of the potential exposure to the toxic agent [13, 20, 21]. In our study, intoxication usually was diagnosed in young or middle-aged male dogs in comparison with IGTS. In previous studies, no male overrepresentation was evident in dogs with intoxication, but most dogs were young or middle-aged [13, 20, 21]. This finding may be explained by the curiosity of younger dogs that may lead them to scavenge more and therefore be more vulnerable to ingesting a potential intoxicant, similar to what has been reported in Angiostrongylus vasorum infection where young dogs are more prone to scavenge snails and slugs [22]. The presentation of dogs with IGTS differed from that of dogs with intoxication, because the former are presented with an acute progressive course, whereas the latter present in a more hyperacute nonprogressive fashion with tremors occasionally being the only neurological finding. Thus, the onset of signs in IGTS occurred > 24 h from the time of presentation, which starts with insidious hyporexia and lethargy that progresses to generalized tremors often accompanied by other vestibulocerebellar signs [3, 18, 23-25]. Dogs with IGTS were young at the age of onset of signs, with a median age of 2 years. Idiopathic generalized tremor syndrome is an immune-mediated disease of young dogs with reported median ages at onset of signs from 9.6 months to 2 years of age [18, 24, 25]. To date, the terminology of IGTS has been inconsistent, and possibly idiopathic may be a misnomer because there is evidence of immune-mediated etiology including histopathology consistent with inflammation in few cases [11], CSF analysis consistent with lymphocytic pleocytosis in some cases, response to immunosuppressive doses of corticosteroids in all cases [18, 23, 24], and recent evidence of auto-antibodies in a small cohort of dogs with severe clinical signs [25]. Additionally, dogs with IGTS may have gastrointestinal signs before development of neurological signs [18]. Idiopathic generalized tremor syndrome has been reported to start with hyporexia and lethargy [18, 24], and 22% of dogs in our study were hyporexic and lethargic. In our study, hyporexia was most likely to occur in dogs with IGTS, which is in agreement with the literature [18, 24]. Hyporexia may be related to nausea associated with severe impairment of the vestibular system, as indicated by the presence of vestibulocerebellar signs. Additionally, dogs with IGTS were most likely to have accompanying vestibulocerebellar signs such as titubation, head tilt, ataxia, menace response deficits, nystagmus or opsoclonus, as reported previously [18, 24]. Some of these signs (e.g., opsoclonus) may not have been consistently recorded in the medical records in both diagnoses, especially in dogs initially examined by non-neurologists, and therefore results should be interpreted cautiously. On the other hand, our study showed that tremors as the sole neurological finding, behavioral changes, bilateral mydriasis, hypersalivation, abnormal mentation, and general hyperesthesia were associated mostly with a diagnosis of intoxication. This observation is in agreement with the fact that most neurointoxications cause diffuse central nervous system disease affecting multiple regions of the brain [26]. Finally, improvement within 48 h from onset of signs without corticosteroid administration occurred exclusively in dogs with intoxication, which may help direct the clinician towards a more appropriate differential diagnosis during the initial monitoring phase of hospitalized dogs.

Tremor in dogs with IGTS had additional intentional head tremor features in our study, likely because of cerebellar involvement in the disease process [11]. Additional focal tremor such as palpebral tremor, mandibular tremor or opsoclonus was most likely to occur in IGTS, as reported previously [18]. Interestingly, dancing sign was observed in some dogs with IGTS. This sign has been observed in dogs and humans diagnosed with orthostatic tremor of high frequency or intensity, and it has been attributed to relief from the feeling of tremor by elimination of weight-bearing [10]. Tremor in IGTS represents kinetic tremor. Despite the fact that IGTS is not a postural tremor, some dogs may obtain relief by lifting the limb and trying to minimize unsteadiness. On the other hand, tremors associated with intoxication do not represent actual tremors because they have irregular rhythm and are usually consistent with generalized fasciculations caused by peripheral nerve hyperexcitability (resembling subcutaneous vermicular movements) [2], or epileptic or nonepileptic myoclonus (when the involuntary movement causes movement of a part of the body) [27] associated with the intoxication. Although our study had limited data on tremors during general anesthesia, usually intoxication-related tremors persisted under general anesthesia in contrast to IGTS tremors. This difference may be explained because their origin may be peripheral nerve hyperexcitability, which can persist during anesthesia [2].

Our study suggests a reconsideration in the diagnostic approach to generalized tremors in dogs. Time is important because the severity of tremors can increase in cases of IGTS, whereas in cases of intoxication increasing severity usually does not occur. Additionally, a basic clinicopathological evaluation for a dog presenting with generalized tremors should include CBC, serum biochemistry (including glucose and electrolytes, including ionized calcium concentration), blood ammonia concentration and bile acid stimulation test. In humans, a genetic panel is obtained commonly in patients with suspected degenerative disease and movement disorders [28]. Genetic testing is not yet common for dogs. However, in dogs with generalized tremors, especially breeds with specific diseases associated with tremors, genetic testing should be considered if commercially available. For instance, in Springer Spaniel (myelin proteolipid protein 1 [PLP1] gene) or Weimaraner (folliculin-interacting protein 2 [FNIP2] gene) puppies with tremors, genetic tests for hypomyelinating disorders should be considered [29, 30].

Our study had some limitations, including its retrospective nature, lack of video documentation for tremor type in each case, lack of detailed tremor analysis for each case, and lack of electromyography in the awake state for all cases.

In conclusion, several diseases were associated with generalized tremors in dogs, but intoxications and IGTS were most common. Clinically, a hyperacute nonprogressive symmetric presentation occasionally with tremors as the only neurological sign may lead to a diagnosis of intoxication. In contrast, an acute progressive often lateralizing presentation of vestibulocerebellar signs along with generalized tremors that do not improve without corticosteroids in the first 48 h warrants a suspected diagnosis of IGTS. This information may assist the clinician in formulating a differential diagnoses list and instituting appropriate diagnostic and treatment plans.