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Pilomotor seizures and status in non-paraneoplastic limbic encephalitis Volume 7, issue 3, September 2005

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Auteur(s) : Stephan Wieser*1, Anna Kelemen*2, Peter Barsi2, Angela Vincent3, Csaba Borbely2, Gyorgy Rasonyi2, Susanne Mueller1, Klaus Hess1, Heinz Gregor Wieser1, Peter Halasz2

1Neurology Clinic, Department of Epileptology and Electroencephalography, University Hospital, Zurich, Switzerland
2National Institute of Psychiatry and Neurology, Budapest, Hungary
3Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

Article reçu le 4 Avril 2005, accepté le 17 Juin 2005

Pilomotor activity is a rare ictal manifestation and is classified as a subtype of autonomic seizures. It occurs either uni- or bilaterally and is often accompanied by other symptoms including all types of partial seizures, but particularly autonomic seizures. Pilomotor seizures originate predominantly in the temporal lobe (Green 1984, Baumgartner et al. 2001, Stefan et al. 2003, Loddenkemper et al. 2004), although other seizure origins have been described (Brody et al. 1960, Seo et al. 2003, Cutts et al. 2002).Limbic encephalitis is a distinct clinical-pathological entity, which affects, as suggested by the name, mainly the medial limbic part of the temporal lobes. The clinical presentation comprises impaired memory functions, behavioral abnormalities and epileptic seizures. T2-weighted magnetic resonance imaging (MRI) shows increased signal intensity in the hippocampal formations. Limbic encephalitis has often a paraneoplastic origin and is most commonly associated with small-cell lung cancer (SCLC); less frequently with testicular cancer, thymoma, Hodgkin’s disease, non-SCLC, and breast, colon, and bladder cancer. In the majority of patients with paraneoplastic limbic encephalitis, specific autoantibodies (mainly to Hu, Ma2 and CV2/CRMP5) are detected in the serum and cerebrospinal fluid (CSF). Idiopathic limbic encephalitis is less frequent (Khan and Wieser 1994, Bien et al. 2000) and has a much better prognosis of recovery following immunotherapy. Recently, an association between reversible, non-paraneoplastic limbic encephalitis and high levels of voltage-gated potassium channel antibodies (VGKC-Ab) has been described (Vincent et al. 2004).We report the case of a patient who was diagnosed with pilomotor seizures due to non-paraneoplastic limbic encephalitis.

Case study

Clinical history

A 42-year-old, previously healthy, right-handed businessman without personal or family history of epilepsy or neurological diseases was admitted in 2002 because of frequent bouts of piloerection, cold shivering and flushing lasting from a few seconds to a few minutes, on one or both sides of the body. Goose bumps were more prominent on the left arm and the face. These episodes were either isolated or were associated with fear, olfactory hallucinations and arrest reactions. Longer seizures were associated with disorientation and amnesia for the ictal episode. During the first two weeks, the patient also suffered from excessive night sweats. These episodes initially occurred about once a week, but then their frequency rapidly increased over few days reaching the stage where they kept recurring every few minutes. In this status-like state, the patient presented psychotic symptoms; fear, illusions, delusions of persecution, and paranoid thinking. Memory functions deteriorated rapidly. Retrograde amnesia was severe and the patient was not able to retain any new information. Antiepileptic drug (AED) therapy was started, but despite AED-polytherapy (carbamezepine, benzodiazepines, phenytoin, gabapentin, phenobarbital, levetiracetam, and valproic acid alone and in combination), seizures persisted.

Investigations

On admission, the detailed neurological examination was normal except for numerous catch-up saccades during smooth pursuit eye movements. The neuropsychological examination showed severe, bilateral memory deficits with retro- and anterograde amnesia, weak encoding and retrieval abilities.

Interictal video-EEG revealed slight slowing of the background activity with mixed alpha and theta activity. Several pilomotor seizures, occurring spontaneously or provoked by hyperventilation, were registered. Clinically these seizures manifested with mostly bilateral and rarely unilateral piloerection (more often on the left than on the right side), sweating and fear, and were accompanied in the EEG by ictal theta pattern, alternating between the sides, mostly on the left, but also on the right and frequently with contralateral propagation ( (figure 1) ). In unilateral pilomotor seizures, the EEG pattern was ipsilateral. T2-weighted, fast spin echo inversion recovery (FSEIR) and FLAIR magnetic resonance imaging (MRI) showed hyperintense signal alterations in both hippocampi, the left being more affected than the right ( (figure 2) ).

CSF contained four white blood cells and normal protein and glucose. No oligoclonal bands and no Cytomegalovirus or Herpes simplex virus was found in the PCR of the CSF.

Blood examination including baseline hematology and biochemistry was normal. Serum electrophoresis indicated slightly decreased albumin and alpha-2 globulin and increased gamma globulin.

Auto-antibodies for RF, ANA, p-/c-ANCA, anti-DNA-, anti-Ro-, anti-La-, antiphospholipid-, antineuronal-, antiribosomal P-, anti-Hu-, anti-Yo-, anti-Ri-, anti-amphiphysin, anti-myelin-associated-glycoprotein-antibodies were negative.

Serum levels of AFP, beta-HCG and CEA were normal.

CT of the chest and the abdomen, MRI of liver, sonography of kidneys and testes, serum protein electrophoresis and bone marrow puncture revealed no evidence of a neoplasm.

Clinical course and follow-up examinations

With the first antiepileptic drug, carbamazerpine, the patient developed a severe rash and had low serum Na+ values. The status-like state stopped after intravenous benzodiazepines and phenytoin were administered. However, seizures persisted despite treatment with the combination of valproate, levetiracetam and phenytoin at high doses. The history and the clinical findings of complex partial seizures including pilomotor seizures and antero- and retrograde amnestic deficits in association with the MRI and electrophysiological findings suggested limbic encephalitis of unknown origin. Since an intensive search for a neoplastic process was negative, we postulated an “idiopathic” genesis. An immune-mediated inflammatory process was suspected and 1000 mg of methylprednisolone /day i.v. were given for five days, followed by oral steroids, that were gradually tapered off over a one-year period. This resulted in cessation of psychotic symptoms and marked seizure reduction. Almost complete cessation of the seizures was achieved only after addition of azathioprine.

Six months after admission, the patient felt much better and had partially returned to his professional activities. Although the patient reported only minor memory deficits and his psychomotor and non-verbal memory functions were improved significantly, verbal learning and recall performances were still markedly impaired according to the formal neuropsychological examination.

The control EEG at this time showed isolated, bi-temporal alpha-theta runs, but normal alpha background activity with no epileptiform activity.

18F-FDG-positron-emission-tomography showed left temporal hypometabolism ( (figure 3) ). 1H-NMR-Spectroscopy of the brain revealed reduced NAA/(Cr+Cho) quotient in the posterior part of the left hippocampus, resulting in a pathological asymmetry index and indicating neuronal loss or neuronal dysfunction in this region ( (figure 4) ). The T2-weighted MRI at this time still showed hyperintense signal alterations in the left hippocampus, but less intense compared to the first MRI. The hyperintense signal changes in the right hippocampus were no longer present.

After one year of immunosuppression, first the steroids, and six months later the azathioprine were discontinued. While on azathioprine only, occasional bouts of gooseflesh recurred, which were always triggered emotionally. When azathioprine was stopped, the piloerection attacks became frequent, 10-20 per day. During these pilomotor seizures, the patient remained fully conscious. The epileptic nature of these attacks was re-confirmed by video EEG. Neuropsychological testing at the time of relapse showed intact visuospatial memory and further slight improvement in verbal learning, with a persisting deficit in verbal recall. The repeated MRI revealed definite high signal on the left. Steroid treatment was started again and the patient became seizure free. VGKC antibodies were measured only after the recurrence of seizures (and the re-initiation of steroids), and were positive at 481 pM (normal values <100 pM).

Two years after the first examination the patient reported a further clear-cut improvement in his state. He no longer suffered physical restrictions and his memory functions had improved so much that he was able to work full time in his previous position as manager. Under an antiepileptic treatment with phenobarbital and levetiracetam, he continued to have rare, short-lasting episodes of piloerection, but without any other accompanying symptoms. Further follow-up examinations yielded no evidence of a neoplasm.

VGKC antibodies were measured again 26 months after the acute phase, and six months after the second trial of steroid discontinuation A an anti-VGKC antibody titer of 3031 pM was evident. At that time, the patient had daily pilomotor seizures, the MRI showed no deterioration and memory functions were still improving. The patient refused reintroduction of immunosuppressants.

Discussion

Our patient is another example of VGKC antibody-positive, non-paraneoplastic limbic encephalitis. Many features of the disease are consistent with those published by Bien et al. (2000), and Vincent et al. (2004), including the male sex, the severe drug-induced rash, and the low serum Na+ values. We did not find any clinical, laboratory or imaging evidence of malignancy, although this cannot be completely ruled out because of the length of the follow-up. However, the recovery after immuno-therapy and the relapse after its discontinuation support our assumption of an immune-mediated process, which was confirmed by VGKC Ab positivity.

To our knowledge, this is the first description of video-EEG documented, pilomotor seizures associated with limbic encephalitis. Ictal pilomotor activity has been found to be associated with tumors, infectious diseases of the CNS, metabolic disorders, cortical malformations, and postoperative and post-traumatic states (review in Roze et al. 2000). Ictal piloerection is typically associated with seizures originating in the temporal lobe (Green 1984, Lesser et al. 1985, Brogna et al. 1986, Tyndel et al. 1986, Ahern et al. 1988, Dupuy and Deroome 1989, Scopetta et al. 1989, Munari et al. 1995, Yu et al. 1998, Baumgartner et al. 2001, Sa’adah et al. 2002, Stefan et al. 2003, Loddenkemper et al. 2004), and an incidence of 3.6% in patients with temporal lobe epilepsy has been reported (Stefan et al. 2002). However, ictal pilomotor activity associated with frontal, fronto-parietal, fronto-temporal or parieto-occipital seizure origin has also been described (Scopetta et al. 1989, Seo et al. 2003, Féré 1904, Cutts et al. 2002, Brody et al. 1960).

The neuroanatomical substrate of ictal pilomotor erection is not known. Normal pilomotor activity is regulated by the central autonomic network, which includes the hypothalamus as the principal regulatory center, as well as the insula, medial prefrontal cortex, periaquaeductal gray matter, pontine parabrachial complex, nucleus of the tractus solitarius and ventrolateral medulla.

In human and animal studies, piloerection was observed during electrical and pharmacological stimulation of the insula (Freeman and Schachter 1995), of the hypothalamus (Walker 1939), of the hippocampus and amygdala (Fish et al. 1993, Kaada et al. 1954), and of the cingulate gyrus (Smith 1945, Ward 1948). Involvement of the premotor area has been suspected as well (Lindsley and Sassaman 1938, Green 1984, Andermann and Gloor 1984). However, spread of ictal discharges from the temporal lobe or insular cortex to the hypothalamus (or related hypothalamic nuclei) has to be considered. The prominence of autonomic symptoms in temporal lobe epilepsy is explained by the strong limbic-hypothalamic connections (Walker 1939, Liporace and Sperling 1998, Wieser 1987). While unilateral ictal piloerection might indicate ipsilateral seizure onset (Loddenkemper et al. 2004), bilateral ictal piloerection is of no lateralizing value. Our patient displayed simple partial pilomotor seizures, which were more prominent and frequent on the left, as in most previously published cases (Stefan et al. 2002, Takeda et al. 2001, Dove et al. 2004).

In the series of Vincent et al. (2004), only one out of 10 patients relapsed. Immunological re-activation may have caused the seizure recurrence in our patient, since the seizures reappeared with tapering of the immunosuppressive therapy and ceased on reintroduction. However, neither MRI findings of inflammation nor deterioration of memory was noticed at the time of seizure recurrence. The development of hippocampal sclerosis, apart from the temporal atrophy, as described by Vincent et al. (2004), might be interpreted as a residuum of the previous LE, which causes chronic temporal lobe epilepsy with the same type of pilomotor seizures that occurred during the acute phase.

Our patient was pharmacoresistant to antiepileptic drugs as were the patients described by other authors. The memory disturbance experienced by our patient is still improving after the long-term steroid treatment, which is consistent with its beneficial effect on the neuropsychological state as observed by Vincent et al. (2004). However, the intensity of the memory problems have varied according to seizure frequency. On the other hand, cognitive disturbances have been more severe and irreversible in most instances of paraneoplastic limbic encephalitis.

Conclusions

Non-paraneoplastic LE might be more frequent than previously thought, and may present as seizures. Pilomotor seizures may be the predominant seizure type associated with limbic encephalitis. Psychotic features may appear transiently during the acute phase of the disease. Prolonged immunosuppressive therapy may provide almost complete recovery. However, relapse may occur after discontinuation of immunosuppressive therapy, and hippocampal sclerosis and chronic epilepsy might evolve as sequelae. This case study draws attention to the possibility of a subacute immunological basis for other cases of focal epilepsies.

Acknowledgements

We thank Dr. Christian Lanz for clinical data, Prof. Alfred Buck and the colleagues at the PET Center in Debrecen, Hungary for the PET, and Prof. Spyridon Kollias for the MR examinations.