A problem that occurs during or after a trip does not necessarily need to have a causal connection with that trip. In case of meningitis / brain inflammation, analysis of cerebrospinal fluid helps to orient the diagnosis.

Mollaret’s meningitis is characterized by repeated episodes of fever, meningismus, and severe headache separated by symptom-free intervals. Individual attacks are sudden, with signs and symptoms reaching maximum intensity within a few hours. Headache, neck pain, generalized muscle aches, and neck stiffness usually persist from one to three days, but may be present for up to three weeks. Following a number of recurrences, which can span a period of years, the disease suddenly disappears. The long-term health of the patient seems not to be adversely affected. Transient neurologic abnormalities (seizures, diplopia, pathologic reflexes, cranial nerve paresis, hallucinations, and coma) occur in as many as 50% of cases. Persistence of neurologic defects should call the diagnosis into question. CSF obtained early in the course of the illness usually demonstrates large, friable "endothelial" cells termed Mollaret’s cells. Mollaret’s cells can be demonstrated by the Papanicolaou stain, and are now considered to be large activated cells of monocyte/macrophage lineage. Mollaret’s cells are considered by many to be the hallmark of Mollaret’s meningitis, and early on may comprise 60% to 70% of the CSF cells. These cells are usually present for only the first 24 hours and can be missed easily. Furthermore, "Mollaret’s cells" are not pathognomonic for Mollaret’s meningitis. After the first 24 hours, the CSF shows a lymphocytic predominance with cell counts usually less than 3,000/mm³. Hypoglycorrhachia (a low CSF glucose concentration), is reported in one-third of patients. CSF protein, especially the gamma globulin fraction, is usually mildly elevated.

Etiology
Recent data suggest that herpes simplex II and, less frequently, herpes simplex I may be etiologic in some if not most cases of Mollaret’s meningitis.

Therapy
Mollaret’s meningitis is a syndrome rather than a disease. As such, the syndrome of Mollaret’s meningitis appears to have multiple etiologies. Presently, herpes simplex II, and to a lesser extent herpes simplex I, appear to be etiologic in most cases. Because of the rarity of this syndrome, there are no large clinical trials comparing one therapy against another. However, acyclovir (intravenous or oral) or valacyclovir (oral only) are worthy of consideration for both therapy and prophylaxis. Other therapies tried include steroids (no benefit) and colchicine 0.5 mg BID (apparent prophylactic benefit in some cases).

Points to Remember

• Mollaret’s meningitis is usually a benign (but painful), self-limited, recurrent, often febrile meningitis.
• Transient neurologic deficits (seizures, cranial nerve paresis, pathologic reflexes) occur in 50% of cases
• Mollaret’s may be caused by herpes simplex II; acyclovir may play a role in prophylaxis and therapy.

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Eosinophilic meningitis ( syn. Alicata’s disease) is defined as CSF pleocytosis with more than 10% eosinophils or with 10 or more eosinophils per µL. The CSF protein concentration is usually elevated, whereas the glucose level is normal or slightly reduced. Peripheral blood eosinophilia does not correlate with CSF eosinophilia.

On a global level, the most frequent etiologies are: Angiostrongylus cantonensis, Gnathostoma spinigerum and neurocysticercosis. One could add cerebral toxocariosis (Toxocara canis) to this list. In the USA, Baylisascaris procyonis and coccidioidomycosis are important entities. Other etiologies of eosinophilic meningitis are cerebral paragonomiasis, neurotrichinosis, cerebral (ectopic) Fasciola hepatica, Strongyloides stercoralis hyperinfection syndrome, infection with Meningonema peruzzi filaria, cerebral/spinal schistosomiasis and cerebral echinococcosis. Reactive meningoencephalitis can occur after the start of DEC treatment of loasis (infection with Loa loa filaria). Non-infectious causes include Hodgkin’s disease, non-Hodgkin’s lymphoma and eosinophilic leukemia. Reactions to ciprofloxacin, ibuprofen, intraventricular vancomycin, gentamycin and iophendylate dye (contrast myelography) as well as foreign bodies such as ventriculoperitoneal shunts or infestation with certain fly larvae (myiasis) are rare causes. Auto-immune diseases and vasculitis should be excluded (post-vaccination encephalitis, SLE, periarteritis nodosa, sarcoidosis, eosinophilic granuloma), as should neurolues and the idiopathic hypereosinophilic syndrome.

In 1938, Angiostrongylus cantonensis was discovered in rat lungs by Chen in Canton, China. Recently, the taxonomical position of the worm as changed and A. cantonensis has been transferred to the genus Parastrongylus, but in this text we will continue to use the generic name Angiostrongylus. Infection with A. cantonensis is the most common etiology of eosinophilic meningitis. Do not confuse this with disease resulting from infection with Angiostrongylus costaricensis. Angiostrongyliasis occurs primarily in Southeast Asia, throughout the Pacific Bassin, including Hawaii, Indonesia, Philippines, Japan and Papua New Guinea, but also in several Caribbean nations (Bahamas, Cuba, Puerto Rico, Dominican Republic, Jamaica). Few cases were discovered in Ivory Coast and Egypt, Madagaskar, Mayotte and Reunion Island. There was even one described case in North America. A large percentage of the rats in New Orleans were found to be infected with Angiostrongylus cantonensis. Occasionally, small outbreaks occur.

Angiostrongyliasis (infection with A. cantonensis, the rat lungworm) has an incubation period of 2-35 days. Symptoms are due to migration of the larvae in the brain and the inflammatory reaction which occurs. The disease presents with acute moderate to severe headache (100%). Besides the headache, patients can complain of eyeball pain. Visual problems can occur, due to involvement of one or more cranial nerves (diplopia, acute strabism, gaze palsy) or due to migration of the larva into the eye, which can lead to retinal detachment and blindness. Facial nerve paralysis occurs occasionally. Nuchal rigidity occurs in about 66% of patients and Brudzinski’s sign is present in ±66%. Transient ataxia can occur. Delirium, seizures and cognitive dysfunction have been observed. Hyperesthesia in various dermatomes occurs. Paresthesias of arms and legs, trunk or face can persist for months, although chronic disease is rare. Vomiting and nausea are self-limited and stop after a few days. Oedema (generalized, legs, facial or migratory) occurs in a minority of patients. Fever occurs in less than 50% of patients. The disease tends to be more serious in children. The disease is self-limiting. Most symptoms disappear spontaneously within 4 weeks of onset (range 2-8 weeks). Mortality is less than 1%.

Eosinophilia of peripheral blood or CSF is not always present on initial laboratory testing. Pleocytosis may be absent early in the course of infection. Larvae are rarely detected in the CSF. Beware of fibrin treads which can mimic larvae. The CSF can be clear or cloudy, but does not contain blood (except in case of a traumatic tap of course). The absence of focal lesions on CT or MRI-scanning of the brain distinguishes A. cantonensis infections from most other helminthic infections of the brain. Enhancement of the meninges and globus pallidus (basal ganglia) can be noted on MRI. Immunodiagnosis is possible in some centers. There is a poor correlation between the serological results of serum and CSF.

Analgesics are usually needed. Steroids (e.g. prednisolone 60 mg/day x 2 weeks or dexamethasone) shorten the duration of the headache. When performing a spinal tap, the opening pressure is increased in about 60% of patients (average 23 cm water; normal 10-20 cm). Many patients notice an improvement after a spinal tap. Repeated spinal taps to reduce the intracranial pressure are sometimes performed. Antihelminthics are thought by some not to be effective and considered to worsen the symptoms, probably because of the inflammatory reaction to antigens released by dying worms. Some clinicians use mebendazole or albendazole, but controlled studies are lacking.

The worms nematodes (Gnathostoma spinigerum) reside in the stomach of cats and dogs. They release eggs in the faeces. The eggs hatch after 10-12 days after reaching water. The first-stage larvae are taken up by Cyclops crustaceans and moult to second stage larvae. After an infected Cyclops is swallowed by a second intermediate host, such as freshwater fish, frogs, snakes, chickens or pigs, a third stage larva develops. People infect themselves by eating raw of undercooked freshwater fish, poultry or pork. The disease is less commonly acquired through drinking water containing infected copepods. In humans, the third-stage larvae (10-25 mm in length) penetrate the gastric wall and migrate through the soft tissues of the human body for as long as 10 to 12 years. Unlike Angiostrongylus, this parasite is not neurotropic, and involvement of the central nervous sytem is an accidental featuere of infection. The clinical presentation is more fulminant than that of angiostrongyliasis. Gnathostoma spinigerum penetrates the central nervous sytem by migrating along nerve roots. The most characteristic feature is radiculitis, with excruciating nerve root pain in the limbs or trunk. Subarachnoid haemorrhage and intracerebral haematoma can develop. Paralysis and urinary retention often develop, followed by involvement of the cranial nerves. Other findings are myelitis and meningoencephalitis. There is important mechanical damage from the migrating larvae, with necrotic tracts in the brain and spinal cord and often haemorrhages. Focal lesions are visible on MRI-scan of the brain. Antihelminthic agents are not effective. Corticosteriods are often used to diminish the inflammation. Permanent neurological deficits are common. Mortality is between 7 and 25%.

The raccoon ascarid Baylisascaris procyonis infects the majority of these animals. Risk factors for infection are exposure to raccoons and pica (geophagy). Adult worms live in the raccoon’s intestines. Eggs are released in the faeces. Ingestion of eggs leads to release of larvae (1600 µm in length) which are carried by the bloodstream to all organs. In humans, the worms tend to invade the central nervous system and eyes. Approximately 5-7% of the ingested eggs reach the brain, resulting in a visceral larva migrans. Treatment is mainly supportive. Corticosteroids are given to reduce inflammation.

In early neurocysticercosis, cerebrospinal fluid eosinophilia occurs in 23-53% of patients. Serology (Taenia solium) and antigen detection techniques should be performed on serum and cerebrospinal fluid. Cerebral paragonomiasis occurs in less than 1% of cases with pulmonary involvement. In trichinosis, CSF eosinophilia is very rare. In spinal or cerebral schistosomiasis, CSF eosinophilia is uncommon. Meningitis due to Coccidioides immitis occurs in up to 50% of patients with disseminated disease. In 70% of cases, CSF eosinophilia occurs, and 30% of patients presented with eosinophilic meningitis, making this fungal infection one of the most frequent causes of eosinophilic meningitis in the USA. Cryptococcal meningitis is rarely associated with eosinophilic pleocytosis.