Keywords

Admission

AP is a 42-year-old female who was admitted to our neuropsychiatric ward with a 2-month history of paranoid psychosis. She reported having lost control of her thoughts when her son unexpectedly arrived in Berlin. She had become increasingly irritable and experienced “unusual things.” She started wandering around town barefoot and prayed. She claimed to have heard bomber planes arriving and helped to prevent the third world war with her prayers. She felt estranged with the country and left alone in a fight against all. Eventually, she attacked a pedestrian with a knife because she suspected him of being a radical who had bewitched his dog.

Background History

AP is reported to have been impulsive and irritable since her childhood. She developed a weakness for gambling in her youth but never came into conflict with the law. There is no history of substance abuse. She attended general school and now works in a restaurant. She is married and has a 16-year-old son. Allegedly, she has always been quite jealous and tries to steer her husband and son clear of others. At the age of 35, she developed renal insufficiency as a result of polycystic kidney disease. She required kidney transplantation and received a living donation from her husband. AP suffered two episodes of stroke, one pontomesencephalic stroke with transient diplopia and one right thalamic ischemic stroke. She was diagnosed with schizophrenia at the age of 40 after a first episode of paranoid psychosis with religious delusions. The productive symptoms remitted under risperidone treatment, but extrapyramidal side effects restricted dosing of the atypical antipsychotic drug to 2 mg per day. Medication adherence was low, and AP eventually discontinued her antipsychotic and immunosuppressive treatment.

Examination

She was alert and orientated. Attention and concentration were reduced and executive functions maintained. Her Mini-Mental State Examination score was 25. Thinking was slowed. She suffered from persecutory delusions and auditory hallucinations. Her affect was blunted. Neurological examination was normal with the exception of left-sided hyperreflexia. A reddish-purple rash was present in the groin (Fig. 28.1).

Fig. 28.1
figure 1

Cluster of angiokeratomas

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Initial Investigations

Routine blood screening revealed elevated levels of creatinine, myoglobin, C-reactive protein (CRP), and a mild anemia. Brain magnetic resonance imaging (MRI) showed old right thalamic and right pontine lacunar infarcts but no signs of leukoencephalopathy or blood-brain barrier disruption (Fig. 28.2).

Fig. 28.2
figure 2

Head MRI shows no gadolinium contrast enhancement in the T1-weighted sequences. The arrowhead indicates an old lacunar infarct in the right medial thalamus

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Progress

We performed a lumbar puncture, which revealed a mild pleocytosis (41/μl, 84 % lymphocytes, 9 % monocytes, 7 % neutrophils), elevated protein level (835 mg/l), and normal lactate and glucose levels in the cerebrospinal fluid (CSF). IgG oligoclonal bands unique to the CSF were detected. Viral encephalitis workup uncovered IgG antibodies specific to herpes simplex virus (HSV) 1 and 2, varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in the serum and CSF. Polymerase chain reaction in the CSF was negative for HSV1, HSV2, VZV, CMV, and EBV deoxyribonucleic acids. Autoimmune screening revealed normal serum levels of antinuclear antibodies, circulating immune complexes, complement C3c and C4, and anticardiolipin antibodies. All coagulation parameters were normal. We suspected autoimmune encephalitis and sent blood and CSF samples to Angela Vincent at the University of Oxford. The autoantibody testing revealed anti-leucine-rich glioma-inactivated-1 (LGI1) antibodies in the CSF and serum.

Differential Diagnosis

The most obvious diagnosis in this case was organic psychosis. We found no evidence of rheumatoid arthritis, lupus, or other rheumatic diseases. The brain MRI findings without signs of demyelination were not suggestive of multiple sclerosis. Instead, the patient’s family history of polycystic kidney disease (mother, uncle, and aunt), arterial hypertension and cardiac disease (father and brother), diabetes, and stroke (brother) suggested Fabry’s disease (Anderson-Fabry disease), a rare X-linked inborn error of metabolism [1]. The diagnosis was confirmed by our dermatologists, who performed a skin biopsy and found lysosomal lipid deposits in endothelial cells of angiokeratomas and reduced α-galactosidase A activity in skin fibroblasts. Ophthalmological assessment of AP revealed corneal opacities (cornea verticillata), a typical ocular sign of Fabry’s disease. We also detected severe cardiac disease with concentric left (and right) ventricular hypertrophy and mitral insufficiency, but no shunt. Carotid and transcranial Doppler ultrasound were normal.

Further Investigation

The presence of CSF-specific oligoclonal bands and a mild lymphocytic pleocytosis, as well as increased serum CRP, indicated an immune response in AP. Interestingly, chronic meningitis and lacunar strokes have previously been described in two young females with Fabry’s disease [2, 3]. Testing for infectious agents or serum autoantibodies was negative. Our screening for disease-relevant autoantibodies revealed serum and CSF antibodies to LGI1, a member of the Kv1 voltage-gated potassium channel complex (VGKC). LGI1 antibodies were first described in patients with limbic encephalitis or epilepsy, all without tumors [4, 5]. Notably, VGKC autoimmunity has been associated with frequent psychiatric manifestations; psychotic symptoms such as hallucinations and delusions occur in more than 20 % of cases [6, 7].

Diagnosis

The diagnosis of autoimmune encephalitis with VGKC complex LGI1 antibodies in a patient with Fabry’s disease was made. She was treated successfully with immunosuppression (mycophenolate mofetil and tacrolimus), antipsychotics (risperidone long-acting injections), and enzyme replacement therapy (agalsidase alfa).

What Did I Learn from This Case?

I learned that it is important to fully examine the patient, including the skin, which provided an important diagnostic cue in this case. The German dermatologist Johannes Fabry first described the characteristic angiokeratoma in what was later to be called Fabry’s disease [8] or Anderson-Fabry disease in recognition of the English surgeon, William Anderson, who independently described the disease. I also learned that heterozygous females are not asymptomatic carriers of the X-linked lysosomal storage disorder as previously assumed, but the majority develop Fabry’s disease with typical organ involvement (Fig. 28.3), including a high risk of cardiac disease and stroke [1, 9, 10].

Fig. 28.3
figure 3

Different clinical manifestations in Fabry’s disease (mod. from [18])

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Finally, I learned that psychiatric symptoms are common in Fabry’s disease. In fact, 50–60 % of individuals with Fabry’s disease suffer from depression [11, 12]. Psychosis has also been reported in Fabry’s disease, but was mostly diagnosed as concurrent schizophrenia [13, 14]. Interestingly, thalamic lesions have been implicated in the pathogenesis of psychotic symptoms in another patient with Fabry’s disease, who also demonstrated increased sensitivity to the extrapyramidal side effects of risperidone [15].

Notably, this is the first case of Fabry’s disease associated with autoimmune encephalopathy. It should be pointed out that a high incidence of autoantibodies (against extractable nuclear antigens, cardiolipin, and phospholipid) has been detected in Fabry’s disease [16]. Moreover, Fabry’s disease can be preceded by autoimmune hypothyroidism [17], suggesting potential elements of overlap.