+ The neuropsychiatry of MS, white matter disorders and autoimmune encephalopathies. John O’Donovan.

+ Multiple Sclerosis: epidemiology 85,000 patients with MS in UK Prevalence is /100,000 Incidence is /100,000 Plymouth 250,000 total population=perhaps up to 400 patients. 2:1 female to male ratio Onset between years of age

+ MS basics: risk versus latitude

+ Aetiology Autoimmune illness link Genes 30% concordance ID versus 5% in dizygotes Hygiene hypothesis? Infections in particular EBV 99% prior infection in MS rather then 90% non affected. Vit D-high levels are protective, sunlight?/latitude Smoking modest risk factor

+ Pathophysiology Genetics+environmental agent = relapse T cells activated, cross BBB, cause inflamatory cascade in white matter which causes acute and chronic lesions. Increasingly apparent, that there is also axonal damage and grey matter damage and damage in NAWM (normal appearing white matter) Ultimately results in loss of myelin which leads to problems with saltatory conduction, axonal loss which is a later stage and wide spread disease within the brain and spinal cord.

+ Clinical types Relapsing remitting 85% of MS as a rule of thumb: 1relapse per year. Secondary progressive 40% at ten years and 80% at twenty years Primary progressive 10-15% of MS, equal male:female ratio

+ Clinical features Frequently presents with optic neuritis Spinal cord: transverse myelitis Chronic spasticity Cerebellar syndrome Spastic paraparesis Soft sensory signs Very varied.

+ Diagnosis Clinical history of lesions disseminated in time and space. MRI CSF VER/BAERs

+ MRI of ms brain.

+ Treatments Steroids Immunosurpression Beta interferons associated with flu and depression Glatiramer acetate:aa compound,reduce immune response Mitoxantrone; antineoplastic Natalizumab;monoclonal antibody

+ Psychiatric features Dementia Prevalence of dementia estimated at 10% Correlates with volume of white matter damage, 30cm squared or above Occurs in well established disease Fluctuates with infection, other factors that influence white matter conduction.

+ Psychiatric features 2 Depression Prevalence is 50% plus Similar to stroke, biological and psychological reactions Responds to SSRIs

+ Psychiatric features 3 Mania/BPAD Increased prevalence of BPAD Manic features Distinction between emotional lability and mania may be difficult Mood stabilisers, valproate.

+ Other white matter disorders which may present to psychiatrists Inflamatory: MS, vasculitis SLE, sarcoidosis, Bechet’s Vascular disease: small vessel disease, Antiphospholipid, CADASIL Infectious: PML,HIV, Lyme, Whipple’s, Syphilis Metabolic: CPM, B12 deficiency Leucodystrophies: adrenoleucodystrophy, metachromatic leucodystrophy, vanishing white matter disease Other: mitochondrial,tumour

+ Basics White matter disorders have a different presentation Remember no cortical signs Concept of sub cortical dementias Slowness, spasticity, disconnection, Emotional lability Depression Apathetic and slow

+ Likely and unlikely causes of white matter abnormality on a scan Vascular MS Everything else is exceedingly rare and there should be clinical evidence to focus the mind. Inflalamatory, infectious evidence Leucodystrophies and other unusual white matter disorders are very rare in adult life, unlikely to be seen by any psychiatrist unless working in a specialist centre.

+ Conclusion about white matter disorders Cognitive disorders and depression are common in all MS is undoubtedly the commonest and will be seen by all psychiatrists who have a busy practice Depression is common in MS Some treatments such as beta interferons are associated with depression Other white matter disorders are uncommon, in general white matter abnormalities on MRI scans tend to be vascular or demyelinating

+ Alexia without agraphia Left occipital stroke and splenium Visual info is bilateral However from left occipital must access right visual identification area Alexia with agraphia orignally described by Djerine

+ Conduction dysphasia Dissconnect between Broca’s and Wernicke’s Repetition impaired Another dissconnection

+ Schizophrenia? DTI white matter tracts Suggestion that disordered connections underlie much of the damage.

+ The autoimmune encephalopathies Unusual collection of illnesses coming to prominence in the last ten years or so and now becoming main stream. They are beginning to seep into the psychiatric literature. In essence, common themes, relative absence of structural imaging changes, pathological autoantibodies or inflamatory responses and a clinical triad of cognitive disturbance, psychiatric disturbance and seizures. They are uncommon and normally present to neurologists as atypical dementias, prolonged unusual deliriums or unusual epilepsies. Suspicion that they are also presenting to psychiatrists and being missed.

+ Autoimmune encephalopathies 2 Hashimoto’s encephalopathy/steroid responsive encephalopathy, high titre of antithyroid antibodies, confusion, seizures and psychiatric prolblems. Voltage gated K channel autoantibody-similar presentation, two types one is paraneoplastic and one is not. About 1/3 is paraneoplastic, 2/3 are not, good prognosis with treatment. Frequently associated with psychiatric features. Limbic encephalitis secondary to neoplasia, associated with breast, ovarian, testicular cancers and specific autoantibodies such as anti Hu and anti Yo, sometimes also associated with cerebellar disease and or posterior column problems.