6: CVS plus

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CVS Plus

Cyclic vomiting syndrome is characterized by severe discrete episodes of nausea, vomiting, and lethargy. Approximately 25% of cases have coexisting neuromuscular disease manifestations (cyclic vomiting syndrome plus). To determine whether patients with cyclic vomiting syndrome and neuromuscular disease represent a distinct sub entity within cyclic vomiting syndrome, a clinical interview was conducted regarding 80 randomly ascertained sufferers of cyclic vomiting syndrome from a disease association database. Cyclic vomiting syndrome plus and “cyclic vomiting syndrome minus,” herein defined as the presence of at least two and zero neuromuscular disease manifestations, were present in 23 and 44 subjects, respectively.

Neuromuscular disease manifestations, including cognitive disorders, skeletal myopathy, cranial nerve dysfunction, and seizure disorders, were found to statistically cluster together among the same subjects.

In addition, subjects with cyclic vomiting syndrome with neuromuscular disease had an earlier age at onset for vomiting episodes and a three to eightfold statistically increased prevalence for certain dysautonomia-related (migraine, chronic fatigue, neurovascular dystrophy) and constitutional (growth retardation and birth defects) disorders. However, subjects with cyclic vomiting syndrome with and without neuromuscular disease were equally likely to have a sibling affected with neuromuscular disease manifestations. A conclusion is that cyclic vomiting syndrome plus, although likely not genetically distinct from cyclic vomiting syndrome minus, represents a distinct phenotypic entity that predicts an earlier onset of disease and increased comorbidity with a distinct list of medical conditions, possibly owing to a higher degree of mitochondrial dysfunction.

Although most people with cyclic vomiting syndrome are otherwise healthy and of normal intelligence, a significant subset have coexisting neuromuscular disorders, including cognitive delay, myopathy, and/or seizure disorders. In this subset, neuromuscular disease manifestations exist between episodes, yet nausea, vomiting, and lethargy are confined to episodes.

Among the 268 sufferers of cyclic vomiting syndrome listed on the International CVSA Research Registry maintained by the Cyclic Vomiting Syndrome Association USA/Canada, 24% have at least one neuromuscular disease manifestation. The clinical observation has been that neuromuscular disease manifestations are not evenly or randomly distributed across the cyclic vomiting syndrome population but are clustered into a significant minority of cases. The term “cyclic vomiting syndrome plus” had previously been coined to indicate cases with cyclic vomiting syndrome and additional neuromuscular disease manifestations. Thus, cases without neuromuscular disease are labeled as “cyclic vomiting syndrome minus.”

Patients with cyclic vomiting syndrome plus have many of the same neuromuscular conditions frequently reported in individuals with mitochondrial disease, and many are evaluated for the possibility of a mitochondrial disorder. Most cases of cyclic vomiting syndrome plus also demonstrate lactic acidosis, energy-deficient patterns on urine organic acid analysis, and pedigrees suggestive of maternal inheritance, suggesting that cyclic vomiting syndrome plus is a phenotype related to mitochondrial dysfunction secondary to predisposing mitochondrial DNA sequence variants. Maternal inheritance is suggestive of mitochondrial DNA involvement because mitochondrial DNA is asexually inherited from the ova only, without recombination.

Subjects were labeled as having cyclic vomiting syndrome with neuromuscular disease (cyclic vomiting syndrome plus) if at least two of the following list of “hard” neuromuscular disease manifestations were present: skeletal myopathy, cranial nerve abnormality, ataxia, seizure disorder, cardiomyopathy, mental retardation, attention-deficit hyperactivity disorder

(ADHD), microcephaly, autism, or pervasive developmental disorder. Individuals with none of these neuromuscular disease manifestations were labeled as having cyclic vomiting syndrome without neuromuscular disease (“cyclic vomiting syndrome minus”).

Subjects in which exactly one neuromuscular disease manifestation is present were not grouped but were pooled with the cyclic vomiting syndrome plus and cyclic vomiting syndrome minus groups for statistics involving all subjects. Learning disabilities, Asperger syndrome, affective and anxiety disorders, and dysautonomia-related conditions were not included in our “hard” neuromuscular disease manifestation list because of the uncertainty of obtaining and verifying the proper diagnosis in the context of our methods and the established association between cyclic vomiting syndrome and dysautonomia. Peripheral neuropathy and cardiac arrhythmia were removed from the list because it appeared on careful evaluation that, in many cases, the symptoms attributed toward these conditions were, in fact, likely secondary to an undiagnosed dysautonomia.

Migraine headaches and colonic dysmotility were recorded as previous reported. A neurovascular dystrophy–like condition (herein called “neurovascular disease”) was recorded for repetitive episodes of focal, transient, and (generally) asymmetric findings of pain, cramping, color change, apparent temperature change, swelling, and/or functional disability, generally in the distal extremities.

Gastroesophageal reflux disease was recorded only if treated by a physician for at least several months. Among the 80 subjects, female subjects outnumbered male subjects by 53 to 27. All subjects report being Caucasian, with one being of Hispanic ethnicity. Children (age < 18 years) comprised 62% of the subjects at the time of the interview, although 80% of the subjects were children at the onset of cyclic episodes of vomiting.

Twenty-three subjects (29%) reported at least two neuromuscular disease manifestations and thus were labeled as “cyclic vomiting syndrome plus.” Forty-four subjects (55%) reported no neuromuscular disease manifestations and thus were labeled as “cyclic vomiting syndrome minus.” The 13 subjects with exactly one neuromuscular disease manifestation, most of whom reported ADHD (5 cases), seizure disorders, or skeletal myopathy (3 cases each), were not subgrouped.

Neuromuscular Disease Manifestations That Define Our Cyclic Vomiting Syndrome Plus Population*

Neuromuscular Disease Manifestation Number (%) Reported Number (%) Reported
Among All 80 Cases Among 23 CVS+ Cases
Skeletal myopathy 16 (20) 14 (61)
Mental retardation‡a 13 (16) 13 (57)
Attention-deficit hyperactivity disordera 12 (15) 7 (30)
Strabismusb 10 (12) 9 (39)
Seizure disorders (excluding simple febrile) 10 (12) 7 (30)
Hearing lossb 6 (8) 5 (22)
Microcephalya 5 (6) 5 (22)
Ataxia 5 (6) 5 (22)
Cardiomyopathy 4 (5) 3 (13)
Autistic spectrum disorder (autism or PDD)a 4 (5) 4 (17)
Ptosisb 3 (4) 3 (13)
Olfactory deficitb 1 (1) 1 (4)
Any cognitive abnormality§ 25 (31) 20 (87)
Any cranial nerve abnormality|| 14 (18) 11 (48)
Two or more neuromuscular disease manifestations (CVS+) 23 (29) 23 (100)

CVS+ = cyclic vomiting syndrome plus;
PDD = pervasive developmental disorder.

* By definition, all of the manifestations listed in this table were absent in all 44 cyclic vomiting syndrome minus cases.

† Skeletal myopathy was defined as hypotonia, weakness, or gross motor delay.

‡ Mental retardation was recorded in children with a tested IQ < 70 or in children not tested if both motor and language function based on the interview were clearly less than a

developmental level of 70.

§ Includes above manifestations labeled with the letter “a.”

|| Includes above manifestations labeled with the letter “b.”

¶ By definition.

Non-Neuromuscular Disease Manifestations Seen in at Least Two of Our Subjects

Condition All Subjects, n (%) CVS+ Group, n (%) CVS– Group, n (% P CVS+ vs CVS–
Gastroesophageal reflux* 33 (41) 10 (43) 17 (39) NS
Colonic dysmotility*† 21 (26) 9 (39) 9 (20) NS
Migraine* 19 (24) 10 (43) 7 (16) .01
Chronic fatigue* 16 (20) 11 (48) 4 (9) < .001
Neurovascular disease* 15 (19) 9 (39) 2 (5) < .001
Affective/anxiety disorders 14 (18) 6 (26) 5 (11) NS
Learning disabilities 12 (15) 5 (22) 4 (9) NS
Birth defects 12 (15) 8 (35) 3 (7) .005
Endocrine disorder (any) 10 (12) 3 (13) 5 (11) NS
Growth retardation (height or weight< 5th percentile) 10 (12) 6 (26) 2 (5) .02
Palpitations/tachycardia* 8 (10) 3 (13) 2 (5) NS
Abnormal temperature regulation* 6 (8) 2 (9) 3 (7) NS
Any dysautonomia-associated condition§ 57 (71) 22 (96) 26 (59) .01

NS = not significant (for all cases in this table: P > .1).


†Most meet the criteria for irritable bowel syndrome.

‡Affective and anxiety disorders were difficult to distinguish using our methods and were lumped together, although the large majority of cases report depression, either unipolar or bipolar.

*A dysautonomic-associated condition.

§The presence of at least one condition marked with an asterisk (*).

Treatment attempts with 61 different chemical agents were recorded, 54 of which were considered to be efficacious by at least one family. The table below lists the most frequent agents recorded. The numbers of subjects in each of the subgroups reported on each medication are small, and no significant intergroup differences were noted, except for cyproheptadine, which is possibly more efficacious in the cyclic vomiting syndrome plus group than the cyclic vomiting syndrome minus group.

Treatments Most Frequently Attempted in Our Subjects

Treatment All Subjects, n (%) CVS+ Group, n (%) CVS– Group, n (%)
Amitriptyline (Elavil) 16/15/5 (52) 5/2/2 (71) 9/9/3 (50)
Cyproheptadine (Periactin) 11/7/3 (61) 5/1/2 (83) 2/5/1 (29)
Propranolol (Inderal) 5/10/0 (33) 1/3/0 (25) 4/5/0 (44)
Abortive or symptomatic (intraictal)
Intravenous dextrose–containing fluids 21/3/0 (88) 7/0/0 (100) 11/1/0 (92)
Ondansetron (Zofran) 42/10/2 (81) 12/4/0 (75) 23/4/2 (85)
Lorazepam (Ativan) 23/7/2 (77) 5/3/2 (62) 14/2/0 (88)
Promethazine hydrochloride (Phenergan) 13/10/0 (57) 5/4/0 (56) 6/6/0 (50)
Sumatriptan succinate (Imitrex) 8/0/1 (100) 2/0/0 (100) 3/0/1 (100)

CVS+ = cyclic vomiting syndrome plus; CVS– = cyclic vomiting syndrome minus.


Data recorded as x/y/z (%) where x = the number of subjects treated reported to have significant benefit, y = the number of subjects treated with insignificant or no benefit, and z = the number of subjects whose side effects were considered troublesome by the family and/or physician; % is the percentage of subjects tried on the medication reporting a significant benefit

(excluding cases discontinued early because of side effects, in which efficacy data is not known). Both response data (positive or negative) and a side effect were reported in some subjects. Specific side effects reported were (in a single subject each unless otherwise specified) as follows: amitriptyline: lethargy (2 subjects), mood swings, abdominal cramping, and syncope; cyproheptadine: weight gain (2), behavioral change, and hallucinations; ondansetron: palpitations and allergy; lorazepam: “untoward reaction” (2); and sumatriptan succinate: hallucinations. P > .1 (not significant) for all subject group comparisons, except for cyproheptadine, whereas P = .048 for cyclic vomiting syndrome plus versus cyclic vomiting syndrome minus yet was not significant with a Bonferroni adjustment for multiple tests.