Historical aspect
Anisakiasis was first recognized in the Netherlands (Van Thiel et al., 1960). The patient was diagnosed as acute localized entritis of terminal ileum. Surgical operation revealed that a small nematode was penetrating the mucus membrane. The larva was identifed as 3rd-stage larva of Anisakis simplex.
Nationwide surveys of anisakiasis in Japan have been compiled are mainly evaluations of cases with eosinophilic granuloma from pathological labaratories at various universities. Since 1955 Ishikura has kept a record of acute localized enteritis, and in 1965 determined the need for a separate pathological entity for the majority of such cases. They were evaluated as intestinal anisakiasis, and show that this disorder is common in the north, with the chronic granuloma and phlegmonous acute intestinal type especially common, since many of the marine organisms that act as paratenic hosts are caught in large volumes in that area.

Marine fishes, especially mackel and squids are most important paratenic hosts in Japan. Anisakis larvae are always found on the surface of internal organs and muscle. The location of larvae were as follows:

Distribution of Anisakis simplex larvae in muscle of common mackerel caaught in coastal waters off Shizuoka Prefecture, Chiba Prefecture (B), sardines (C) and squids.

Diagnosis of the acute form of intestinal anisakiasis has been increasing rapidly, beginning with the use of the endoscope to establish the presence of larvae in cases of peritonitis displaying acute symptoms. With the increasing use of this method in Hokkaido and across the rest of the nation, the incidence of intestinal anisakiasis has changed. There are still problems in separating cases with intestinal anisakiasis; the impossibility of determining lar-vae in the intestinal cavity when the wall is perforated; the increase in cases recovering without surgery; and the decrease in parasitologically established cases, Ieaving the ratio of gastric to intestinal cases at less than 1 to 22 (Table 1), where only 567 of 12,586 are cases intestinal anisakiasis. Intestinal anisakiasis is different from cancer, where a histopathological diagnosis is possible even when the pathogenic agent has not been established.

Acute intestinal anisakiasis may be histopathologically determined without a trace of the larvae, making an epidemiological diagnosis difficult to establish. Diagnosis of probable intestinal anisakiasis is based on rapid advances in clinical experience, X-ray, ultrasonography, and immuno-serodiagnosis. Discussion of the suitability of such a diagnosis is still going on, and if agreement among re-searchers can be achieved, the number of cases of intestinal anisakiasis will increase dramatically with the ratio of intestinal to gastric anisakiasis consequently changing. The main problems with epidemiological statistics for anisakiasis relate to the sources of infection. In the last ten years the incidence in Hokkaido and Kyushu has been reversed, with changes in the cycle of parasites in the host marine organisms. These changes have been most remarkable in Alaska pollack, mackerel, and sardines.

Pathological Aspect
1. The Fate of Orally Infected Larvae (Animal Experiments)

It has been noted that some orally administered larvae are expelled through the anus, verified by Ruitenberg, who considered it important that such larvae were dead and digested at evacuation, with no reports of living evacuated larvae. Ruitenberg did extensive experiments with oral infection, and related them to larval penetration of the walls of the abdominal and intestinal cavities, and also noted experiments on histopathological determinations of infecting larvae migrating into the digestive tract wall. Myers (1963) reported orally administered larvae in the abdomen, small intestine, large intestine, pancreas, and liver, while Young (1969) found coiled larvae that had penetraed into the mesentry.

2. Intraperitoneal infection with Anisakis larvae.

There is considerable difficulty in comparing experimental results due to the complexity of determining fish species, the freshness of the raw fish, and differences in experimental animals and experimental procedures. However, the number of larvae penetrating the intestinal tract wall and entering the abdominal cavity is similar to the number that stop in the wall of the intestinal tract and die there. Larvae are found in practically all organ tissue, the caul, mesentery, abdominal wall, Liver, pancreas, spleen, uterus, urinary bladder, testicles, ovaries, sperm duct, thyroid gland, muscle, fat, and other tissue. Yoshimura (1979) reported on 13 cases from Honshu with what he termed extragastro intestinal anisakiasis in which larvae were found in the digestive wall, and the author (1989) has recognized 45 such cases as well.

These larvae had penetrated the gastric and intestinal walls and reached the abdominal cavity. Where the digestive tract wall is perforated, experiments have shown that larvae disappear into the gastric wall within 10 minutes, and from endoscopic examinations perforation has been reported within seconds. Penetration takes place within a very short time with the physical stimulation resulting in subjective symptoms which soon subside and may not be paid attention to explaining the frequently found asymptomatic cases where larvae are identified of autopsy.

3. The invasive course of larvae into the abdominal cavity

Larvae administered orally pass through the wall of the digestive tract and enter the abdominal cavity, where they reach the serous membranes of organs and often produce numerous eosinophilic cell granuloma. Compared with other fish and squid, a large proportion of larvae from the blood of Trachurus japonica penetrate into the abdominal cavity, while Somber japonica larvae were found to enter the abdominal cavity after 10 hours, and in order of incidence concentrated in the omentum, momentary, and various organs. No penetration of the small intestine was found with larvae from Theragra chalcogramma, only perforation of the gastric wall; Larvae were found in omentum, muscle, and fat tissue. Reports of Todarodes pacificus state that the parasitic larvae behave in much the same manner, entering the abdominal cavity via the gastric wall, but rather than concentrating in the omentum and mesentery, many were found in muscle and fat tissue or scattered in the serous membrane of organs. There was no clear indication that the seriousness of the infection in different experimental animals was dependent upon the host species, however, this may be due to differences in the time from infection until examination. The experimental results indicate that the number of larvae penetrating the abdominal cavity are between 1/3 and 1/4 of the total.

Extra-gastrointestinal anisakiasis cases are those where the ailment was diagnosed outside the gastric and intestinal canal, although recently there have been more discoveries of larvae penetrating into the abdominal cavity, with larvae being found just after perforation of the small intestine membrane, or in the abdominal cavity after penetration of the small intestine. Yoshimura et al.(1979) reported one case with stomach penetration and eosinophilic cell granuloma in the caul, and another with perforation in the end section of the illus, and there are more reports of such cases. Many physicians have verified the perforation of the mucous membrane from bleeding observed endoscopically while, Mizugaki et al. (1970) has shown histological experimental results with a strong cell reaction at second infection and perforation outside the stomach and intestine with extensive bleeding and internal bleeding in the mucous membrane. This is considered to be a result of localized reactions to secretion and excrement (ES antigen).

4. The first infection, re-infection and double infection of larvae.

Experimental studies on rabbits have been conducted, where they were subjected to a subcutaneous first infection with Anisakis larvae, which stayed alive for seven days and caused a foreign body reaction in the tissue. At re-inflection dead larvae appeared from the second day, the surrounding edema and flare was clearly histologically acute exudative inflammation with infiltration of immune cell neutrocytes and eosinophilic cells. The exudative inflammation quickly subsided and there was abscess and granuloma formation around the dead larvae. When the re-infection used soluble fraction fluid instead of live larvae, supernatant fluid generally produced an instantaneous allergic reaction, and caused a delayed allergic reaction with sedimented antigen. This brought antigen directly to the stomach and intestinal walls, and even when live larvae were buried there, the stomach reaction was weaker than in the intestine. The proportion of larvae entering the stomach and intestinal walls at the first and later infections were determined in separate experiments, with more larvae found to penetrate the walls of immunized animals. This experiment did not study larvae that had penetrated into the abdominal cavity an aspect which requires further investigation. In the Netherlands, attention has been drawn to the "double hit" theory, which is that acute exudative inflammation caused by intestinal anisakiasis results from penetration by a single larvae offering immunization for only about 4 months. This local hypersensitivity was quickly questioned by Ruitenberg who considered it to be acute allergic reaction at re-infection.

Together with anisakiasis, so-called skip lesions occur in great numbers. To study this phenomena we orally administered larvae to rabbits which then showed abscess and granuloma morbidity (symptoms of the first infection) in their digestive tracts. After 3 weeks Anisakis larval antigens were injected in the ear vein of the rabbits, causing acute exudation in the vicinity of the reinfection, showing that the inflammation in the area of the first infection has became infected again. With skip lesions there is a simultaneous elective outbreak of the ailment similar to the localized morbidity, however, when the site of the first infection and the re-infection are different, it is differentiated from a skip lesion. The experiments also showed that tissue morbidity at re-infection was most severe where the greatest penetration had taken place, indicating that the strongest changes occurred in the earliest affected parts. Changes in the vicinity of the remains of intrusions into the abdominal cavity were weak (light bleeding and edema), and although clinical observation of repeated Anisakis infections have been reported, more details will be established when a thorough survey of the abdominal cavity is made at surgery.

5. Complications with bacillus infection.

It is estimated that one-third of the Anisakis larvae eaten with marine organisms are evacuated through the anus, onethird die in the walls of the stomach and intestine, and one-third die forming granuloma or after penetrating the abdominal cavity. To enter the abdominal cavity, the wall of the digestive tract must be penetrated, and this is more common in the intestinal than the gastric form studies in which laparotomy was performed because of acute stomach ailments report abdominal fluid present in about 70010 of cases. In early stages the abdominal fluid is lemon yellow and clear, becoming opaque then yellow and turbid as the illness worsens. This leads experienced physicians to suspect secondary infection, but microscopic observations do not show bacteria in the sediment of the abdominal fluid.

Ishikura (1970) described 2 cases out of 132 subjects with bacteria in the histopathological samples, a further 5 cases with accumulation of neutrocyies or necrotic areas between the mucous and serous membranes which were also considered to show bacterial infection. Agglomeration of bacteria in the tissue of one of 6 cases was reported by Saito (1966), though these cases did not show ulcerated necrosis of the mucous membrane and the bacterial infection must have taken place from the intestine via larval perforations. Naka (1969) reported on bacterial cultivation revealing mucous in the abdominal fluid and intestinal serous membrane and found 7 cases out of 65 with coli baccillus and staphylococcus, and of 23 cases with fibrous fur 4 had bacteria in the mesentary.

We injected 30 Anisakis larvae into the abdominal cavity of rabbits, and injected antigen into the ear vein three months later. The immunized rabbits had antigen injected in the lymphatic cavity under the serous membrane of the ileum by Fisher's method and simultaneously nonpathogenic coli baccilla were injected at the same site before closing off the abdomen. These rabbits were later subjected to repeated laparotomy and tissue from the intestinal wall was observed under the microscope. The observations were conducted for 40 days and revealed ulceration of the mucous membrane, necrosis, and necrotic abcesses with numerous neutrocytes under the mucous membrane; the appearance of giant cells was accelerated and necrotic perforations were apparent. This coincides with observations of acute anisakiasis in humans, but more comprehensive observations are necessary to determine whether the pathogenic changes appear as Crohn's disease when it becomes chronic.

6. The immune mechanisms in Anisakis larvae infections in humans.

Based on immune response experiments with animals, infections of the abdominal cavity were found to create immunity and led to speculation that the immunity created by larvae that had penetrated into the abdominal cavity was stronger than that created by larvae that had entered the digestive tract wall and died there, and that this may be the situation wih human cases of anisakiasis. This hypothesis is supported by the increasing number of laparotomies performed as a result ,of acute symptoms of the primary infection in which intestinal anisakiasis has been determined. The increase appears to be due to more thorough examinations of the stomach by surgeons performing laparotomies on intestinal anisakiasis cases.

Primary infections of the digestive tract walls are rarely diagnosed since they are often assymptomatic but may be discovered during laparotomies performed for other ailments or at post mortems. Re-infection with anisakiasis larvae cause violent immune reactions leading to acute symptoms (mainly ileus) that result in laparotomy which then leads to the discovery of signs of the primary infection. As described in another section (with the pathology of the mild form of intestinal anisakiasis) , this activation of the first infection may mistakenly be interpreted as the appearance of a wave-like phenomenon or a relapse change.

Endoscopical findings

Care should be taken not to mistake the worm penetrating the gastric wall for the stringlike mucus. As seen on closer observation, as Anisaks simplex larva shows a thin, strinlike appearence and its color is milk-white, while a Pseudoterranova decipience larva is broder and yellow or yellowish-brown in color.

The endoscopic features of acute gastric anisakiasis were as follows: (a) Existence of Anisakis larvae; (b) edematous hypertrophic gastric folds; (c) increase of gastric secretion and gastric peristalsis; (d) the findings of mucosal lesions through which Anisakis larvae penetrated were as follows: 120 cases (46%) of edema, 64 cases (25%) of redness, 48 cases (19%) of coagulation, 16 cases (6%) of hemorrhage, and ten (4%) cases of ulceration; (e) erosions in the other gastric mucosa were seen at a smaller incidence than erosive gastrtis.

Edematous hypertrophic gastric folds were observed along the long axis of the stomach, primarily occurring on the side of greater curvature. The folds numbered one in 69 cases (27%), two in 116 cases (45%), and three in 52 cases (20%). Thus, in the largest number of cases there were two folds. With regard to the site of parasitic penetration in connection with edematous hypertrophic gastric folds, there were as many as 196 cases (76%) with penetration on the oral side, 32 cases (12%) in the middle portion, 25 cases (10%) on the anal side , and five cases (2%) having local swelling.