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AuliVerkkoniemi-Ahola

Uncommon Infections of the Central Nervous System

PML-Progressive multifocal leukoencephalopathy

  • PML is a rare disease of the white matter of the brain that is caused by the opportunistic JC (John Cunningham) virus (JCV), a polyomavirus that has become pathogenic. Certain potent pharmacotherapies of cancer and autoimmune diseases increase the risk of disease through reactivation of the JCV. PML occurs as a rare adverse effect of these drugs.
    • The harmless primary JCV infection often occurs in childhood already. The opportunistic virus remains in the body. About one in two adults has JCV antibodies, meaning that they carry the virus.
    • JCV causes the severe PML only rarely in cases where the virus is reactivated and modified as a result of a disease impairing the patient's immunity (HIV infection) or medication (several monoclonal antibodies, immunosuppressive and immunomodulatory drugs) and causes a progressive disease of the white matter of the brain.
    • Reactivated JCV is an aggressive pathogen.

Risk groups

  • Patients on certain biological or cytotoxic drugs or the most effective immunomodulators
    • These drugs are most commonly given to organ transplant recipients, patients with cancer or haematological disease or highly active forms of certain diseases, such as rheumatic diseases, skin disorders, vasculitis, inflammatory bowel diseases and MS.
    • If a patient has never been exposed to a primary JCV infection (tests negative for JCV antibodies), the risk of developing PML is virtually nonexistent.
  • PML used to occur in 4-6% of patients with AIDS but, thanks to effective HIV treatments, its prevalence has decreased.

Symptoms

  • Psychiatric symptoms (changes to mood, personality or behaviour)
  • Cognitive impairment, orientation problems, memory problems
  • Speech and communication problems (aphasia)
  • Paralyses
  • Rotary vertigo
  • Convulsions
  • Visual disturbances, visual field defects

Diagnosis

  • Clinical symptoms and findings and knowledge of any medication greatly affecting immunity
  • The most sensitive examination is MRI of the brain, which can reveal extensive changes in the white matter of the brain caused by the disease at the preclinical stage, already.
  • MRI findings consistent with the disease should be confirmed by JCV-PCR assay of cerebrospinal fluid (CSF). Due to the sensitivity of MRI and the ultrasensitive JCV-PCR assay, there is virtually no need for diagnostic brain biopsy any more.

Treatment

  • There is no curative treatment so far.
  • If the disease is suspected, immunocompromising medication should be withdrawn.
  • Elimination of the biological drug by plasmapheresis should be considered unless several months have elapsed since the administration of the last dose of the biological drug.
  • The immune reconstitution inflammatory syndrome (IRIS) will develop within a few weeks from the withdrawal of biological medication and requires glucocorticoid treatment. Untreated IRIS may be fatal.

Prognosis

  • PML is a progressive disease leading to death or permanent disability within 3-6 months. The prognosis depends on the underlying disease and on the spread of the disease.
  • The prognosis of patients with MS who have been given natalizumab is better than that of others if the disease is diagnosed at a clinically mild or asymptomatic stage by regular MRI, and PML changes are not widespread.

Prion diseases

  • The diseases are not caused by ordinary microbes but by pathogenic prion proteins.
  • The highly unusual type of infection was demonstrated by transferring diseased central nervous system tissue to test animals, which fell ill after a long asymptomatic latency stage. The prion protein turns pathogenic when it occurs in a different conformation (PrPSc) from a normal protein (PrPc).
  • According to the hypothesis PrPSc is capable of changing prion proteins normally occurring in the human body to a false conformation, which leads to the development of prion disease and to disease progression in a kind of chain reaction.
  • Prion diseases are very rare and typically:
    • have a very long incubation period - from several months to decades
    • cause central nervous system symptoms
    • show very rapid progression as soon as clinical symptoms occur.
  • There is no curative treatment available and no treatment that can delay the course of the disease. Prion diseases are always fatal.
  • Spongiform encephalopathy is a typical neuropathological change.

Creutzfeldt-Jakob disease (CJD)

  • Four forms of the disease are known: sporadic, hereditary, iatrogenic, and variant CJD, which is the form of bovine spongiform encephalopathy (BSE) occurring in humans.

Sporadic CJD (sCJD)

  • The most common prion disease in man
  • Incidence in Finland approximately 1.4/1 000 000 per year
  • Finnish patients develop the disease at around the age of 65 years.
    • Hereditary CJD develops 12 years earlier, on an average.
  • About half of the patients have mild prodromal symptoms, such as vertigo, headaches, fatigue or sleeplessness, for a few weeks before actual clinical symptoms.
  • The clinical picture normally involves rapid progression, subacute development of dementia, balance problems, ataxia and myoclonic twitches.
  • The symptoms may take many forms, including confusion, mood swings, epilepsy, paralyses, clumsiness of the limbs, dyskinesia, loss of speech or predominantly occipital symptoms (cortical blindness and visual hallucinations). Patients often lose their mobility in a few weeks.
  • The disease is usually fatal within 3-5 months from the beginning of clinical symptoms.

Diagnosis

  • The first or controlled MRI of the brain often shows typical signal enhancement in the area of the basal ganglia and the thalamus.
  • The significance of EEG has decreased. In some patients, only dyscrasia or slow electrical activity of the brain can be seen and several recordings are needed.
    • The typical changes emerge at a late stage. In advanced CJD, 80-90% of patients have a typical EEG finding.
  • 14-3-3 and tau protein concentrations in CSF are in most cases elevated, but this finding is not specific to CJD.
  • Detection of transformed prion protein (PrPSc) in CSF (RT-QuIC test) is specific to prion diseases. If the result is positive, it is very probable that the patient has either CJD or another prion disease.
  • A definite diagnosis can be made based on neuropathological post mortem findings.
    • A neuropathological examination is also important for differentiating between sCJD and vCJD.

Precautions

  • Even though the only confirmed forms of iatrogenic transmission of CJD are by central nervous tissue or corneal transplantation, it is advisable to use blood and body fluid precautions during treatment.
  • The causal agent is resistant to several common disinfectants but sensitive to sodium hydroxide.

Variant CJD (vCJD)

  • Bovine spongiform encephalopathy (BSE), a prion disease of cattle ("mad cow disease") was first identified in Great Britain in 1986. In 1996 BSE was confirmed to infect humans and cause variant CJD.
    • Between 1996 and 2013, 229 cases of vCJD were diagnosed in 11 countries in and outside Europe (most of them in Great Britain and France).
    • The first case of BSE in cattle was diagnosed in Finland in 2001 but thanks to the ensuing food safety measures, no case of vCJD has been diagnosed in humans in Finland or in any other Nordic country, and the disease has been virtually eradicated from all of Europe.
  • Nearly all patients are younger than 45. The mean incubation period of the disease is 10 years.
  • The first symptoms are usually psychiatric (depression, anxiety, withdrawal).
  • In addition, there is typically painful dysaesthesia. Ataxia develops in about 6 months.
  • Dementia and myoclonia appear only at an advanced stage of the disease.
  • The duration of the disease is longer than that of sCJD. It leads to death in 14 months, on an average.
  • Three cases have been reported worldwide where vCJD may have been transmitted by blood transfusion, with the donor unaware of being a carrier of the disease.

Diagnosis

  • Clinical picture
  • The "pulvinar high signal" in MRI is positive in 90% of patients with vCJD.
  • Li-14-3-3 is negative in at least half of the patients. Knowledge regarding the CSF PrPSc RT-QuIC test is inadequate, and the test is not used in vCJD yet.
  • EEG may be normal or show diffuse slow waves.
  • High concentrations of the pathological prion protein (PrPSc) are seen in lymphatic tissue, particularly, in the subclinical phase already, and tonsil biopsy can therefore be used for diagnosis.

SSPE - subacute sclerotic panencephalitis

  • Encephalitis caused by the measles virus in children and young adults. Measles vaccination programmes have rendered this disease extremely rare. However, some parents may decide not to have their children vaccinated.
  • The disease is slowly progressive. Symptoms include deterioration of psychological capacity, motor disturbances, and muscle twitches.
  • Usually results in death in less than two years.

Diagnosis

  • The CSF sample usually shows a slightly increased leukocyte count, increased protein concentration (> 1000 mg/l), increased IgG index and rubeola antibodies.
  • EEG shows a typical finding.

References

  • Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216(4542):136-44. [PubMed]